Korean clinical practice guideline for benign prostate hyperplasia 전립선비대증진료권고안 후원 : 근거창출임상연구국가사업단

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1 Korean clinical practice guideline for benign prostate hyperplasia 전립선비대증진료권고안 후원 : 근거창출임상연구국가사업단

2 Korean clinical practice guideline for benign prostate hyperplasia 전립선비대증진료권고안 후원 : 근거창출임상연구국가사업단

3 Korean clinical practice guideline for benign prostate hyperplasia 대한비뇨기과학회전립선비대증진료권고안발간에부쳐 인체의여러장기들중전립선은잘드러나지않는곳에있기에그기능과해부가의학적견지에서주목을받게된것은장기자체보다전립선비대증이라는병명에기인한탓이크다고할수있습니다. 전립선의해부학적비대에수반되어발생하는하부요로증상인전립선비대증은최근수명연장과더불어급격하게증가되어궁극적으로는장년남성의대부분에서발병하는증후군이라고할수있습니다. 이러한유병률의증가는의학적연구와치료방법의개발로이어졌고, 여기서파생된다양한접근방법및치료법들은본질환에대한사회적관심의환기와아울러표준화된진료권고안이필요한배경이되었습니다. 그간국내의의학은주로서양의시스템과치료를소화하는데맞추어져왔으나, 우리비뇨기과학은여러선후배교수님들의열정과노력을통해한국인에서의전립선과관련질환에대한데이터를꾸준히축적해왔습니다. 본진료지침은비록외국의진료권고안들보다그출발이다소늦었고일부외국의권고안들을참고하였지만우리나라사람을대상으로한최신의치료경향을포함하고있습니다. 무엇보다그개발과정에있어교육워크숍과여러차례의개발회의를통한과학적이고합리적인방법론을수용하고두차례의공청회를통한다양한의견들을통합하여임상진료의일선에서바로적용할수있는최적화된내용을담고있는점이큰장점이라하겠습니다. 특히진료권고안이다학제를통한개발이어야한다는의학회의지침을충실히반영하였고근거창출임상연구국가사업단의과제로수행되어우수평가를받았습니다. 의학은지속적으로발전하는것이기에앞으로나올새로운치료법에의해오늘의내용이달라질수있겠지만, 본진료권고안의가치는현재의지식은물론사회적으로는비뇨기과를넘어우리나라보건의료에서추구할공통적인지향을정리한데있다고생각합니다. 이어려운개발과정에서수고해주신김형지개발위원장, 여정균책임연구자이하모든선생님들께깊이감사드리며, 앞으로전립선비대증과씨름하는모든의료인들에게이책자가값지게쓰여지기를희망합니다. 대한비뇨기과학회장주명수 2

4 전립선비대증진료권고안 대한비뇨기과학회전립선비대증발간사 전립선비대증은남성에서하부요로증상을일으키는대표적인질환으로비뇨기과에서중요한자리를차지해온질환이지만우리나라의진료상황을반영하고형식또한제대로갖춘가이드라인이없었던것이사실입니다. 이번에개발된전립선비대증진료권고안은이러한부분을보완하여 1년간공을들여만든가이드라인이며향후개정판을통하여그내용을더욱알차게만들어나갈수있는토대가될수있으리라생각합니다. 특히가이드라인개발방법을잘따르고두차례에걸친공청회를통하여개원의선생님들의의견을충분히듣고반영할수있어서더욱의미가깊다고하겠습니다. 근거창출임상연구국가사업단의연구비지원을받고대한의학회인증을통하여우수평가를받은것또한다행스러운일이라하겠습니다. 본책자가비뇨기과의사는물론전립선비대증에관심이있는분들에게큰도움이되기를기대합니다. 끝으로본책자를만들기위해노고를아끼지않으신김형지개발위원회위원장님과온갖궂은일을도맡아진행하신여정균책임연구자를비롯한진료권고안발간에참여하여주신모든분들께깊은감사의말씀을드립니다. 대한배뇨장애요실금학회장김준철 3

5 Korean clinical practice guideline for benign prostate hyperplasia Contents 서론 본문 진단 치료 1. IPSS 배뇨일지 요속검사, 잔뇨량검사 DRE, 전립선초음파 PSA 생활습관개선, 대기요법 약물치료 알파차단제 α 환원효소억제제 항콜린제 약물치료-병합요법 알파차단제와 5α환원효소억제제 알파차단제와항콜린제 알파차단제와 PDE5억제제 94 4

6 전립선비대증진료권고안 9. 급성요폐와도뇨관치료 경요도전립선절제술 경요도수술 최소침습술 추적관찰 전문진료의뢰사항 134 부록 권고안요약표 용어의정의 진료지침평가표 (K-AGREE 2.0 평가결과 ) 권고안매트릭스 델파이합의결과표 근거검색식 문헌고찰에인용한참고문헌의근거요약표 174 5

7 Korean clinical practice guideline for benign prostate hyperplasia 저자명단 책임저자여정균 ( 인제대서울백병원비뇨기과, 연구책임자 ) 공동저자 ( 가나다순 ) 구호석 ( 인제대서울백병원내과 ) 김광택 ( 가천대인천길병원비뇨기과 ) 김경우 ( 인제대서울백병원가정의학과 ) 김두상 ( 순천향대천안병원비뇨기과 ) 김명기 ( 전북대전북대학교병원비뇨기과 ) 이승환 ( 연세대신촌세브란스병원비뇨기과 ) 정성진 ( 서울대분당병원비뇨기과 ) 조영삼 ( 성균관대강북삼성병원비뇨기과 ) 조원진 ( 조선대광주병원비뇨기과 ) 최 훈 ( 고려대안산병원비뇨기과 ) 김재헌 ( 순천향대서울병원비뇨기과 ) 김태범 ( 가천대인천길병원비뇨기과 ) 김형지 ( 단국대천안병원비뇨기과, 개발위원회위원장 ) 권호장 ( 단국대예방의학교실, 방법론전문가 ) 김현정 ( 고려대예방의학교실, 방법론전문가 ) 노준화 ( 광주기독병원비뇨기과 ) 문경현 ( 울산대울산병원비뇨기과 ) 박현준 ( 부산대부산대학교병원비뇨기과 ) 배재현 ( 고려대안산병원비뇨기과 ) 신동길 ( 부산대부산대학교병원비뇨기과 ) 도움주신분 이유경 ( 순천향대부천병원진단검사의학과, 대한의학회임상진료지침실행위원회위원 ) 지선미 ( 한국보건의료연구원진료지침협력연구팀팀장 ) 양상국 ( 건국대충주병원비뇨기과, 검토위원회위원장 ) 양승옥 ( 서울보훈병원비뇨기과 ) 오철영 ( 한림대평촌성심병원비뇨기과 ) 우승효 ( 을지대대전병원비뇨기과 ) 유정우 ( 타워비뇨기과개원의, 강남 ) 유호송 ( 전남대전남대학교병원비뇨기과 ) 윤동희 ( 타워비뇨기과개원의, 종로 ) 이성호 ( 한림대동탄병원비뇨기과 ) 이승욱 ( 한양대구리병원비뇨기과 ) 6

8 전립선비대증진료권고안 Male LUTS 핵심질문 Evaluation History / Physical * examination IPSS / QOL Voiding diary Urinalysis / Creatinine Uroflow / PVR * DRE / Prostate sono PSA KQ 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다진단에도움을주는가? KQ 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을주는가? KQ 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을주는가? KQ 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가더정확한평가를할수있는가? KQ 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? P 23 P 26 P 29 P 34 P 37 Treatment Conservative treatment Medical treatment Surgical treatment Follow up Refer to Urologist KQ 6. 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? KQ 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적으로고려되어야하는가? KQ 8. 전립선비대증환자에서병용요법이알파차단제단독사용보다치료효과를높일수있는가? KQ 9. 전립선비대증환자에서급성요폐발생시 TWOC 는수술적치료전에우선적으로고려되어야하는가? KQ 10. 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서우선적으로고려되어야하는가? KQ11. 전립선비대증환자에서심각한기저질환등으로수술에적당하지않은경우에는어떠한치료가권장되는가? KQ 12. 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇이며, 추적관찰의기간은어떻게설정하여야하는가? KQ 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰해야하는경우는무엇인가? P 47 P 53 P 85 P 101 P 110 P 128 P 128 P 134 * PVR: post-voided residual urine, IPSS: international prostate symptom score, QOL: quality of life, DRE: digital rectal examination, PSA: prostate specific antigen, TWOC: trial without catheter 40 세이상남성하부요로증상환자에서진단및치료의접근방법과관련핵심질문 7

9 Korean clinical practice guideline for benign prostate hyperplasia 권고안요약표 권고사항권고등급근거수준 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다진단에도움을주는가? 1-1. 국제전립선증상점수 (IPSS) 는치료에대한반응이나추적관찰중증상악화를판단하는데있어중요한 요소이다. 따라서치료를시작하고자하는환자들에게치료전 IPSS 를작성하기를권고한다. 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을주는가? Strong B 2-1. 배뇨일지가병력청취로부터얻어진정보를명확히하고정확한진단에도움이된다. Strong B 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을주는가? 3-1 하부요로증상이있는전립선비대증환자에게선택적으로요속검사를시행한다. Strong C 3-2. 하부요로증상이있는전립선비대증환자에게선택적으로잔뇨량검사를시행한다. Strong C 3-3. 하부요로증상이있는전립선비대증환자에서전문의의평가가필요한경우요속검사와잔뇨량측정을 시행한다. 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가더정확한평가를할수있는가? Strong B 4-1. 정확한전립선의해부학적인평가를위해서는직장수지검사외에전립선초음파가필요하다. Strong B 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? 세이상의하부요로증상을호소하는전립선비대증환자에서전립선특이항원검사를해야한다. Strong A 6. 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? 6-1. 경증의전립선비대증환자는대기요법이적절하다. Strong B 6-2. 하부요로증상을가진환자에게약물치료전또는약물치료와동시에생활습관개선에대한교육을시행하여야한다. 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적으로고려되어야하는가? 7-1. 전립선비대증으로인해중등도이상의증상을보이는경우는약물치료가일차적으로권장된다. 그러나, 방광돌이있는경우, 방광기능장애를동반한방광게실이있는경우, 상부요로의확장으로인한신기능부전이동반된경우, 약물치료에도불구하고요폐, 요로감염, 혈뇨가반복되거나배뇨증상, 배뇨후잔뇨량의호전이없는경우에는수술치료가고려되어야한다 α환원효소억제제는중등도이상의하부요로증상을호소하는환자에서직장수지검사또는전립선초음파검사에서전립선크기가크거나혈청전립선특이항원검사에서전립선비대증의진행가능성이보이는경우장기간처방을고려해야하는치료약물이다 항콜린제는중등도이상의하부요로증상을보이는환자중방광자극증상을주로호소하는환자에서고려될수있으며, 방광출구폐색이심하거나배뇨후잔뇨량이많은경우신중한사용이필요하다 알파차단제는중등도이상의하부요로증상을보이는전립선비대증환자에게우선적으로고려되어야하는치료약물이다. 8. 전립선비대증환자에서병용요법이알파차단제단독사용보다치료효과를높일수있는가? 8-1. 전립선비대증환자에서알파차단제와 5알파환원효소억제제병용요법은알파차단제단독요법보다하부요로증상완화에효과적인치료방법이다. Strong Strong Strong Strong Strong Strong B B A A A A 8

10 전립선비대증진료권고안 8-2. 알파차단제와항콜린제병용요법은중등도이상의하부요로증상을갖는환자에서알파차단제단독요법의효과가불충분할경우에시행한다. 8-3 알파차단제와항콜린제병용요법은배뇨후잔뇨량이많고방광출구폐색이의심되는남성에서는신중하게시행한다 PDE5 억제제와알파차단제의병용투여는중등도이상의하부요로증상을감소시키는데있어알파차단제단독요법보다효과적이다. Strong Strong Weak A A A 9. 전립선비대증환자에서급성요폐발생시 TWOC (Trial without catheter) 는수술적치료전에우선적으로고려되어야하는가? 9-1. 급성요폐발생시 TWOC는수술적치료전에고려할수있다. Strong A 9-2. 급성요폐를치료하는데있어요도도관유치전후알파차단제사용이도움이된다. Strong B 9-3. 요도도관은급성요폐후 2-7일간유치하는것이도움이된다. Strong B 10. 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서우선적으로고려되어야하는가? 경요도전립선절제술은전립선비대증수술에우선적으로고려된다. Strong C gm 이상의큰전립선비대증환자에서경요도를통한내시경수술은개복전립선수술과함께 1차수술법으로고려할수있다. 11. 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경우에는어떠한치료가권장되는가? 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우간헐적자가도뇨또는도뇨관유치를권장한다 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우 TUNA 또는 TUMT 를고려할수있다. 그러나장기적인치료효과 ( 재치료및증상개선정도 ) 는 TURP 에비해좋지않다 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우전립선내약물주입이시도되고있으나임상적용은권고하지않는다. Strong Strong Strong Strong A B A A 12. 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇이며, 추적관찰의기간은어떻게설정하여야하는가? 전립선비대증치료후추적관찰간격과검사의종류는개별환자의중증도와임상지표를고려하여임상의사의경험이나판단에따른다 전립선비대증의진행을확인하기위해서는국제전립선증상점수, 직장수지검사, 혈청전립선특이항원검사, 요속검사, 잔뇨량측정그리고전립선초음파등을시행한다. 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰해야하는경우는무엇인가? 전립선비대증환자에서하부요로증상이 1차약물치료로호전되지않는경우에는비뇨기과의사에게의뢰해야한다 전립선비대증환자에서요로감염, 혈뇨, 반복적인요폐색과같은하부요로증상의객관적인이상이나악화소견이동반될때비뇨기과의사에게의뢰하여야한다 전립선비대증환자에서혈청전립선특이항원검사가정상범위를벗어나거나직장수지검사에서이상소견이관찰되는경우전립선암과의감별을위해비뇨기과의사에게의뢰하여야한다. Strong Strong Strong Strong Strong C C B A A NA: Not Applicable 9

11 Korean clinical practice guideline for benign prostate hyperplasia 전립선비대증진료권고안의한계점 전립선비대증진료권고안을개발하면서느낀문제점은양질의국내자료가적고, 대부분의양질의자료는역학적특성이다른서양 ( 북미와유럽 ) 의자료라는것이다. 국내진료의특성을명확하게반영하지못하는한계점이있지만근거중심방법론으로수행된의학적근거를존중하여야한다. 현실에서당연시되는진료방법이고전문가동의가이루어진경우근거부족을이유로일방적으로제외하는경우또한맹점이라고생각된다. 향후개정판에서는그내용과근거를보완하여진료방법의모호한부분을해소해나가길기대한다. 전립선비대증진료권고안에서권고하지않는부분은진료현장에서피하길바라지만권고안에없는부분은하지말아야된다는규제를의미하지않는다. 우리의의료보험제도와진료현장의실제상황사이의갭을줄여나가는데도움이되기를바란다. 전립선비대증진료권고안은법적지위및구속력을가지지않으며, 실제 임상에서이루어지는환자의치료결과에대한책임은치료담당자에게직접 귀속되고전립선비대증진료권고안개발위원회는그책임을지지않는다. 10

12 전립선비대증진료권고안 서론 1. 목적우리나라의고령화진행속도는세계에서상위권에진입하였고그로인한노인인구의질환도증가일로에있다. 남성의대표적인노화질환인전립선비대증은급속한고령화에따라유병률또한급속히증가하고있다. 하지만우리나라에서전문가에의한진료권고안의개발은매우제한적으로이루어졌고그또한외국진료권고안의번역수준에머물러있다. 이에본전립선비대증진료권고안을개발하여전립선비대증질환을가지고있는환자의진단및치료에있어근거중심의진료를위한정보를제공하고자한다. 또한진단에필요한검사에대한정보와약물치료및수술치료에대한기본적정보를제공하며진단적평가와치료에대한효과성을평가하고정보를제공하고자한다. 본진료권고안은향후전립선질환의진단및치료에있어근거기반치료를확산시키는데일차적도구로활용될수있을것으로기대한다. 2. 진료지침을적용할대상집단 40 대이상성인남성중하부요로증상을호소하는경우 3. 진료지침의이용자본진료권고안은전립선비대증을진료하는데종사하는일차및이차의료기관의의사와비뇨기과전문의에게양질의진료를제공하는데도움을주는근거중심의진료선택을하도록하기위해만들게되었다. 4. 진료지침의범위본진료권고안은전립선비대증의진단, 치료에대한포괄적인내용을담고있다. 실제임상에서적용이가능한내용위주의핵심질문을통하여도움을주고자하였다. 전립선비대증의질환이시작되는 40대이상의성인을대상으로진행한연구를근거로하였다. 과학적근거가부족하거나논란이큰부분은본진료권고안에서제외하였으나, 일부근거가부족하더라도임상적의의가있 11

13 Korean clinical practice guideline for benign prostate hyperplasia 고전문가들의의견이일치되는부분은수정델파이기법 (modified Delphi method) 을통한합의 과정을거쳐권고안에포함시켰다. 5. 진료지침개발및검토자본진료권고안의개발을위해대한비뇨기과학회, 대한가정의학회, 대한배뇨장애요실금학회, 대한예방의학회에서개발을위임하였다. 전립선비대증진료권고안의작성을위하여대한비뇨기과학회, 대한가정의학회, 대한배뇨장애요실금학회에서추천한전립선비대증전문가로구성된전문가그룹이 2014 년 3월 6일첫회의를가지면서구체적인개발위원회를만들어개발작업을진행하였다. 방법론전문가로대한예방의학회권호장 ( 단국대예방의학교실 ), 메타분석및체계적문헌고찰을위해김현정 ( 고려대예방의학교실 ) 이참여하였다. 개발위원회 ( 가나다순, 17명 ) 김광택 ( 가천대, 인천 ), 김경우 ( 인제대가정의학과, 서울 ), 김명기 ( 전북대, 전주 ), 김재헌 ( 순천향대, 서울 ), 김태범 ( 가천대, 인천 ), 김형지 ( 단국대, 천안, 위원장 ), 노준화 ( 광주기독병원, 광주 ), 배재현 ( 고려대, 안산 ), 양승옥 ( 보훈병원, 서울 ), 여정균 ( 인제대, 서울, 책임연구자 ), 오철영 ( 한림대, 안양 ), 유호송 ( 전남대, 광주 ), 이승욱 ( 한양대, 구리 ), 이승환 ( 연세대, 서울 ), 조영삼 ( 성균관대, 서울 ) 조원진 ( 조선대, 광주 ), 최 훈 ( 고려대, 안산 ) 진료지침검토자 ( 가나다순, 7명 ) 진료지침검토를위해서내과전문의, 비뇨기과개원의를포함하여구성하였다. 구호석 ( 인제대내과, 서울 ), 김두상 ( 순천향대, 천안 ), 문경현 ( 울산대, 울산 ), 박현준 ( 부산대, 부산 ), 양상국 ( 건국대, 충주 ), 우승효 ( 을지대, 대전 ), 윤동희 ( 타워비뇨기과, 개원의, 서울 ) 6. 진료지침연구비지원 본진료권고안은근거창출임상연구국가사업단의임상진료지침개발사업 2013 년하반기 2 차과 12

14 전립선비대증진료권고안 제로선정되어개발되었고인제대학교산학협력단이주관연구기관으로진행하였다. 7. 진료지침의갱신 본진료권고안은새로운진단방법및치료약물의개발, 새로운수술법의출현과관련된연구 결과의축적에따라 4-5 년주기로개정되어야한다. 8. 권고안개발방법개발방법에대한도움을위해임상진료지침수용개작매뉴얼 ver 2.0( 한국보건의료연구원 2011) 과임상진료지침개발매뉴얼 ver 1.0( 한국보건의료연구원 2011) 을참고하여개발하였다. 자료검색및메타분석을위해관련전문가에게자문을구하였다. 1) 핵심질문도출핵심질문의도출을위하여 population, intervention, comparison, outcome (PICO) 의원칙하에임상질문에필요한필수요소를포함시키고자하였다. P (population) 는전립선비대증환자혹은질병의특징에관한사항으로정의되고, I (intervention) 는진단법혹은치료법을포함한중재, C (comparison) 는특정중재법과비교가되는비교군, O (outcome) 는진단의유용성혹은치료결과로정의되며가급적이네가지요소를최대한포함시키고자하였다. 본진료권고안은핵심질문 13개를선정한후 12개핵심질문은이미개발되어있는외국또는국내의다른권고안을바탕으로수용개작을하고가장활용도가높을약물치료에관한한개의핵심질문은직접개발하기로하였다. 개발위원회의회의를거쳐국내진료상황에주요하며활용도가높은핵심질문을한개선정하였다. 2) 진료치침검색수용개발을위해기존의진료권고안을검색하였다. 검색을위해다양한검색자료원을활용하였는데 PubMed, Cochrane Library, National Guideline Clearing House, CMA Infobase, SIGN, NICE 그리고국내진료권고안검색을위해 KoreaMed, KmBase, RISS를이용하였고검색이어려운경우대한비뇨기과학회의자문을받았다 ( 부록진료지침검색원 ). 검색색인단어는전립선비대증관련색인단어 ( benign prostate hyperplasia OR lower urinary tract symptoms 13

15 Korean clinical practice guideline for benign prostate hyperplasia disease ) 와진료지침관련색인단어 ( guideline OR guideline prostate hyperplasia OR guideline adherence OR practice guideline OR practice guidelines as topic OR clinical guideline OR consensus OR recommendation ) 의조합으로검색하였다. 주제별혹은형식별검색을통해다섯건의외국진료권고안과한건의국내진료권고안을검토하였다. 출판일자의범위를 2009년 1월 1일부터 2013 년 12월 31일까지로한정하였고, 영어또는한국어로표기된권고안만을선택하였으며개정판이있는경우최신판을선정하였다. 전문가합의에의한지침 (expert consensus), 단체등을대표하지않고한명이쓴권고안을제외하여최종적으로여섯건의권고안을선정하였다. 3) 진료지침의평가및선택수용개발을위해검색기준에부합하는진료권고안의질평가를위하여대한의학회임상진료지침전문위원회에서배포한 K-AGREE 2.0 (AGREE 2.0 의한국형버전 ) 평가개발척도를활용하여진료권고안질평가를하였다. 검색된 6개권고안에대하여전문가초빙워크숍을통해평가방법을교육받은개발위원회위원 12인이평가하였고, 3점이상차이가난항목에대하여재평가를실시하였다. 영역별표준화점수를산출하고각영역의점수를비교하여최종적으로평가영역 3번개발의엄격성표준화점수가 50% 이상인세개의지침을선정하였다 ( 부록 3. 진료지침평가표 ). 4) 권고안결정및초안작성문헌고찰을위한근거의검색은 PubMed ( 와 Embase ( 를사용하였고, 년사이에인간을대상으로하고영어로출간된논문중각각의문항에적합한검색식을만들어근거를검색하고초록을검토하여각각의문항과관련있는근거문헌을선정하였다. 2000년이전문헌중중요한문헌은평가를통해포함하도록하였다. 최근에출간된체계적고찰이나메타분석이있는경우에는그이전에출간된낮은근거수준의문헌은배제하였고증례보고등도배제하였다. 각각의검색식은부록에표기하였다 ( 부록 6. 근거검색식 ). 근거수준은 2011 년도에 Oxford Centre for Evidence-Based Medicine (CEBM) 에서발표한근거수준의기준중진단, 예후및치료이익분야에서의근거수준평가기준을참고로하여세단 14

16 전립선비대증진료권고안 계로정의하였다. 권고수준은델파이합의안의질문별중위수값에따라 strong, weak 두단계로 정의하였다. 표 1. 근거수준및권고수준의정의 근거수준 (Level of evidence) 의등급체계정의 근거수준 A B 정의 Level 1, 여러개의 Level 2 연구 한개의 Level 2 연구, 여러개의 Level 3 연구 C 한개의 Level 3 연구, Level 4, 5 Level of study 등급체계정의 Level 진단예후치료이익 1 Systematic review, Meta-analysis 2 Individual cross sectional studies with consistently applied reference standard and blinding 3 Non-consecutive studies, or studies without consistently applied reference standards** 4 Case-control studies, or poor or non-independent reference standard** Systematic review, Meta-analysis Inception cohort studies Cohort study or control arm of randomized trial* Case series or case-control studies, or poor quality prognostic cohort study** Systematic review, Meta-analysis Randomized trial or observational study with dramatic effect Non-randomized controlled cohort/follow-up study** Case-series, case-control studies, or historically controlled studies** 5 Mechanism-based reasoning Mechanism-based reasoning * Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size. ** As always, a systematic review is generally better than an individual study. 15

17 Korean clinical practice guideline for benign prostate hyperplasia 권고수준의정의 수준 Strong (score 7-9) Weak (score 1-6) 정의 Most or all individuals will be best served by the recommended course of action. Not all individuals will be best served by the recommended course of action. There is a need to consider more carefully than usual individual patient s circumstances, preferences, and values. 권고안도출과채택을위해델파이방법을사용하였다. 권고안개발그룹의대표성과전문성을담보하기위하여총 15인의패널로구성하였다. 초안을바탕으로한평가지는 13개의질문에 30 개문항이었다. 설문은총 3회실시하였고, 각문항에대한권고안이적절한가에대한응답척도는 9점척도를이용하였다. 1-3점은 동의안함, 4-6점은 불명확, 7-9점은 동의함 영역으로정의하였고각영역에응답한패널리스트가 75% 이상이면합의가된것으로정의하였다. 델파이합의를위한조사표에는각문항에대해수용하려고선정한타권고안들의권고등급, 검색한근거문헌에기초한근거수준, 응답척도 (9점척도 ), 기타의견제시를위한공간으로구성하였다. 다음라운드에서는합의에이르지못한문항에대해전체패널리스트들의점수에대한중앙값과질문지를받는패널리스트가이전라운드에서응답했던점수를표시하였고이전라운드에서합의된문항은제외하였다. 이전라운드에서합의에실패한문항에대한수정은하지않았고패널리스트에의해제시된기타의견은없었다. 총 30개의문항중 1차설문에서 12개, 2차설문에서 15 개그리고 3차설문에서나머지 3개의문항에대한합의가이루어졌다. 각라운드의응답률은 1차 88.2%, 2차 76.5%, 3차 100% 였다. 델파이합의결과표는부록에표기하였다. 선정된권고에따라진료권고안초안을집필하였다. 델파이합의를위한패널 ( 가나다순, 15명 ) 김명기 ( 전북대, 전주 ), 김재헌 ( 순천향대, 서울 ), 김태범 ( 가천대, 인천 ), 김형지 ( 단국대, 천안, 위원장 ), 노준화 ( 광주기독병원, 광주 ), 배재현 ( 고려대, 안산 ), 신동길 ( 부산대, 부산 ), 양승옥 ( 보훈병원, 서울 ), 오철영 ( 한림대, 안양 ), 유정우 ( 타워비뇨기과, 서울 ), 이성호 ( 한림대, 동탄 ), 정성진 ( 서울대, 분당 ), 조영삼 ( 성균관대, 서울 ), 조원진 ( 조선대, 광주 ), 최 훈 ( 고려대, 안산 ) 16

18 전립선비대증진료권고안 5) 개발 (De Novo) 을위한체계적문헌고찰및메타분석 개발을결정한핵심질문 (8 번질문 ) 에대한문헌고찰및메타분석을위해통계전문가의도움을 받아시행하였다. (1) 문헌검색핵심질문에따른문헌검색은 Medline, Embase, Cochrane library, KoreaMed 등의검색원을이용하여연구설계및언어의제한없이검색하였다. 문헌검색에사용한주제어는각검색원에서논문을색인하기위해개발된표준화된의학용어 (Medline:MeSH, Embase:emtree) 와자연어를이용하여검색하였다. 각핵심질문은 PICO 기법 (Population or Patient problem, Intervention, Comparison, Outcome) 을이용하여도출하였으며, 문헌검색의과정, 근거표, 메타분석으로제시하였다. 논문제목과초록을통해선정기준에부합하지않는문헌을배제하였으며필요한경우에는논문전문을검토하였다. 선택된논문전문을자세히검토한후핵심질문에해당되는자료를추출하기위해표준화된근거표와메타분석표를작성하였다. (2) 메타분석각핵심질문은각각의근거표를작성한후, 메타분석을하였다. 메타분석은 RevMan (version 5.3) 을이용하였다. 메타분석이어려운경우에는각각의연구결과를기술하는방식으로결과를제시하였다. (3) 개별문헌의평가개별문헌에대한평가는연구설계에따라구분하여각각의도구를이용하여평가하였다. 무작위배정실험연구의경우 Cochrane 그룹에서권고하는비뚤림의위험 (risk of bias) 의다섯가지항목으로평가하였다. 6) 외부검토및승인본권고안은근거창출임상연구국가사업단의연구비지원으로개발되었으나사업단및개발에참여한학회는권고안의개발에영향을주지않았다. 진료권고안개발위원회와합의에의해채택된권고안의검증을위한검토위원회는각각독립적으로활동하였다. 17

19 Korean clinical practice guideline for benign prostate hyperplasia 두차례의외부공청회를개최하여의견을수렴하였고, 개발에참여한대한비뇨기과학회, 대한 가정의학회, 대한배뇨장애요실금학회의인증을받았다. 대한의학회임상진료지침정보센터의평가 시스템을통해동료평가를받고대한의학회의인증을받았으며우수인증마크를획득했다. 18

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21 Korean clinical practice guideline for benign prostate hyperplasia

22 진단 IPSS 배뇨일지요속검사, 잔뇨량검사 DRE, 전립선초음파 PSA

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24 전립선비대증진료권고안 KQ 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다 진단에도움을주는가? 권고사항권고수준근거수준 1-1. 국제전립선증상점수 (IPSS) 는치료에대한반응이나추적관찰중증상악화 를판단하는데있어중요한요소이다. 따라서치료를시작하고자하는환자들 에게치료전 IPSS 를작성하기를권고한다. Strong B 전립선비대증환자를처음진료시병력청취와함께증상을체크할수있는검증된설문지가필요하다. 전립선비대증환자가치료를원하는것은증상이생활의질을변화시키기때문이다. 따라서증상의수량화는질환의정도나치료효과의평가및관찰시증상의진행정도를평가하는데중요하다. 주로국제전립선증상점수 (International Prostate Symptom Score:IPSS) 가추천되는데이설문지가증상의빈도나정도를판단하는데비체계적인면담보다유용하기때문이다 [1-7]. IPSS는 1992 년에미국비뇨기과학회의주관으로만들어졌으며본래의명칭은미국비뇨기과학회증상설문 (AUA-7) 이다. IPSS는 1993년세계보건기구가주관한전립선비대증국제자문회의에서기본적인검사기준으로채택되었고, 이후한글을포함한각국의언어로번역되어이를이용하여역학조사나치료효과판정등에대한다양한연구가진행되고있다 [8]. IPSS는총 8개로이루어진문항들 ( 잔뇨감, 빈뇨, 간헐뇨, 요절박, 약뇨, 복압배뇨, 요주저, 야간뇨 ) 에대해증상의중증도에따라 0-5 점의점수를매겼으며, 증상과관련된일곱항목을이용하여 mild (0-7), moderate (8-19),severe (20-35) 로나눌수있다. 그리고 IPSS 생활만족도는전립선비대증에의한삶의질을측정하는것이다. IPSS는환자스스로작성이가능하며또한진료현장에서의료제공자에의해서도작성이가능하다. 아울러치료의효과를판정하는데에도연속적으로측정할수있다. 국제전립선증상점수와다른전립선비대증검사의심한정도는완전히일치하는것은아니며증상점수만으로는환자가느끼는문제의정도를전적으로판단할수없다 [9-11]. 하부요로증상이있는모든환자에게 IPSS 혹은다른종류의타당성이증명된배뇨설문지를 23

25 Korean clinical practice guideline for benign prostate hyperplasia 가능한한반드시작성하여환자의기초증상을확인할필요가있다. 근거표 KQ 1 1. Barry MJ, Fowler FJ, Jr., O Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148: ; discussion 64. Case-control study 210 BPH patients and 108 control subjects To invent and validate symptom index for BPH The final AUA symptom index includes 7 questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On revalidation, the index was internally consistent (Cronbach's alpha = 0.86) and the score generated had excellent test-retest reliability (r = 0.92). Scores were highly correlated with subjects' global ratings of the magnitude of their urinary problem (r = 0.65 to 0.72) and powerfully discriminated between BPH and control subjects (receiver operating characteristic area 0.85). Finally, the index was sensitive to change, with preoperative scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (p < 0.001). The AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols Level of Study 4 7. O Leary MP, Wei JT, Roehrborn CG, Miner M; BPH Registry and Patient Survey Steering Committee. Correlation of the International Prostate Symptom Score bother question with the Benign Prostatic Hyperplasia Impact Index in a clinical practice setting. BJU Int 2008;101: Large, multicenter, longitudinal observational study 6,439 To evaluate the association between the International Prostate Symptom Score (IPSS) bother question (BQ) and a validated disease-specific quality-of-life questionnaire, the Benign Prostatic Hyperplasia (BPH) Impact Index (BPH-II), using the BPH Registry and Patient Survey database. The mean (sd) score of the IPSS BQ was 2.5 (1.4) and of the BPH-II was 2.8 (2.8). Based on responses to the BPH-II, at least half the men reported that their urinary symptoms were associated with physical discomfort, worry about their health, and bothersomeness. The IPSS BQ score was significantly correlated (P < 0.001) with the BPH-II (r = 0.68) and each of its four questions (physical discomfort, r = 0.52; worry about health, r = 0.53; bothersomeness of trouble with urination, r = 0.67; and time kept from usual activities, r = 0.44). Level of Study 2 24

26 전립선비대증진료권고안 참고문헌 1. Barry MJ, Fowler FJ, Jr., O Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148: ; discussion Bolognese JA, Kozloff RC, Kunitz SC, Grino PB, Patrick DL, Stoner E. Validation of a symptoms questionnaire for benign prostatic hyperplasia. Prostate 1992;21: Bosch JL, Hop WC, Kirkels WJ, Schroder FH. The International Prostate Symptom Score in a community-based sample of men between 55 and 74 years of age: prevalence and correlation of symptoms with age, prostate volume, flow rate and residual urine volume. Br J Urol 1995;75: Epstein RS, Deverka PA, Chute CG, Panser L, Oesterling JE, Lieber MM, et al. Validation of a new quality of life questionnaire for benign prostatic hyperplasia. J Clin Epidemiol 1992;45: Netto Junior NR, D Ancona CA, de Lima ML. Correlation between the International Prostatic Symptom Score and a pressureflow study in the evaluation of symptomatic benign prostatic hyperplasia. J Urol 1996;155: Choi HR, Chung WS, Shim BS, Kwon SW, Hong SJ, Chung BH, et al. Translation validity and reliability of I-PSS Korean Version. Korean J Urol 1996;37: O Leary MP, Wei JT, Roehrborn CG, Miner M; BPH Registry and Patient Survey Steering Committee. Correlation of the International Prostate Symptom Score bother question with the Benign Prostatic Hyperplasia Impact Index in a clinical practice setting. BJU Int 2008;101: Kim JH, Doo SW, Yang WJ, Song YS. Homogeneity among the korean international prostate symptom score questionnaires used in real practice. Korean J Urol 2013;54: Weissfeld JL, Fagerstrom RM, O Brien B. Quality control of cancer screening examination procedures in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21:390S-9S. 10. Roehrborn CG. Accurate determination of prostate size via digital rectal examination and transrectal ultrasound. Urology 1998;51: Roehrborn CG, Sech S, Montoya J, Rhodes T, Girman CJ. Interexaminer reliability and validity of a three-dimensional model to assess prostate volume by digital rectal examination. Urology 2001;57:

27 Korean clinical practice guideline for benign prostate hyperplasia KQ 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을 주는가? 권고사항권고수준근거수준 2-1. 배뇨일지가병력청취로부터얻어진정보를명확히하고정확한진단에도 움이된다. Strong B 배뇨일지 (voiding diary) 는환자의객관적인임상정보를제공한다 [1,2]. 아직까지공인된표준배뇨일지형태는없지만 3-7 일간의배뇨일지는배뇨장애를평가하는데유용한도구이다. 배뇨일지로 24시간요량, 배뇨횟수, 배뇨간격, 배뇨분포, 요실금이일어나는시간과유발요소, 기능적방광용적을측정할수있다 [3-6]. 배뇨일지에서알수있는빈뇨와야간뇨의정도는국제전립선증상점수에의해알수있는하부요로증상과유의한상관관계가있다. 정확한배뇨평가를위해서는환자의일상생활중에도지속적으로배뇨일지를작성해야한다 [7,8]. 배뇨일지를통해서 24시간동안배뇨량을파악하여수분섭취량의증가여부를확인할수있고, 배뇨량이줄거나각각의배뇨량이일정치않은지를확인하여과민성방광을의심할수도있다 [7]. 수면도중배뇨량이 24시간총배뇨량의 35% 이상을의미하는야간다뇨 (nocturnal polyuria) 는오로지배뇨일지를통해서만진단될수있다 [7]. 빈뇨나야간뇨같은저장증상의주원인은요량의증가나기능적방광용적의감소이므로, 배뇨일지를정확하게기록하여배뇨의양과횟수를양적으로측정함으로써정확한원인을진단할수있다. 또한배뇨일지는시간제배뇨 (timed voiding) 와방광훈련 (bladder training) 같은행동치료를시행할때기초자료가된다. 저장증상을호소하는전립선비대증환자의초기검사로 24 시간배뇨일지의기록은기본검사이다. 배뇨일지는비침습적이며, 비용이저렴하고, 하부요로증상의평가에중요한정보를제공한다. 26

28 전립선비대증진료권고안 근거표 KQ 2 3. Gisolf KW, et al. Analysis and reliability of data from 24-hour frequency-volume charts in men with lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2000;38: Observational study 160 men with BPH To analyse the data from frequency-volume charts and to study the reliability of these charts in men with LUTS due to BPH Another 28 patients who met all other criteria did not complete the frequency-volume charts correctly. Agreement exists between reported voided volumes in the literature and those found by us. We found a significant correlation (p<0.001) between nycturia and score on symptom question 7, and between diuria and score on symptom question 2 of the AUA symptom index. The difference between results obtained from frequency-volume charts completed during 24 h and those obtained from charts completed during three or more 24-hour periods was negligible with respect to the variation of data at an individual level. Frequency-volume charts are reliable in the investigation of patients with LUTS due to BPH. Reporting on frequency-volume charts during just 24 h is sufficient to gain insight into their voiding habits during normal daily life. Level of Study 3 8. Groutz A, Blaivas JG, Chaikin DC, Resnick NM, Engleman K, Anzalone D, et al. Noninvasive outcome measures of urinary incontinence and lower urinary tract symptoms: a multicenter study of micturition diary and pad tests. J Urol 2000;164(3 Pt 1): Prospective observational study 109 To assess the test-retest reliability of a 24, 48 and 72-hour micturition diary and pad test in patients referred for the evaluation of urinary incontinence and lower urinary tract symptoms The number of pads and total weight gain appeared to be reliable measures of the 24, 48 and 72-hour pad tests. For the 24-hour diary the total number of incontinence episodes was a reliable measure, while the total number of voiding episodes was marginally reliable (mean CCC and , respectively). For the 48-hour diary the number of incontinence episodes and total number of voiding episodes were reliable measures (mean CCC 0.78 and 0.83, respectively), while for the 72-hourdiary each parameter was highly reliable (CCC 0.86 and 0.826, respectively). However, an increased test period was associated with decreased patient compliance. Level of Study 3 27

29 Korean clinical practice guideline for benign prostate hyperplasia 참고문헌 1. Abrams P, Klevmark B. Frequency volume charts: an indispensable part of lower urinary tract assessment. Scand J Urol Nephrol Suppl 1996;179: Reynard JM, Yang Q, Donovan JL, Peters TJ, Schafer W, de la Rosette JJ, et al. The ICS- BPH Study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. Br J Urol 1998;82: Gisolf KW, van Venrooij GE, Eckhardt MD, Boon TA. Analysis and reliability of data from 24-hour frequency-volume charts in men with lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2000;38: Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T, et al. Clinical guideline for male lower urinary tract symptoms. Int J Urol 2009;16: Homma Y, Kawabe K, Tsukamoto T, Yamaguchi O, Okada K, Aso Y, et al. Estimate criteria for efficacy of treatment in benign prostatic hyperplasia. Int J Urol 1996;3: Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2009;181: Weiss JP, van Kerrebroeck PE, Klein BM, Norgaard JP. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol 2011;186: Groutz A, Blaivas JG, Chaikin DC, Resnick NM, Engleman K, Anzalone D, et al. Noninvasive outcome measures of urinary incontinence and lower urinary tract symptoms: a multicenter study of micturition diary and pad tests. J Urol 2000;164(3 Pt 1):

30 전립선비대증진료권고안 KQ 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을 주는가? 권고사항권고수준근거수준 3-1. 하부요로증상이있는전립선비대증환자에게선택적으로요속검사를시행한다 하부요로증상이있는전립선비대증환자에게선택적으로잔뇨량검사를시행한다 하부요로증상이있는전립선비대증환자에서전문의의평가가필요한경우요속검사와잔뇨량측정을시행한다. Strong Strong Strong C C B 요속검사는시간당배뇨량을측정하여배뇨기능에대한유용한정보를제공하는비침습적이고간편한검사이다. 요속검사에이상소견이있을경우방광출구폐색이나배뇨근기능이상을의심할수있다. 하지만요속검사와잔뇨량측정은반복측정에대한개연성이떨어지는타당성문제가존재한다. 환자는평소의배뇨처럼편안한환경에서요의가느껴질때자연스럽게배뇨하도록하며, 배뇨량이 150 ml 이상되어야의미있는결과를얻을수있다. 정상최대요속은일반적으로 ml/sec 이며, 최대요속은배뇨량에따라변하며나이가증가함에따라감소한다. 최대요속이 10 ml/sec 이하인경우압력요류검사 (pressure-flow study) 에서알수있는방광출구폐색일경우가비교적높게나타난다 [1-4]. 이런경우수술치료에좋은반응을보일확률이높다. 하지만방광근력저하와방광출구폐색을구분하지는못하기때문에치료법결정을위한보다정확한진단을위해서는압력요류검사가필요하다. 잔뇨량측정은초음파를이용하는방법과도뇨관을이용하여측정하는방법이있다. 초음파를이용하는경우는비침습적인장점이있는반면도뇨관을이용한방법보다는정확하지못한단점이있다. 반면도뇨관을이용하여측정하는경우는정확하지만침습적방법으로환자에게불편함을주는단점이있다. 초음파를이용한잔뇨량측정은도뇨관을이용하여잔뇨량을측정하는경우와정확도가상당히일치하기때문에잔뇨량이많이남을거라고의심되는환자에서시행해보는것이좋다 [5,6]. 29

31 Korean clinical practice guideline for benign prostate hyperplasia 요속검사와잔뇨량측정은초기검사에서는선택적으로시행할수있지만, 방광출구폐색이의심되는환자에서약물치료실패시요속검사를평가하여다음검사또는치료를진행하고, 방광저장증상을호소하는환자에게항콜린제를투여하기전에잔뇨량측정을고려해야한다 [7]. 전립선비대증환자에서요속검사및잔뇨량측정이배뇨장애의패턴을진단하는지그참고치에대한연구가있었지만실제로치료법결정에도움이되는지에대한연구는아직까지보고된바가없다. 근거표 KQ 3 1. Oelke M, Hofner K, Jonas U, de la Rosette JJ, Ubbink DT, Wijkstra H. Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume. European Urology 2007;52: Prospective study 160 patients The aim of this prospective study was to compare the diagnostic accuracy of detrusor wall thickness (DWT), free uroflowmetry, postvoid residual urine, and prostate volume (index tests) with pressure-flow studies (reference standard) to detect bladder outlet obstruction (BOO) in men. One hundred sixty men between yr of age (median: 62 yr) were included in the study; 75 patients (46.9%) had BOO according to pressure-flow studies. The results of all investigated index tests differed significantly between obstructed and non-obstructed men. DWT was the most accurate test to determine BOO: the positive predictive value was 94%, specificity 95%, and the area under the curve of ROC analysis There was an agreement of 89% between the results of DWT measurement and pressure-flow studies. Level of Study 3 2. Poulsen AL, Schou J, Puggaard L, Torp-Pedersen S, Nordling J. Prostatic enlargement, symptomatology and pressure/flow evaluation: Interrelations in patients with symptomatic BPH. Scandinavian Journal of Urology and Nephrology Supplementum 1994;157: Prospective study 188 patients Benign prostatic hyperplasia (BPH) is the most common pathologic condition to afflict the aging male. Many patients with symptomatic BPH undergo prostatectomy without rigorous evaluation. Three concepts should be considered before any treatment of a patient with symptomatic BPH; Prostatic enlargement, symptomatology and bladder outflow obstruction. 30

32 전립선비대증진료권고안 Neither uroflowmetry, symptomatology nor prostate size correlated well with bladder outlet obstruction. The positive predictive value for infravesical obstruction was 88% if a maximum flow rate under 10 ml/s was used. Symptomatology could not be used to differentiate between patients with bladder outlet obstruction and patients without obstruction. The positive predictive value for infravesical obstruction was 76% if a prostate volume over 40 ml was chosen. Level of Study 3 3. Reynard JM, Peters TJ, Lim C, Abrams P. The value of multiple free-flow studies in men with lower urinary tract symptoms. British Journal of Urology 1996;77: Prospective study 165 patients To assess the variability of free-flow studies in men presenting with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) and to determine the sensitivity, specificity and predictive values of consecutive measurements of maximum flow rate for the presence of bladder outlet obstruction (BOO) at several threshold values. The mean Qmax on void 1 was 10.2 ml/s and the mean maximum value for Qmax between voids 1 and 2 was 12.5 ml/s. For voids 1, 2 and 3, the mean maximum Qmax was 13.9 ml/s and for voids 1 to 4 it was 15.2 ml/s. There were no significant changes in PVR among any of these voids. There was a statistically significant, although small, decrease in voided volume between voids 1 to 3 and voids 1 to 4. The specificity and PPV of Qmax for BOO increased with each subsequent void, such that using a threshold value for Qmax of 10 ml/s on the fourth void, the specificity and PPV for BOO were 96% and 93%, respectively. Level of Study 3 4. Reynard JM, Yang Q, Donovan JL, Peters TJ, Schafer W, De la Rosette JJMC, et al. The ICS- 'BPH' Study: Uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. British Journal of Urology 1998;82: Prospective study 1,271 patients To explore the relationship between uroflow variables and lower urinary tract symptoms (LUTS): to define performance statistics (sensitivity, specificity, positive and negative predictive values) for maximum urinary flow rate (Qmax) with respect to bladder outlet obstruction (BOO) at various threshold values; and to investigate the diagnostic value of low-volume voids. The relationship between symptoms and uroflow variables was poor. The mean difference between home-recorded and clinic-recorded voided volumes was -48 ml. Qmax was significantly lower in those with BOO (9.7 ml/s for void 1) than in those with no obstruction (12.6mL/s; P<0.001) and Qmax was negatively correlated with obstruction grade (Spearman's correlation coefficient -0.3, P<0.001), even when controlling for the negative correlation between age and Qmax 31

33 Korean clinical practice guideline for benign prostate hyperplasia (Spearman's partial correlation coefficient -0.29, P<0.001). A threshold value of Qmax of 10 ml/ s had a specificity of 70%, a positive predictive value (PPV) of 70% and a sensitivity of 47% for BOO. The specificity using a threshold Qmax of 15 ml/s was 38%, the PPV 67% and the sensitivity 82%. Those voiding <150 ml (n=225) had a 72% chance of BOO (overall prevalence of BOO 60%). In those voiding >150 ml the likelihood of BOO was 56%. The addition of a specific threshold of 10 ml/s to these higher volume voiders improved the PPV for BOO to 69%. Level of Study 3 5. D'Silva KA, Dahm P, Wong CL. Does this man with lower urinary tract symptoms have bladder outlet obstruction?: The Rational Clinical Examination: a systematic review. JAMA 2014;312: systematic review To systematically review the evidence on (1) the diagnostic accuracy of office-based tests for bladder outlet obstruction in men with lower urinary tract symptoms; and (2) the accuracy of the bladder scan as a measure of urine volume because management decisions rely on measuring postvoid bladder residual volumes. Among males with lower urinary tract symptoms, the likelihood ratios (LRs) of individual symptoms and questionnaires for diagnosing bladder outlet obstruction from the highest quality studies had 95% CIs that included 1.0, suggesting they are not significantly associated with one another. An International Prostate Symptom Score cutoff of 20 or greater increased the likelihood of bladder outlet obstruction (positive LR, 1.5; 95% CI, ), whereas scores of less than 20 had an LR that included 1.0 in the 95% CI (negative LR, 0.82; 95% CI, ). We found no data on the accuracy of physical examination findings to predict bladder outlet obstruction. Urine volumes measured by a bladder scanner correlated highly with urine volumes measured by bladder catheterization (summary correlation coefficient, 0.93; 95% CI, ). In patients with lower urinary tract symptoms, the symptoms alone are not enough to adequately diagnose bladder outlet obstruction. A bladder scan for urine volume should be performed to assess patients with suspected large postvoid residual volumes. Level of Study 1 참고문헌 1. Oelke M, Hofner K, Jonas U, de la Rosette JJ, Ubbink DT, Wijkstra H. Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume. European Urology 2007;52: Poulsen AL, Schou J, Puggaard L, Torp-Pedersen S, Nordling J. Prostatic enlargement, symptomatology and pressure/flow evaluation: Interrelations in patients with symptomatic BPH. Scandinavian Journal of Urology and Nephrology Supplementum 1994;157:

34 전립선비대증진료권고안 3. Reynard JM, Peters TJ, Lim C, Abrams P. The value of multiple free-flow studies in men with lower urinary tract symptoms. British Journal of Urology 1996;77: Reynard JM, Yang Q, Donovan JL, Peters TJ, Schafer W, De la Rosette JJMC, et al. The ICS- BPH Study: Uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. British Journal of Urology 1998;82: D Silva KA, Dahm P, Wong CL. Does this man with lower urinary tract symptoms have bladder outlet obstruction?: The Rational Clinical Examination: a systematic review. JAMA 2014;312: Marks LS, Dorey FJ, Macairan ML, Park C, dekernion JB. Three-dimensional ultrasound device for rapid determination of bladder volume. Urology 1997;50: McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, Donnell RF, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol 2011;185:

35 Korean clinical practice guideline for benign prostate hyperplasia KQ 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가 더정확한평가를할수있는가? 권고사항권고수준근거수준 4-1. 정확한전립선의해부학적인평가를위해서는직장수지검사외에전립선초 음파가필요하다. Strong B 직장수지검사는전립선비대증초기평가에있어서필수적인검사이다. 초진방문시에하복부와외부생식기관찰등의신체검사의일환으로진행되어야한다. 직장수지검사를통해결절이만져지거나딱딱하게만져지는부분이있으면조직검사를고려해야한다. 전립선초음파검사는전립선비대증에있어서초기평가에필수적인검사는아니지만사정관폐쇄유무, 정낭의병변을확인하기위하여필요하다. 또한전립선석회화, 전립선실질내고반향및저반향에코, 전립선주위정맥총확장, 전립선피막의불규칙성, 전립선요도주위부의불규칙성같은이상소견을관찰할수있다. 전립선비대증진단에있어전립선크기의측정은중요하다. 그이유는전립선크기가전립선비대증의임상적경과와치료에대한반응에영향을주기때문이다 [1,2]. 전립선초음파를시행하여얻을수있는또하나의장점은방광내전립선돌출정도를알수있다는것이다. 방광내전립선돌출정도는 5 mm 미만, 5 mm 이상그리고 10 mm 미만, 10 mm 이상으로나눌수있으며이돌출정도는요역동학검사상의방광출구폐색정도와유의한상관관계를보였다 [3-5]. 전립선크기를측정하는데있어서전립선초음파의정확도는직장수지검사에비해타당성이인정되고있다. 실제로전립선암으로전립선적출술을시행한대규모지역사회연구에서전립선초음파및직장수지검사의정확도를전립선실제크기와비교하였을때직장수지검사의정확도가많이떨어지며특히전립선크기가작은경우에는정확도가더떨어진다고보고되었다 [6]. 직장수지검사로전립선크기를측정하는것은실제로사이즈가 40 cc 이상으로큰경우에는전립선초음파에비해전립선크기를과소평가하는경우가많으며 [7] 단순직장수지검사만으로는전립선크기를정확히알아내기가쉽지않고 3D 모델화를하는등별도의노력이있어야정확한크 34

36 전립선비대증진료권고안 기의측정이가능하다 [8]. 근거표 KQ 4 6. Loeb S, Han M, Roehl KA, Antenor JA, Catalona WJ. Accuracy of prostate weight estimation by digital rectal examination versus transrectal ultrasonography. J Urol 2005;173:63-5. Cross-sectional study 2,238 To evaluated the relative accuracy of these weight estimates by comparing them to prostate weight following radical retropubic prostatectomy DRE estimates of prostate weight by multiple examiners correlated poorly with RRP specimen weight (r = ). However, TRUS estimates correlated moderately well (r = ). TRUS provided more accurate estimates of prostate weight for smaller glands, although it generally underestimated gland weight compared to the weight of the surgical specimen.in a large, community based prostate cancer screening study prostate weight estimated by DRE was shown to correlate poorly with actual prostate weight. Compared with DRE, TRUS provides a better estimate of prostate weight. In addition, TRUS measurements were more accurate in smaller prostate glands. Level of Study 3 7. Roehrborn CG, Girman CJ, Rhodes T, Hanson KA, Collins GN, Sech SM, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology 1997;49: Cross-sectional study 397 To correlate prostate size estimates performed by single or multiple examiners through digital rectal examination (DRE) with volume measured by transrectal ultrasound (TRUS) and to propose measures for predicting prostatevolume using DRE estimates in clinical settings DRE estimates and TRUS volumes were significantly correlated (r = 0.4 to 0.9), but prostate size was underestimated by 25% to 55% for men with a prostate volume over 40 ml..according to receiver operating characteristic curves, surface area (SA) showed a 70% and 76% chance of correctly identifying men with prostate volume greater than 30 or 40 ml, respectively; those with larger prostates were best distinguished by SA greater than 7 cm2 (sensitivity greater than 0.74, specificity greater than 0.50). Level of Study 3 35

37 Korean clinical practice guideline for benign prostate hyperplasia 8. Roehrborn CG, Sech S, Montoya J, Rhodes T, Girman CJ. Interexaminer reliability and validity of a three-dimensional model to assess prostate volume by digital rectal examination. Urology 2001;57: Cross-sectional study 121 To evaluate the interexaminer reliability and accuracy compared with transrectal ultrasound (TRUS) of a three-dimensional (3D) model and other scales to improve the estimation of prostate volume by digital rectal examination (DRE). DRE size estimates and TRUS volume were moderately to highly correlated in men without prostate cancer. A 3D sizing model showed comparable reliability and correlation with TRUS. Although the DRE estimates generally tend to underestimate the TRUS-measured prostate volume, these tools may be useful in identifying men with enlarged prostate glands. Level of Study 3 참고문헌 1. Marks LS, Roehrborn CG, Wolford E, Wilson TH. The effect of dutasteride on the peripheral and transition zones of the prostate and the value of the transition zone index in predicting treatment response. J Urol 2007;177: Peeling WB. Diagnostic assessment of benign prostatic hyperplasia. Prostate Suppl, 1989;2: Foo KT. Decision making in the management of benign prostatic enlargement and the role of transabdominal ultrasound. Int J Urol 2010;17: Chia SJ, Heng CT, Chan S, Foo KT. Correlation of intravesical prostatic protrusion with bladder outlet obstruction. BJU Int. 2003;91: Nose H, Foo KT, Lim KB, Yokoyama T, Ozawa H, Kumon H. Accuracy of two noninvasive methods of diagnosing bladder outlet obstruction using ultrasonography: intravesical prostatic protrusion and velocity-flow video urodynamics. Urology 2005;65: Loeb S, Han M, Roehl KA, Antenor JA, Catalona WJ. Accuracy of prostate weight estimation by digital rectal examination versus transrectal ultrasonography. J Urol 2005;173: Roehrborn CG, Girman CJ, Rhodes T, Hanson KA, Collins GN, Sech SM, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology 1997;49: Roehrborn CG, Sech S, Montoya J, Rhodes T, Girman CJ. Interexaminer reliability and validity of a three-dimensional model to assess prostate volume by digital rectal examination. Urology 2001;57:

38 전립선비대증진료권고안 KQ 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? 권고사항권고수준근거수준 세이상의하부요로증상을호소하는전립선비대증환자에서전립선특이 항원검사를해야한다. Strong A <PSA 의정의및 PSA 수치에미치는여러인자 > 전립선특이항원 (prostate specific antigen, PSA) 은 prostate gland cell에서생산되는단백질이며, 혈액에서측정할수있다. PSA는 human kallikrein family의한 member 이고전립선의 ductal epithelium으로부터분비된다. 정상적인생리환경에서, prostatic duct 의 epithelial basement membrane은 PSA가전신순환 (systemic circulation) 으로들어가는것을방지하는방어막역할을한다 [1]. 일반적으로혈액에서 PSA 수치가낮게유지되는것이정상이지만, 전립선암 (prostate cancer) 또는다른양성전립선질환으로 PSA 수치가상승할수있다. 나이가들수록양성전립선질환과전립선암이더흔하게발생하는데, 가장흔한양성전립선질환은만성전립선염 (chronic prostatitis, also known chronic pelvic pain syndrome) 과전립선비대증 (benign prostatic hyperplasia, BPH) 이다. 그외요로감염 (urinary tract infection) 과관련된전립선염증 (prostatic inflammation) 과요폐 (urinary retention), 도뇨 (urethral catheterization) 와관련된 trauma 등이 PSA 수치를상승시킬수있다 [1]. 이와는반대로, 항안드로젠 (anti-androgen) 또는 5α환원효소억제제 (5-alpha reductase inhibitor) 는 PSA 수치를 50% 정도낮출수있다 [2-6]. < 전립선암선별검사로서의역할 > PSA 수치의상승은전립선암의가능성이있음을의미하기때문에 [7-9], 전립선비대증이의심되어내원한환자들에게전립선암을감별할필요가있는경우 PSA 검사를시행해야한다. PSA 검사는기대여명 (life expectancy) 이 10년이상이고전립선암의진단이환자의치료방향을변화시킬수있을때해야한다 [7]. PSA 검사에따른위양성과위음성의결과뿐만아니라, 전립 37

39 Korean clinical practice guideline for benign prostate hyperplasia 선조직검사후생길수있는합병증등을포함하는 PSA 검사의이익 (benefit) 과위험 (risk) 에대해환자와충분히상의하여야한다 [7]. 전립선암의진단과관련된불확실성때문에, 특정한 PSA 수치에따라어떤환자에게전립선초음파를이용한전립선조직검사를시행할지여부를임상적으로잘판단해야한다 [7]. 기대여명이 10년미만이거나, 전립선암치료의적응증이아닌환자는일반적으로 PSA 수치의측정은권장되지않는다. 하지만, 적어도 10년이상의기대여명을가지고있는환자, 그리고전립선암을진단함으로써치료를변화시킬수있고 PSA 수치의측정이전립선크기등을추정하여하부요로증상 (LUTS) 에대한치료를변화시킬수있는경우 PSA 검사를시행하여야한다 [10]. 전립선암이없는환자에서의 PSA 수치는전립선크기를짐작할수있는유용한지표가될수있으며, 전립선비대증진행 (BPH progression) 의위험도를예측할수있다 [11]. < 전립선크기예측 > 지금까지많은연구에서혈중 PSA 수치가전립선크기와관련이있으며 [12-14], 전립선비대를유용하게예측할수있다고보고하고있다 [15]. 우리나라에서시행된대규모다기관연구 [16] 에서도, 전립선크기와혈중 PSA 수치는연령의존형 (age-dependent) 로그선형관계를보였으며, 또한 PSA는전립선의다양한크기의기준값 (30, 40 and 50 ml) 을잘예측하는인자였다 [16]. 이연구에서한국인에서의 PSA와전립선크기와의관계는백인 (Caucasian) 과비슷하였으나, 한국인은백인 (Caucasian) 에비해낮은 PSA 수치와작은전립선크기를가졌다 [16]. 또한전립선크기가 40 ml 이상임을예측할수있는 PSA 수치의 age-specific criteria 는 60대, 70대, 80대에각각 > 1.3 ng/ml, >1.7 ng/ml, >2.0 ng/ml이었다 [16]. 이처럼혈중 PSA 검사는하부요로증상을동반한환자에서전립선크기의예측인자이며, 임상적결정을내리는데도움이된다 [7]. < 질환진행예측 > PSA 수치를측정한사람과측정하지않은사람간의하부요로증상의치료효과를직접적으로비교한근거는아직까지없다. 또한 PSA 수치가증상진행 (progression) 을예측하는예측인자임을제시하는 data 역시아직까지는일관적이지않으며, PSA 수치가전립선비대증의진행예측과관련하여임상적으로의미가없다는보고도있다 [17,18]. 하지만, 혈중 PSA 기저치와질환의진행과의관련성에대해회귀분석 (regression analysis) 을시행한많은연구에서혈중 PSA 수치가전 38

40 전립선비대증진료권고안 립선비대증의진행을예측하였다. Roehrborn 등 [19] 은혈중 PSA 수치와전립선크기는향후질환의진행을예측할수있음을보고하였다. 여러연구에서혈중 PSA 기저치가높을수록전립선비대증진행 (overall BPH progression) 가능성과수술과같은침습적치료 (invasive therapy) 를받게되는발생률 (incidence rate) 이높았다 [20-23]. 혈중 PSA 기저치가대조군 (placebo 군 ) 에서증상악화를예측하는인자이고, 대조군과비교하여 Finasteride 5 mg 치료군의유의한증상호전을예측할수있었다 [24]. 삶의질의변화와치료전 PSA 수치가유의한음의상관관계가있다고보고하였다 [25]. 국제전립선증상점수 (IPSS) >7 의 Odds ratio (95% CI) 가 PSA 수치에따라 PSA 2: 1.0, PSA>2-4: 1.62( ), PSA>4-10: 2.64 ( ), PSA >10: 4.28 ( ) 인것으로보고하였다 [26]. 결론적으로 40세이상의전립선비대증환자에서혈중 PSA 수치의측정은전립선암과의감별, 전립선크기예측, 질환의진행예측그리고치료법결정을위해필요하다. 근거표 KQ Crawford ED, Wilson SS, McConnell JD, Slawin KM, Lieber MC, Smith JA, et al. Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 2006;175: Longitudinal follow up of the placebo arm of an RCT with 4 years follow up - Men with BPH and moderate to severe symptom (AUASS) mean 17 (range of 8-20). - The average age was 62 years. (N=737) Analysis of data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression Baseline PSA level was associated with symptom progression. At 4 years, the cumulative probability and incidence rate of overall BPH progression was significantly higher in the baseline high PSA group (p<0.001). Incidence rate of 4 points increase in AUASS was significantly higher in the high PSA group (4.5 vs. 2.8 events/100 person year). The incidence rate of acute urinary retention and invasive therapy was also significantly higher in the group with higher baseline PSA. Level of Study McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr., Dixon CM, Kusek JW, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:

41 Korean clinical practice guideline for benign prostate hyperplasia RCT double blinded (4 arms) - N: 3047 out of 4391 screened, - Mean age: 62.6 ± 7.3 To know the long-term effect of these drugs, singly or combined, on the risk of clinical progression Prognosis value of PSA, based on placebo arm [Data from Crawford 2006] - Overall BPH progression was defines as the first occurrence of an increase of at least 4 points in the AUASS, AUR, urinary incontinence or renal insufficiency or recurrent UTI - Cumulative probability of BPH progression (4 year follow up) PSA 1.6 ng/ml: 24% PSA<1.6 ng/ml: 13.5% P<0.001 (values read from graph) - Incidence rate of overall BPH progression (events/100 person year) PSA 1.6 ng/ml: 5.9 PSA<1.6 ng/ml: 3.1 P= Incidence rate of 4 points increase in AUASS (events/100 person year) PSA 1.6 ng/ml: 4.5 PSA<1.6 ng/ml: 2.8 P= Incidence rate of AUR (events/100 person year) PSA 1.6 ng/ml: 1.0 PSA<1.6 ng/ml: 0.3 P= Incidence rate of invasive therapy (events/100 person year) PSA 1.6 ng/ml: 1.8 PSA<1.6 ng/ml: 0.8 P=0.018 Level of Study Roehrborn CG, Boyle P, Bergner D, Gray T, Gittelman M, Shown T, et al. Serum prostatespecific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54: RCT with follow up of 4 years. - Men with clinical BPH, moderate to severe symptoms - Serum PSA ng/ml with negative biopsy - N: 3040 (Drop outs: 1157) - Group 1 Finasteride 5mg/day - Group 2 Placebo Notes: Baseline PSA was divided into 3 tertiles: First ( ) Second ( ) Third ( ) To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. - Baseline PSA predicts deterioration of symptoms in untreated patients. Baseline PSA predicts improvement of symptoms for those patients treated with finasteride relative to placebo Baseline PSA does not predict improvement of symptoms in the finasteride treatment group alone. - Mean Change in Quasi-AUA Symptom Score (± SE) over time (years 1-4) for each PSA tertile in placebo patients (group 2): 1st tertile had a significantly better long-term symptom improvement than those in other tertiles p < There was no significant difference between long term symptom improvement between 2nd and 3rd tertiles p= Mean Change in Quasi-AUA Symptom Score (± SE) over time (years 1-4) for each PSA tertile group 1 vs. group 2: 1st tertile Not sig. 2nd tertile (p=0.004) 3rd tertile (p=0.001) 40

42 전립선비대증진료권고안 Level of Study Laguna MP, Kiemeney LA, Debruyne FM, de la Rosette JJ. Baseline prostatic specific antigen does not predict the outcome of high energy transurethral microwave thermotherapy. J Urol 2002;167: Cohort - N: Age (mean, range): 66.3 ( ) To assessed the prognostic value of baseline prostate specific antigen (PSA) for outcome after high energy transurethral thermotherapy in patients with lower urinary tract symptoms. Linear regression: Change in QoL vs. pretreatment PSA Spearman r: linear regression coefficient : P value: 0.01 Level of Study Tubaro A, La Vecchia C. The relation of lower urinary tract symptoms with life-style factors and objective measures of benign prostatic enlargement and obstruction: An italian survey. Eur Urol 2004;45: Cross sectional, observational - Age: years - N: Drop outs: 64/866, 802 analysed - Age (mean, range): 64 (50-80) The association between the severity of LUTS and prostate volume, prostate-related variables and general life-style factors was investigated in a large number of patients with persistent LUTS suggestive of BPH (LUTS/BPH). Multiple logistic regressions: IPSS >7 vs. PSA (ng/ml), IPSS<7 is the reference Odds ratio (95%CI) PSA 2: 1.0 PSA>2-4: 1.62 ( ) PSA>4-10: 2.64 ( ) PSA>10: 4.28 ( ) Level of Study 2 참고문헌 1. National Clinical Guideline Centre. The management of lower urinary tract symptoms in men. London D Amico AV1, Roehrborn CG. Effect of 1 mg/day finasteride on concentrations of serum prostate-specific antigen in men with androgenic alopecia: a randomised controlled trial. Lancet Oncol 2007;8:

43 Korean clinical practice guideline for benign prostate hyperplasia 3. Tsukamoto T, Endo Y, Narita M. Efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia. Int J Urol 2009;16: Andriole GL, Kirby R. Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol 2003;44: Andriole GL, Marberger M, Roehrborn CG. Clinical usefulness of serum prostate specific antigen for the detection of prostate cancer is preserved in men receiving the dual 5alpha-reductase inhibitor dutasteride. J Urol 2006;175: Marks LS, Andriole GL, Fitzpatrick JM, Schulman CC, Roehrborn CG. The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations. J Urol 2006;176: Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J; International Scientific Committee. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2009;181: Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T, et al: Japanese Society of Neurogenic Bladder. Clinical guideline for male lower urinary tract symptoms. Int J Urol 2009;16: Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al: European Association of Urology. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013;64: AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 2003;170: Levitt JM, Slawin KM. Prostate-specific antigen and prostate-specific antigen derivatives as predictors of benign prostatic hyperplasia progression. Curr Urol Rep 2007;8: Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317: Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999; 53: Vesely S, Knutson T, Damber JE, Dicuio M, Dahlstrand C. Relationship between age, prostate volume, prostate-specific antigen, symptom score and uroflowmetry in men with lower urinary tract symptoms. Scand J Urol Nephrol 2003;37: Gupta A, Aragaki C, Gotoh M, Masumori N, Ohshima S, Tsukamoto T, et al. Relationship between prostate specific antigen and indexes of prostate volume in Japanese men. J Urol 2005;173: Chung BH, Hong SJ, Cho JS, Seong DH. Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: a multicentre study. BJU Int 2006;97: Carter HB, Landis P, Wright EJ, Parsons JK, Metter EJ. Can a baseline prostate specific antigen level identify men who will have lower urinary tract symptoms later in life? J Urol 2005;173: O Leary MP, Roehrborn C, Andriole G, Nickel C, Boyle P, Hofner K. Improvements in benign prostatic hyperplasia-specific quality of life with dutasteride, the novel dual 5alpha-reductase inhibitor. BJU Int 2003;92: Roehrborn CG, McConnell JD, Saltzman B, Bergner D, Gray T, Narayan P, et al; PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Storage (irritative) and voiding (obstructive) symptoms as predictors of benign prostatic hyperplasia progression and related outcomes. Eur Urol 2002;42: Crawford ED, Wilson SS, McConnell JD, Slawin KM, Lieber MC, Smith JA, et al. Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 2006;175: McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr., Dixon CM, Kusek JW, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:

44 전립선비대증진료권고안 22. McConnell JD, Barry MJ, Bruskewitz RC. Benign prostatic hyperplasia: diagnosis and treatment. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, Bautista OM, Kusek JW, Nyberg LM, McConnell JD, Bain RP, Miller G, et al. Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials 2003;24: Roehrborn CG, Boyle P, Bergner D, Gray T, Gittelman M, Shown T, et al. Serum prostatespecific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54: Laguna MP, Kiemeney LA, Debruyne FM, de la Rosette JJ. Baseline prostatic specific antigen does not predict the outcome of high energy transurethral microwave thermotherapy. J Urol 2002;167: Tubaro A, La Vecchia C. The relation of lower urinary tract symptoms with life-style factors and objective measures of benign prostatic enlargement and obstruction: An italian survey. Eur Urol 2004;45:

45 Korean clinical practice guideline for benign prostate hyperplasia

46 치료 생활습관개선, 대기요법 약물치료 알파차단제 5α 환원효소억제제항콜린제 약물치료 - 병합요법 알파차단제와 5α 환원효소억제제알파차단제와항콜린제알파차단제와 PDE5 억제제 급성요폐와도뇨관치료 경요도전립선절제술 경요도수술최소침습술 추적관찰 전문진료의뢰사항

47

48 전립선비대증진료권고안 KQ 6. 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? 권고사항권고수준근거수준 6-1. 경증의전립선비대증환자는대기요법이적절하다. Strong B 6-2. 하부요로증상을가진환자에게약물치료전또는약물치료와동시에생 활습관개선에대한교육을시행하여야한다. Strong B < 대기요법 > 하부요로증상을지닌환자중많은경우는증상이심하지않아약물치료나수술적치료와같은적극적인치료가필요하지않다. 국제전립선증상점수표의증상점수가 7점이하인경도의하부요로증상을가진환자는치료하지않고경과를지켜보는대기요법의대상이될수있다. 또한국제전립선증상점수표의증상점수가 8점에서 19점사이인중등도의환자도하부요로증상에따른불편함이없다면대기요법의대상이될수있다. 대기요법시행후일부증상은자연적으로호전이되기도하고, 수년간증상의변화없이유지될수있다 [1]. 중등도의하부요로증상을호소하는환자들에서대기요법과경요도전립선절제술의효과를비교한대규모무작위배정연구결과, 대기요법군의 36% 는 5년안에결국수술을받았으며나머지 64% 는대기요법을유지하였다. 수술을받은군을분석하였을때, 수술전불편함의정도가컸던환자일수록수술결과가좋았다 [2]. 또다른대규모연구에서는대기요법을시행한결과 1년째 85% 가증상의변화가없었으나, 5년째는 65% 가병의진행을보였다 [3,4]. < 교육, 생활습관개선 > 대기요법을시작할때교육및행동요법의효과를비교한연구에서세차례의행동요법교육을받은군은교육이없었던군에비해 3, 6, 12개월째국제전립선증상점수표의증상점수가각각 5.7 점, 6.5 점, 5.2 점더낮았으며, 이후약물또는수술치료를받게되는경우는각각 10% (vs 42%), 27% (vs 57%), 32% (vs 64%) 로적었다 [5]. 그러나대기요법과생활습관개선이하부요로증상에미치는영향에대한연구는아직많지않으며, 위와같은결과차이의원인에대해서는아직명확 47

49 Korean clinical practice guideline for benign prostate hyperplasia 히밝혀진것은없다. 국제전립선증상점수중등도이상의환자에서대기요법을고려할경우증상불편정도를반드시 확인하고대기요법중병의진행위험이있음을염두해두어야한다. 대기요법중급성요폐색이 나신장기능부전, 결석과같은합병증이드물게발생할수있다 [6,7]. 따라서이에대해환자에게교 육하고추적관찰을할수있도록하며, 주기적인검사를통해환자의하부요로증상을재평가하는 것이중요하다. 대기요법환자에게다음과같은교육및생활습관개선을권장한다 [1,4,8,9]. 현재환자의하부요로증상에대해교육하고이해시킨다. 하부요로증상의원인이암으로인한것이아님을확인하고이해시킨다. 주기적인추적관찰을받도록한다. 빈뇨와야간뇨로불편한경우특정시간대의수분섭취량을줄이도록한다. 특히야간뇨가 문제인경우늦은오후와저녁시간의수분섭취를제한하도록권장한다. 이뇨작용과방광자극효과가있어빈뇨, 급박뇨, 야간뇨를일으킬수있는카페인과알코올 섭취를줄이거나피하도록한다. 긴장을푼편안한상태에서소변을나누어보는이중배뇨 (double voiding technique) 를시도 해본다. 배뇨후소변이몇방울흘러나오는점적이문제인경우회음부부터요도를훑어내는방법 (urethral milking) 을시도해본다. 저장증상의개선을위해방광용적이나배뇨간격을늘릴필요가있을경우소변이마려운느 낌이들때소변을참아보는방광훈련을시도해본다. 복용중인약물들을확인하고배뇨에영향을주는약 ( 예, 이뇨제 ) 의복용시간을조정하거나 가급적배뇨에영향이적은약으로교체한다. 배뇨를악화시킬수있는변비를치료하도록한다. 근거표 KQ 6 1. Isaacs JT. Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. Prostate 1990;3(Suppl):1-7. Review 48

50 전립선비대증진료권고안 To summarize Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. These comparisons demonstrate that 1) placebo treatment does not affect the natural history of the disease; 2) spontaneous improvement usually occurs within the first 6 months of initial presentation of symptoms, if it is to occur at all; and 3) 3-6 months of follow-up are needed to determine if a patient is going to get worse. Thus, to evaluate accurately the potential benefit of any medical intervention for symptomatic BPH, placebo-controlled clinical trials will be required and should be of at least 6 month's duration. Level of Study 5 2. Flanigan RC, Reda DJ, Wasson JH, et al. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic BPH: a Department of Veterans Affairs cooperative study. J Urol 1998;160:12-6. Control arm of randomized trial 280: TURP 276: Watchful waiting 5 year follow-up To know the outcomes after 5 years of follow-up for men who were randomized to receive TURP or watchful waiting for moderate symptoms of BPH. Treatment failure rates were 10% for TURP versus 21% for watchful waiting (p = ). The crossover rate at 5 years was 36% and was positively associated with the degree of bother. Level of Study 3 3. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. New Engl J Med 1995;332:75-9. Control arm of randomized trial 280: TURP 276: Watchful waiting 3 year follow-up To know the outcomes after 3 years of follow-up for men who were randomized to receive TURP or watchful waiting for moderate symptoms of BPH. Of the men assigned to the watchful-waiting group, 65 (24 percent) underwent surgery within three years after the assignment. Surgery was associated with improvement in symptoms and in scores for urinary difficulties and interference with activities of daily living (P<0.001 for all comparisons). Level of Study 3 4. Netto NR, de Lima ML, Netto MR, et al. Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urol 1999;53:

51 Korean clinical practice guideline for benign prostate hyperplasia Study without consistently applied reference standards / Cohort study 479 patients 50 to 81 years old (mean age 63) with lower urinary tract symptoms attributed to BPH. To know the variability of bladder outlet obstruction and mild lower urinary tract symptoms in patients with benign prostatic hyperplasia (BPH) followed up by watchful waiting. Of 50 patients with mild symptoms, 16 (32%) had bladder outlet obstruction. After a period of 9 to 22 months (mean 17) of watchful waiting, these 16 patients were reviewed. Twelve (75%) of the 16 had bladder outlet obstruction reconfirmed by pressure-flow studies, and 3 (18.8%) of 16 had increased symptoms (moderate symptomatic) and underwent treatment. A total of 4 (25%) of 16 patients still had mild voiding disturbances. The remaining 34 patients with no obstruction had annual routine follow-up and had persistent mild symptom scores and normal uroflowmetric results. Level of Study 4 5. Brown CT, Yap T, Cromwell DA, et al. Self-management for men with lower urinary tract symptoms a randomized controlled trial. BMJ 2007;334:25. Control arm of randomized trial men (mean age 63 (SD 10.7) years), referred by general practitioners to urological outpatient departments with uncomplicated lower urinary tract symptoms. - Self management and standard care (n=73) or standard care alone (n=67). 12 months follow-up To evaluate the effectiveness of self management as a first line intervention for men with lower urinary tract symptoms At three months, treatment failure had occurred in 7 (10%) of the self management group and in 27 (42%) of the standard care group (difference=32%, 95% confidence interval 18% to 46%). Corresponding differences in the frequency of treatment failure were 42% (27% to 57%) at six months and 48% (32% to 64%) at 12 months. At three months, the mean international prostate symptom score was 10.7 in the self management group and 16.4 in the standard care group (difference=5.7, 3.7 to 7.7). Corresponding differences in score were 6.5 (4.3 to 8.7) at six months and 5.1 (2.7 to 7.6) at 12 months. Level of Study 3 6. Ball AJ, Feneley RC, Abrams PH. The natural history of untreated prostatism. Br J Urol 1981;53: Study without consistently applied reference standards / Cohort study 107 patients with symptoms of prostatic obstruction in whom prostatectomy was not clinically indicated. 5 year follow-up To evaluate the natural history of patients with symptoms of prostatic obstruction Ten had subsequently required surgery and 97 remained untreated. In the majority, symptoms did not worsen and only 2 developed acute retention. 50

52 전립선비대증진료권고안 Level of Study 4 7. Kirby RS. The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 2000;56(5 Suppl 1):3-6. Review To summarize our current understanding of the natural history of benign prostatic hyperplasia Age is a strong independent risk factor for the development of AUR. Transurethral resection of the prostate was more effective than watchful waiting in preventing AUR, as shown in the Veteran's Affairs Cooperative Study. Data from the Olmsted County study revealed that urinary flow decreases and prostate size increases with advanced age. Level of Study 5 8. Yap TL, Brown C, Cromwell DA, et al. The impact of self-management of lower urinary tract symptoms on frequency-volume chart measures. BJU Int 2009;104: Control arm of randomized trial 140 men with uncomplicated lower urinary tract symptoms. 12 months follow-up To assess the effect of a self-management programme (SMP) on actual voiding behaviour using frequency-volume chart (FVC) data. Of the 140 patients, 104 completed the FVC data at baseline; at 3, 6 and 12 months charts were received from 99, 95 and 70, respectively. Baseline FVC variables were equivalent between the randomized groups. At 3 months the mean voided volume had increased in the SMP group and differed from the control group by a mean (95% confidence interval, CI) of 57 (33-83) ml. The total number of voids and episodes of nocturia were also lower in the SMP group, with a mean (95% CI) decrease of 2.6 (-3.6 to -1.5) and 0.7 (-1.1 to -0.3) episodes, respectively. These changes were maintained at 6 and 12 months. Level of Study 3 9. Brown CT, van der Meulen J, Mundy AR, et al. Defining the components of self-management programme in men with lower urinary tract symptoms: a consensus approach. Eur Urol 2004;46: multidisciplinary panel rating An eight member multidisciplinary panel rated 94 items To define the components of a self-management programme of lifestyle and behavioural interventions for symptom control in men with uncomplicated LUTS. 51

53 Korean clinical practice guideline for benign prostate hyperplasia The panel agreed that 57 of the original 94 items were appropriate to be incorporated in the self-management programme. These interventions were contained within the following categories: patient assessment prior to starting a self-management programme (6), education and reassurance (4), fluid management (6), caffeine (4), alcohol (2), concurrent medication (2), types of toileting (2), bladder re-training (15), miscellaneous (1), and implementation of a selfmanagement programme (15). Level of Study 4 참고문헌 1. Isaacs JT. Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. Prostate 1990;3(Suppl): Flanigan RC, Reda DJ, Wasson JH, et al. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic BPH: a Department of Veterans Affairs cooperative study. J Urol 1998;160: Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. New Engl J Med 1995;332: Netto NR, de Lima ML, Netto MR, et al. Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urol 1999;53: Brown CT, Yap T, Cromwell DA, et al. Self-management for men with lower urinary tract symptoms a randomized controlled trial. BMJ 2007;334: Ball AJ, Feneley RC, Abrams PH. The natural history of untreated prostatism. Br J Urol 1981;53: Kirby RS. The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 2000;56(5 Suppl 1): Yap TL, Brown C, Cromwell DA, et al. The impact of self-management of lower urinary tract symptoms on frequency-volume chart measures. BJU Int 2009;104: Brown CT, van der Meulen J, Mundy AR, et al. Defining the components of self-management programme in men with lower urinary tract symptoms: a consensus approach. Eur Urol 2004;46:

54 전립선비대증진료권고안 KQ 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적 으로고려되어야하는가? 권고사항권고수준근거수준 7-1. 전립선비대증으로인해중등도이상의증상을보이는경우는약물치료가일차적으로권장된다. 그러나, 방광돌이있는경우, 방광기능장애를동반한방광게실이있는경우, 상부요로의확장으로인한신기능부전이동반된경우, 약물치료에도불구하고요폐, 요로감염, 혈뇨가반복되거나배뇨증상, 배뇨후잔뇨량의호전이없는경우에는수술치료가고려되어야한다. Strong B α환원효소억제제는중등도이상의하부요로증상을호소하는환자에서직장수지검사또는전립선초음파검사에서전립선크기가크거나혈청전립선특이항원검사에서전립선비대증의진행가능성이보이는경우장기간처방을고려해야하는치료약물이다. Strong A 7-3. 항콜린제는중등도이상의하부요로증상을보이는환자중방광자극증상 을주로호소하는환자에서고려될수있으며, 방광출구폐색이심하거나배뇨후잔뇨량이많은경우신중한사용이필요하다. Strong A 7-4. 알파차단제는중등도이상의하부요로증상을보이는전립선비대증환자에게우선적으로고려되어야하는치료약물이다. Strong A 전립선비대증치료방법의선택은각종관련검사의결과뿐만아니라환자의선호도나치료방침 의기대효과, 부작용이나합병증, 비용등을감안하여야한다 알파차단제현재국내에서전립선비대증약물치료에사용가능한알파차단제에는 terazosin, doxazosin, alfuzosin, tamsulosin, silodosin, naftopidil이있다. 약제간비교에의하면언급한알파차단제들은적절한용량에서비슷한효능을나타내는것으로알려져있다 [1]. 여러무작위위약- 대조군연구에서밝혀진바에따르면, 알파차단제는보통국제전립선증상점수를약 35-40% 감소시켜주고최대요속을약 20-25% 증가시켜준다 [2-13]. 일부 53

55 Korean clinical practice guideline for benign prostate hyperplasia open-label 연구에서는국제전립선증상점수가 50% 까지감소하고최대요속은 40% 까지증가하는것으로나타났다 [1,14]. 1년미만의경과관찰에서는전립선크기가알파차단제효능에영향을끼치지않았지만, 1년이상에서는 40 ml 미만의작은전립선을가진환자에서더우수한약물효능을보였다 [14]. 장기간관찰연구에서알파차단제는전립선크기를감소시켜주지않으며급성요폐를막지못하는것으로나타났다 [2]. 가장흔한부작용은무기력, 어지러움, 기립성저혈압이다. 혈압감소가고혈압환자에게는이득이될지모르나일부무기력및어지러움은혈압감소에의한증상으로볼수있다. 혈관확장효과는 doxazosin, terazosin에서가장두드러지며 alfuzosin, tamsulosin에서는훨씬적다 [15]. 따라서 doxazosin, terazosin 은치료를시작할때용량적정 (dose titration) 이필요하다. 심혈관계질환을갖고있거나혈관에작용하는약물 ( 각종항고혈압제제, 발기부전에사용되는 PDE5억제제 ) 을복용중인환자는알파차단제에의한혈관확장에더욱민감할수있다 [16]. 알파차단제가오랫동안광범위하게사용되어왔지만 2005년에이르러서야처음으로수술중홍채이완증후군 (intraoperative floppy iris syndrome) 이보고되었다 [17]. 대부분의보고는 tamsulosin 과관련된것이었는데, 다른알파차단제에비해 tamsulosin 이높은위험도를보이는것인지또는 tamsulosin 이타약제에비해광범위하게사용되었기때문인지는명확하지않다 [18]. 백내장수술전알파차단제를처방하지않도록주의하는것은물론알파차단제를복용중인환자에서도백내장수술이계획된경우라면약물을중지해야한다. 배뇨증상과발기부전이동반된경우알파차단제치료가성기능을더욱악화시키지는않는다. 알파차단제가성욕을저해시키지않으며발기능에약간의이득이있는것으로평가되나종종비정상적사정을일으킨다는문제점을갖고있다 [19]. 보통비정상적사정은역행성사정일것으로판단되나최근자료에서는젊은연령에서비정상적사정을보이는경우상대적인무사정증에기인하는것으로도보고하고있다. 비정상적사정은앞서언급한다른약물보다 tamsulosin 에서더빈번하고, silodosin 과같이알파1A 수용체에더욱선택적인약물에서비정상적사정에대한위험이더큰것으로나타났다 [19,20]. 문헌고찰에따르면, silodosin, naftopidil은아직관련연구가많지는않으나저용량의 tamsulosin 에준하는증상호전을보이는것으로나타났다 [21,22] α 환원효소억제제 5α 환원효소억제제의종류에는 dutasteride 와 finasteride 가있다. Dutasteride 는 5α 환원효소 54

56 전립선비대증진료권고안 1유형과 2유형을모두저해하고, finasteride 는 5α환원효소 2유형만을저해하는약제이다. 상기약제들은전립선상피세포의세포사멸 (apoptosis) 을조장하여전립선크기가줄어들면서효과를나타낸다 [23]. 위약에비해임상적으로효과를나타내는시기는적어도 6-12 개월의치료기간이경과한이후이다. 전립선비대로하부요로증상을호소하는환자가 5α환원효소억제제를복용한지 2-4년이지나면국제전립선증상점수가약 15-30% 감소하고전립선크기도약 18-28% 감소하며최대요속은약 ml/s 증가하는것으로나타났다 [24-33]. 또한, 5α환원효소억제제는급성요폐및수술필요성에대한장기간 (1년이상 ) 의위험을감소시켜주는것으로보고되었다 [28,30,34,35]. Finasteride 에의한증상호전은치료전전립선크기에따라다른데, 전립선이 40 ml보다작은경우나 PSA 1.4 ng/ml 이하인경우위약군에비해별로효과적이지않을것으로여겨진다 [36,37]. 한편, dutasteride 는치료전전립선크기가 ml인경우에도최대요속을상승시키는것으로나타났다 [38,39]. 두약제는몇몇연구간간접비교를통해살펴봤을때, 하부요로증상의치료에거의동등한효능을보이는것으로보고되었다 [40]. 한국인의평균전립선크기는 50대이상모든연령대에서서양인의평균전립선크기에비해 5-10 ml 작은것으로나타났다 [41]. 평균전립선크기가큰서양인을대상으로진행된연구들을근거로얻어진외국의진료지침권고를그대로받아들이는것은적합하지않다. 서양인기준의연구에근거한전립선용적 30 ml 또는 PSA 1.4 ng/ml 이상인경우 5α환원효소억제제사용권고는한국성인남성의전립선용적기준에맞추어조정되어야한다. 이에대한명확한근거를제시하기위한국내연구가필요하다. 5α환원효소억제제를복용한지 6-12 개월이경과한후에는전립선특이항원수치가약 50% 감소하므로 [40], 전립선특이항원수치의해석에유의하여야한다. 5α환원효소억제제의성기능관련부작용으로는성욕감소, 발기부전, 역행성사정과같은사정장애, 사정실패, 정액량감소가있으며 [30,33,40], 여성형유방도환자의 1-2% 에서보고된다 항콜린제현재국내에서사용가능한주요항콜린제에는 tolterodine, trospium, solifenacin, fesoterodine, propiverine, oxybutynin Imidafenacin이있다. 과민성방광에서주로처방되는약으로전립선비대증에서는자극증상을호소할때고려해볼수있는약제들이다. 55

57 Korean clinical practice guideline for benign prostate hyperplasia Tolterodine 은 open-label 연구에서 주복용후주간빈뇨, 야간뇨, 절박요실금, 국제전립선증상점수가복용전에비해유의하게호전되는것으로나타났다 [42,43]. 한편, 무작위위약-대조군연구에서는 tolterodine 복용군의경우위약군에비해절박요실금, 주간및 24시간빈뇨가유의하게줄어드는것으로나타났다. 야간뇨, 절박뇨, 국제전립선증상점수도대부분줄어들었으나통계적으로유의하지는않았다 [44-46]. 항콜린제는배뇨후잔뇨량증가와요폐에대한위험때문에방광출구폐색이심한전립선비대증환자에서는일반적으로권장되지않는다. 중등도이하의방광출구폐색이있는환자에서는 tolterodine 을사용하였을때위약군에비해배뇨후잔뇨량은유의하게증가하였지만, 급성요폐발생에는차이가없었다 [47]. Tolterdine 의가장흔한부작용은입마름이며, 7-24% 의빈도로발생한다 [41,45,46]. 대규모의무작위연구들에따르면 tolterodine 복용군에서요폐, 변비, 설사, 졸림과같은부작용은대조군과비슷한빈도를보였다 [48,49]. 방광자극증상을보이는전립선비대증환자에관한연구는대부분 tolterodine과일부 fesoterodine 에서수행되기는했지만, 대개다른항콜린제에서도효과나부작용은비슷할것으로받아들여진다 일차치료법으로서약물치료와수술치료의비교일차치료법으로서약물치료와수술치료의임상결과를직접적으로비교한연구는확인되지않았다. 다만, 치료비용기준으로살펴봤을때중등도증상인환자에서는약물치료가, 심한증상인환자에서는수술치료가비용대비효과적인것으로나타났다 [49]. 두치료간의직접적인비교연구는없지만, 주요진료지침들에서는수술을고려해야하는경우에대해다음과같이권장하고있다. EAU (2012) 전립선비대로인해재발성또는치료불응성인요폐, 범람성요실금, 재발성요로감염, 방광돌이나방광게실, 치료저항성육안적혈뇨, 상부요로의확장 (± 신기능부전 ) 이발생했을경우수술치료를필요로한다 ( 절대적적응증 ). 또한, 보존적치료나약물치료에도불구하고하부요로증상이나배뇨후잔뇨량의호전이불충분한경우수술을고려할수있다 ( 상대적적응증 ). 56

58 전립선비대증진료권고안 AUA (2010) 전립선비대로인한신기능부전, 재발성요로감염, 방광돌, 육안적혈뇨가있거나다른치료에 불응성인하부요로증상을보이는경우수술치료가권장된다. 방광게실은반복성요로감염이 나진행성의방광기능장애가동반되지않으면수술의절대적적응증이아니다. NCGC (2010) 배뇨증상이심각한경우, 보존적치료나약물치료가실패한경우또는적절하지않은경우수 술을권장한다. 경증또는중등도의증상인환자에게는수술치료전에다른치료법을시도해 야한다. 이를토대로미루어보았을때, 수술의적응증이동반된상황에서는처음부터수술을권장할수있으나중등도이하의증상을보이는환자에서는약물치료가일차적으로고려되어야하는것이적절하다고판단된다. 또한, 수술여부는수술에따른합병증위험, 수술비용등을치료이득과비교하여환자의입장에서결정하여야한다. 전립선비대에따른수술방법은다음과같은것들이있으며, 경요도적전립선절제술 (TURP) 이아직까지는수술치료의기준으로받아들여지고있다. Transurethral resection of the prostate (TURP) Transurethral incision of the prostate (TUIP) Transurethral vaporization of the prostate (TUVP) Photoselective vaporization of the prostate (PVP) Transurethral holmium laser ablation of the prostate (HoLAP) Holmium laser resection of the prostate (HoLRP) Transurethral holmium laser enucleation of the prostate (HoLEP) Open prostatectomy Laparoscopic and robotic prostatectomy (considered investigational) 근거표 KQ 7 1. Djavan B, Chapple C, Milani S, et al. State of the art on the efficacy and tolerability of alpha1- adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 2004;64:

59 Korean clinical practice guideline for benign prostate hyperplasia Systematic review 33 studies, 22,562 patients To aim in the present report to update the analysis published in 1999 to assess whether these α1-ar antagonists can be distinguished with regard to efficacy and/or tolerability All α1-ar antagonists have comparable efficacy in improving symptoms and Qmax when administered at their full therapeutic dose. α1-ar antagonists that require dose titration and are initiated at subtherapeutic doses (eg, terazosin) have a slower onset of action than α1-ar antagonists that can be initiated at their full therapeutic dose (eg, tamsulosin). The main difference between α1-ar antagonists relates to their tolerability profile, with alfuzosin (especially the XL formulation) and tamsulosin (especially the 0.4 mg o.d. dose) better tolerated than doxazosin (including the GITS formulation) and terazosin. As demonstrated in the direct-comparative studies, tamsulosin tends to interfere less with blood pressure regulation and induces slightly less vasodilatory AEs than alfuzosin. This seems particularly to be the case in the elderly and patients with cardiovascular disease and/or comedication. Abnormal ejaculation has mainly been reported in placebo-controlled trials with tamsulosin. In direct-comparative trials, its incidence with tamsulosin was comparable or slightly greater than that with alfuzosin and greater than that with terazosin. However, it seems that patients with LUTS/BPH are more likely to discontinue α1- AR antagonist therapy because of vasodilatory AEs such as dizziness than abnormal ejaculation and that over-all sexual function is improved with all α1-ar antagonists, including tamsulosin. Vasodilatory AEs may lead to falls, fractures, and institutionalization, in particular in the elderly or very elderly and/or in those with concomitant cardiovascular comorbidity/co-medication. Level of Study 1 2. McConnell JD, Roehrborn CG, Bautista O, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Randomized, placebo-controlled trial 3,047 patients To compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia The risk of overall clinical progression-defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection-was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. Level of Study 2 58

60 전립선비대증진료권고안 3. Jardin A, Bensadoun H, Delauche-Cavallier MC, et al. Alfuzosin for treatment of benign prostatic hypertrophy. The BPH-ALF Group. Lancet 1991;337: Randomized, placebo-controlled trial 518 patients To assess the long-term efficacy and safety of alfuzosin, a selective alpha 1-adrenergic antagonist Obstructive and irritative symptoms, assessed according to the Boyarsky scale, significantly improved in the alfuzosin group compared with the placebo group (p = ). Fewer patients in the alfuzosin group than in the placebo group dropped out due to lack of efficacy (6.8% vs 14.6%, p = 0.004) and the prevalence of spontaneous acute urine retention was lower in the alfuzosin group (0.4% vs 2.6%, p = 0.04). By 6 months, mean urinary flow rates had increased (p less than 0.05) and residual volume had decreased (p = 0.017) in the alfuzosin group, although the two groups were broadly similar with respect to increase in peak flow rate. The overall incidence of adverse events was similar in the two groups, which led to the withdrawal of 10.8% and 9.0% of patients, respectively. Level of Study 2 4. Buzelin JM, Roth S, Geffriaud-Ricouard C, et al. Efficacy and safety of sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. ALGEBI Study Group. Eur Urol 1997;31: Randomized, placebo-controlled trial 390 patients To assess the efficacy and safety of a sustained-release (SR) formulation of alfuzosin, a selective alpha(1)-blocker, in patients with symptomatic benign prostatic hyperplasia (BPH) SR-alfuzosin significantly improved urinary symptoms versus placebo assessed using the I-PSS (-31 vs. -18%, p = 0.007) and Boyarsky (-30 vs. -16%, p < 0.001) scores, with a direct correlation between both scores. Maximum flow rate increased significantly with SR-alfuzosin (+2.4 ml/ s, i.e. +29%) compared with placebo (+1.1 ml/s, i.e. +14%, p = 0.006). Residual urine was also significantly reduced with SR-alfuzosin. Overall, SR-alfuzosin was as well tolerated as placebo. Nine patients dropped out for adverse events with SR-alfuzosin (4.6%) and 14 (7.1%) with placebo. The incidence of vasodilation-related events (dizziness, postural symptoms, headache) with SR-alfuzosin (3.1%) was similar to that of placebo (3.6%). No first-dose effect was observed compared with placebo. The reduction in supine blood pressure with SR-alfuzosin was minor (< or = 5 mmhg), both in normotensive and hypertensive patients. Level of Study 2 5. van Kerrebroeck P, Jardin A, Laval KU, et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol 2000;37:

61 Korean clinical practice guideline for benign prostate hyperplasia Randomized, placebo-controlled trial 447 patients To assess the efficacy and safety of a new prolonged release formulation of the uroselective alpha (1)-blocker alfuzosin for a once-daily dosing regimen in patients with lower urinary tract symptoms (LUTS) suggestive of symptomatic benign prostatic hyperplasia (BPH) Both alfuzosin formulations significantly improved urinary symptoms versus placebo assessed using the International Prostate Symptom Score (alfuzosin 10 mg once daily: -6.9; alfuzosin 2.5 mg thrice daily: -6.4; placebo: -4.9, p = 0.005). Peak flow rate increased significantly with alfuzosin 10 mg once daily (+2.3 ml/s, p = 0.03 vs. placebo) and with alfuzosin 2.5 mg thrice daily (+3.2 ml/s, p< vs. placebo) compared to placebo (+1.4 ml/s). Overall both formulations of alfuzosin were well tolerated in comparison with placebo. In addition, vasodilatory adverse events appeared to be less frequent with the once daily than the thrice daily formulation (6.3 vs. 9.4%, respectively). No first-day effect was reported with alfuzosin once daily and the effect on blood pressure did not differ from those observed in placebo, both in normotensive and hypertensive patients. No specific sexual dysfunction including ejaculation disorder was reported in the alfuzosin 10 mg once-daily group. Level of Study 2 6. MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 2005;66: Systematic review 11 studies, 3,901 patients To evaluate the efficacy and adverse effects of alfuzosin for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH) The search strategy identified 11 trials involving 3,901 men with a mean age of 64 years. Eight trials were placebo-controlled studies, two were alfuzosin versus alternative alpha-blockers, and one was alfuzosin versus finasteride and combination alfuzosin/finasteride therapy. The study durations were short term, 4 to 26 weeks. The mean baseline symptom scores and peak urinary flow rates were indicative of moderate BPH. Alfuzosin (7.5 or 10 mg) improved lower urinary tract symptoms assessed by the International Prostate Symptom Score compared with placebo. The mean absolute change from baseline was -5.4 points for alfuzosin compared with -3.6 points for placebo, a weighted mean difference of 1.8 points (three studies). Alfuzosin increased the peak urinary flow more than did placebo, although the improvement varied across the eight studies. Symptom and flow improvements were generally comparable to that with combination therapy and with other alpha1-blockers. Alfuzosin had good short-term tolerability, and the numbers of study withdrawals were comparable to those with placebo and controls. Efficacy and short-term safety were similar across the various (immediate-release, sustained, and once-daily) formulations. Level of Study 1 7. Kirby RS, Andersen M, Gratzke P, et al. A combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int 2001;87:

62 전립선비대증진료권고안 Level of Study 2 Randomized, placebo-controlled trial 795 patients To report an integrated analysis of two previous studies fully characterizing the clinical utility of the controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin in the treatment of benign prostatic hyperplasia (BPH) Both doxazosin GITS and doxazosin-s significantly improved the symptoms of BPH, as shown by a 45% reduction for each in total IPSS from baseline to final visit, compared with a 34% reduction in patients on placebo. Doxazosin GITS and doxazosin-s produced comparable improvements in Qmax that were significantly greater than with placebo, with a greater improvement sooner after treatment with doxazosin GITS than with doxazosin-s. Nearly half of the patients on doxazosin GITS had symptom relief at the 4-mg starting dose. A similar number of patients in both doxazosin groups were titrated to the maximum dose. Secondary outcomes were consistent with the primary effects. Both doxazosin GITS and doxazosin-s produced significant improvements in sexual function according to IIEF scores among those with dysfunction at baseline. The overall incidence of adverse events was similar among patients treated with doxazosin GITS and placebo, and slightly lower than those on doxazosin-s. There was no apparent difference in the type of adverse events reported for the two formulations of doxazosin, although most adverse events were reported at a lower frequency with doxazosin GITS. 8. Chapple CR, Wyndaele JJ, Nordling J, et al. Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta-analysis of two randomised, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group. Eur Urol 1996;29: Meta-analysis 2 studies, 575 patients To evaluate the efficacy and safety of modified-release tamsulosin 0.4 mg once daily compared with placebo in patients with benign prostatic enlargement, lower urinary tract symptoms and prostatic obstruction (symptomatic BPH) Maximum urinary flow rate improved to a greater extent in the tamsulosin group (1.6 ml/s, 16%) than the placebo group (0.6 ml/s, 6%) (p = 0.002). Total Boyarsky symptom score also improved to a greater extent in the tamsulosin group (3.3 points, 35.1% reduction) than the placebo group (2.4 points, 25.5% reduction) (p = 0.002). Significantly more tamsulosin patients (66%) than placebo patients (49%) had a > or = 25% decrease in total symptom score at endpoint (p < 0.001). Twelve weeks of treatment with tamsulosin also produced significant improvements in average urinary flow rate (p = 0.005) and voiding or "obstructive" (p = 0.008) and storage or "irritative' (p = 0.017) symptom scores. The incidence of drug-related adverse events was comparable for the tamsulosin and placebo groups (13 and 12% respectively, p = 0.802). The same applies to the incidence of adverse events commonly attributed to alpha 1-adrenoceptor antagonists, such as dizziness, headache, postural hypotension, syncope, asthenia, somnolence and rhinitis. There were no clinically significant changes in blood pressure or pulse rate in tamsulosin patients compared with placebo patients both in hypertensive and normotensive BPH patients. Level of Study 1 9. Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 1998;51:

63 Korean clinical practice guideline for benign prostate hyperplasia Randomized, placebo-controlled trial 756 patients To evaluate the efficacy and safety of two once-daily doses of tamsulosin, the first selective alpha1a-antagonist studied in clinical trials Statistically significant improvements in all efficacy parameters were observed in tamsulosintreated compared with placebo-treated patients. Additionally, the 0.4-mg/day dose demonstrated a rapid onset of action (4 to 8 hours) based on Qmax after the first dose of double-blind medication. A review of the safety parameters demonstrated excellent tolerance at 1 week after the initial 0.4-mg/day dose and continued tolerance during the additional 12 weeks of 0.4- and 0.8-mg/day dosing. The incidence of positive orthostatic test results in the tamsulosin groups was comparable to that observed in the placebo group. Adverse events were comparable in the 0.4-mg/day tamsulosin and placebo groups and were somewhat higher in the 0.8-mg/day tamsulosin group. Level of Study Wilt TJ, Mac Donold R, Rutks I. Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2003;(1):CD Systematic review 14 studies, 4,122 patients To assesse the effects of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) compatible with BPH Fourteen studies involving 4,122 subjects met inclusion criteria. Study duration ranged from 4-26 weeks, and no placebo-controlled study lasted longer than 13 weeks. The mean age of subjects was 64 years. Baseline symptom scores and urine flow rates demonstrated that men had moderate LUTS. Tamsulosin improved symptoms and peak urine flow relative to placebo. The weighted mean differences (WMD) for mean change from baseline for the Boyarsky symptom score for 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were -1.1 points (95% CI = -1.49, -0.72; 12% improvement) and -1.6 points (95% CI = -2.3, -1.0; 16% improvement), respectively. The WMD for mean change from baseline in peak urine flow were 1.1 ml/sec (95% CI = 0.59, 1.51) and 1.1 ml/sec (95% CI= 0.65, 1.48) for 0.4 mg and 0.8 mg, respectively. Tamsulosin (0.2 mg-0.4 mg) was as effective as other alpha antagonists and the phytotherapeutic agent Permixon in improving symptoms and flow rates though the doses of all alpha-antagonists studied may not have been optimal. Discontinuations from treatment for any reason and discontinuations "due to adverse events" were similar in the low dose tamsulosin (0.2 mg) and placebo groups but increased to 16% in trials utilizing a 0.8 mg dose of tamsulosin. Low dose tamsulosin was generally well tolerated although not all the trials reported specific adverse events. The most frequently reported adverse events that were significantly greater than placebo included dizziness, rhinitis and abnormal ejaculation. Adverse effects increased markedly as tamsulosin dosing increased, and were reported in 75% of men receiving the 0.8 mg dose. Men receiving a 0.2 mg dose tamsulosin were less likely to discontinue treatment compared to men receiving terazosin. Level of Study 1 62

64 전립선비대증진료권고안 11. Brawer MK, Adams G, Epstein H. Terazosin in the treatment of benign prostatic hyperplasia. Terazosin Benign Prostatic Hyperplasia Study Group. Arch Fam Med 1993;2: Randomized, placebo-controlled trial 160 patients To evaluate the efficacy and tolerability of terazosin, a long-acting selective alpha 1-receptor antagonist, in patients with benign prostatic hyperplasia Terazosin-treated patients had decreases in Boyarsky obstructive, irritative, and total scores of 3.3 (52%), 1.3 (29%), and 4.6 (42%), respectively, compared with decreases of 0.7 (12%), 0.4 (9%), and 1.1 (11%), respectively, in the placebo group (P <.05). Peak urine flow increased by a mean of 2.6 ml/s (30%) in terazosin-treated patients and 1.2 ml/s (14%) in placebo-treated patients (P < or =.05). Adverse events that differed significantly in the two groups were dizziness (19% in the terazosin group vs 5% in the placebo group) and urinary tract infection (1% in the terazosin group vs 10% in the placebo group). Level of Study Roehrborn CG, Oesterling JE, Auerbach S, et al. The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator Group. Urology 1996;47: Randomized, placebo-controlled trial 2,084 patients To determine the clinical effectiveness and safety of alpha (1)-blockade therapy versus placebo in the treatment of men with moderate to severe symptoms of prostatism in a communitybased population under usual care conditions AUA-SS (0 to 35 point scale) improved from a baseline mean of 20.1 points by 37.8% during terazosin (n=976) and by 18.4% during placebo (n=973) treatment (P<0.001). Similarly, statistically superior improvements were observed in regard to the AUA-BS, BII, and the QQL score in the terazosin-treated patients. Peak urinary flow rate improved from a baseline of 9.6 ml/s (both regional treatment groups) by 2.2 ml/s in the terazosin group (n=137) and by 0.7 ml/s in the placebo group (n=140) (P< or = 0.05). Treatment failure occurred in 11.2% of terazosin- and 25.4% of placebo-treated patients (P<0.001; Kaplan-Meier adjusted withdrawal rates of 365 days). Withdrawal from study drug treatment due to adverse events occurred in 19.7% of terazosinand 15.2% of placebo-treated patients (P<0.001). Level of Study Wilt TJ, Howe RW, Rutks I, et al. Terazosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002;(4):CD Systematic review 17 studies, 5,151 patients 63

65 Korean clinical practice guideline for benign prostate hyperplasia To evaluate the effectiveness and adverse effects of the alpha-blocker, terazosin, for treatment of urinary symptoms associated with BPO 17 studies involving 5,151 subjects met inclusion criteria (placebo-controlled (10); alpha-blockers (7); finasteride alone or in combination with terazosin as well as placebo (1); microwave therapy (TUMT) (1). Study duration ranged from 4-52 weeks. Mean age was 65 years and 82% of men were white. Baseline urologic symptom scale scores and flow rates demonstrated that men had moderate BPO. Efficacy outcomes were rarely reported in a fashion that allowed for data pooling but indicated that terazosin improved symptom scores and flow rates more than placebo or finasteride and similarly to other alpha antagonists. The pooled mean percentage improvements for the Boyarsky symptom score was 37% for terazosin versus 15% for placebo (n=4 studies). The mean percentage improvement for the American Urological Association symptom score (AUA) was 38% compared to 17% and 20% for placebo and finasteride, respectively (n = 2 studies). The pooled mean improvement in the International Prostate Symptom Score (IPSS) (40%) was similar to tamsulosin (43%). Peak urine flow rates improved greater with terazosin (22%), than placebo (11%) and finasteride (15%) but did not differ significantly from the other alpha-blockers. The percentage of men discontinuing terazosin was comparable to men receiving placebo and finasteride but was greater then with other alphaantagonists. Adverse effects were greater than placebo and included dizziness, asthenia, headache and postural hypotension. Level of Study Michel MC, Mehlburger L, Bressel HU, et al. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prost Dis 1998;1: Open-label, observational study (no control group) 19,365 patients To compare treatment efficacy in subgroups of patients with the a1-blocker tamsulosin In a comparison of patients aged <61, 61±70 and >70 y thepretreatment IPSS increased with age in both studies (Table 1). However, the treatment-associated reduction of the IPSS was very similar in all three age groups with a mean reduction of _9 points corresponding to _50% (Table 1). The pretreatment Qmax decreased with age in both studies (Table 1). While the tamsulosin-induced absolute increases of Qmax were slightly smaller in the oldest compared to the youngest age group (4.3_0.2 vs 5.1_0.2 ml/s and 4.3_0.1 vs 4.8_0.1 ml/s in studies 1 and 2, respectively; P<0.05), the relative increases of Qmax were similar in all age groups, that is _40% (Table 1). To study treatment effects in relation to disease severity, patients were stratified according to their pretreatment IPSS (0±7, 8±19 and 20±35, Table 2), Qmax (<10, 10± 15 and >15 ml/s, Table 2) and post-voiding residual urine (<100 and _100 ml, Table 2). with the most severe symptoms benefited at least as much from tamsulosin treatment as those with mild or moderate symptoms and, if anything, had even greater improvements (Table 2). Even more importantly 42% and 50% of patients had an IPSS _20 and a Qmax<10 ml/s prior to treatment, but only 5% and 15%, respectively, remained in that category after four weeks of tamsulosin treatment (Figure 1). Among patients with _100 ml residual urine before treatment only 15% remained in that group after four weeks of treatment, while all others dropped to <100 ml residual urine, and 41% of patients had values of <50 ml. Level of Study 3 64

66 전립선비대증진료권고안 15. Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related safety profile and efficacy of a-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract 2008;62: Meta-analysis 30 studies, 1,053 patients To evaluate the safety profile and efficacy of alpha1-adrenergic receptor blockers (A1Bs) currently prescribed for benign prostatic hyperplasia (BPH) Of 2389 potential citations, 25 were usable for evaluation of safety data, 26 for efficacy. A1B use was associated with a statistically significant increase in the odds of developing a vascular-related event [odds ratio (OR) 2.54; 95% confidence interval (CI): ; p < ]. The odds of developing a vascular-related adverse event were: alfuzosin, OR 1.66, 95% CI: ; terazosin, OR 3.71, 95% CI: ; doxazosin, OR 3.32, 95% CI: and tamsulosin, OR 1.42, 95% CI: A1Bs increased Q(max) by 1.32 ml/min (95% CI: ) compared with placebo. Difference from placebo in American Urological Association symptom index/ International Prostate Symptom Score was points (95% CI: to -1.14). Level of Study Barendrecht MM, Koopmans RP, de la Rosette JJ, et al. Treatment for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: the cardiovascular system. BJU Int 2005;95(Suppl.4): Systematic review Not specified in detail review the physiological basis of cardiovascular side-effects of α1-ar antagonists, identify risk factors for these side-effects, and describe their interaction with specific drugs α1-ar antagonists are a reasonably well-tolerated drug class, but cardiovascular side-effects can occur, and these can lead to serious morbidity such as falls and fractures. Although the available data are not conclusive, it appears that patients with cardiovascular comorbidities and those concomitantly using antihypertensives and/or PDE-5 inhibitors might be particularly at risk. The safety of tamsulosin in such risk groups is better documented than that of other α1-ar antagonists, and this should affect drug choice in patients with LUTS/BPH belonging to any of these risk groups. Level of Study Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg 2005;31: Consecutive retrospective study/prospective cohort study 511 patients/741 patients To assess the incidence and possible causative factors of a newly recognized syndrome, the intraoperative floppy iris (IFIS) 65

67 Korean clinical practice guideline for benign prostate hyperplasia Three percent (16/511) of the patients in the retrospective study, representing 3.0% (25/706) of the total eyes, were taking tamsulosin (Flomax) for benign prostatic hypertrophy. The overall prevalence of IFIS was 2.0% (10/511 patients). The syndrome was noted intraoperatively in 63.0% (10/16) of the tamsulosin patients but in none of the 11 patients on other systemic alpha-1 blockers. In the prospective study of 900 consecutive cataract surgeries, the prevalence of IFIS was 2.2% (16/741 patients). Ninety-four percent (15/16) of the IFIS patients were taking or had taken systemic tamsulosin. Twenty-six patients (36 eyes) in the 2 studies had IFIS associated with systemic tamsulosin. Sphincterotomies and mechanical pupil stretching were ineffective in maintaining adequate pupil dilation in this surgical population. Level of Study Michel MC, Okutsu H, Noguchi Y, et al. In vivo studies on the effects of a1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits. Naunyn-Schmiedeberg s Arch Pharmacol 2006;372: Animal study In study I we compared the potential of various α1-adrenoceptor antagonists to inhibit the mydriatic effects of phenylephrine in pentobarbital-anaesthetised rabbits. In study II we established effective doses of these drugs for antagonising the effects of phenylephrine on intraurethral pressure (IUP) in order to establish ratios for ocular effects vs. those for the desired effects in the lower urinary tract. In study III we determined the potential of these α1- adrenoceptor antagonists to affect pupil diameter in conscious rabbits. Study I: The mean basal pupil diameter in the vehicle group was 7.15±0.11 mm, and similar basal values were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). The first phenylephrine injection (30 μg/kg i.v.) transiently (for about 20 s) increased pupil diameter in the vehicle group by 0.96±0.13 mm, and similar dilatations were observed in all groups receiving the α1 adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). Four additional consecutive phenylephrine injections caused roughly similar pupil dilatation. On the other hand, alfuzosin (30 1,000 μg/kg), doxazosin (30 1,000 μg/kg), naftopidil (300 10,000 μg/kg), prazosin ( μg/kg), tamsulosin (1 30 μg/kg) and terazosin (30 1,000 μg/kg) dose-dependently inhibited phenylephrine-induced pupil dilatation without affecting the duration of the mydriatic response in a relevant manner. study II: The mean basal IUP in the vehicle group was 21.9±2.8 cmh2o, and similar basal values were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). The first phenylephrine injection (30 μg/kg i.v.) transiently (for about 70 s) increased IUP in the vehicle group by 43.1±5.7 cm H2O, and similar elevations were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). Three additional consecutive phenylephrine injections caused roughly similar IUP elevation. On the other hand, alfuzosin ( μg/kg), doxazosin ( μg/kg), naftopidil (300 3,000 μg/kg), prazosin ( μg/kg), tamsulosin (1 10 μg/kg) and terazosin ( μg/kg) dosedependently inhibited phenylephrine-induced IUP elevation without affecting the duration of the response in a relevant manner. A comparison of the ED50 values for inhibition of pupil dilatation and IUP elevation demonstrated that each antagonist required similar doses for inhibition of the two responses. 66

68 전립선비대증진료권고안 Level of Study 4 Study III: The mean basal pupil diameter in the vehicle group was 6.73±0.27 mm, and similar basal values were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). The pupil size remained relatively stable over the entire 8-h observation period in the vehicle-treated group. All α1-adrenoceptor antagonists tested dose-dependently reduced pupil size with maximum miotic effects after 15 min, except for terazosin where maximum effects were observed after 30 min. Of note, the lowest tested antagonist doses in this study corresponded to or even exceeded the doses that caused almost maximum inhibition of phenylephrineinduced pupil dilatation except for naftopidil ;nevertheless, these doses failed to cause statistically significant miosis except for terazosin, and for most drugs only 30- to 100-fold higher doses (3-fold higher for naftopidil) caused detectable miosis. 19. van Dijk MM, de la Rosette JJ, Michel MC. Effects of a1-adrenoceptor antagonists on male sexual function. Drugs 2006;66: Systematic review Not specified in detail To consider methodological issues in the analysis of adverse effects on sexual function associated with the use of α-blockers, and then summarize the effects of individual α-blockers Numerous studies have reported on possible adverse effects of α-blocker treatment on sexual function. Adverse α-blocker effects on sexual desire, erectile function, ejaculatory function and global sexual function occur in few patients only, and in some cases even improved functions have been reported. In this regard, it should be considered that the overwhelming majority of findings come from BPH patients, that is a condition with major effects on quality of life. When α-blockers improve BPH symptoms, associated improvements of sexual function may reflect a generally improved perception of wellbeing. Therefore, caution needs to be applied when extrapolating findings from BPH to, for example, hypertensive patients, who have not been studied extensively in this regard. There appears to be little difference between α-blockers with regard to effects on sexual function. A notable exception the effect of tamsulosin on ejaculatory function, now proposed to be (relative) anejaculation rather than retrograde ejaculation. While adverse effects of tamsulosin on ejaculatory function have been well documented, the magnitude of differences with other α-blockers is insufficient to be detectable as statistically significant unless very large patient numbers are compared, and the incidence of abnormal ejaculations in OLS is low. Therefore, the possibility of abnormal ejaculation with tamsulosin must be weighed against the unparalleled cardiovascular safety record of this agent when choosing the most appropriate α-blocker for an individual patient. Level of Study Kawabe K, Yoshida M, Homma Y; Silodosin Clinical Study Group. Silodosin, a new a1aadrenoceptorselective antagonist for treating benign prostatic hyperplasia: a results of a phase III randomised, placebo-controlled, double-blind study in Japanese men. BJU Int 2006;98: Randomized, placebo-controlled trial 67

69 Korean clinical practice guideline for benign prostate hyperplasia 457 patients To verify the efficacy and safety of the new alpha1a-adrenoceptor-selective antagonist silodosin compared with tamsulosin and placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) In all, 457 patients were randomized (silodosin 176, tamsulosin 192 and placebo 89). The change in the total IPSS from baseline in the silodosin, tamsulosin and placebo groups was -8.3, -6.8 and -5.3, respectively. There was a significant decrease in the IPSS vs placebo in the silodosin group from 1 week. In the early-stage comparison, silodosin showed a significant decrease in IPSS vs tamsulosin at 2 weeks. The change in QoL from baseline was -1.7, -1.4 and -1.1 in the silodosin, tamsulosin and placebo groups, respectively; silodosin showed a significant improvement in the QoL score vs placebo. In the subgroup of patients with severe symptoms (IPSS > or = 20) silodosin also gave a significantly better improvement than placebo (-12.4 vs -8.7). The incidence rates of adverse events and drug-related adverse events were, respectively, 88.6%, 82.3% and 71.6% and 69.7%, 47.4% and 36.4%, respectively. The most common adverse event in the silodosin group was abnormal ejaculation, which occurred more often in the silodosin than in the tamsulosin group (22.3% vs 1.6%). However, only five men (2.9%) discontinued treatment for abnormal ejaculation. Level of Study Garimella PS, Fink HA, Macdonald R, et al. Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. Cochrane Database Syst Rev 2009;(4):CD Systematic review 8 studies, 744 patients To evaluate the efficacy and adverse effects of naftopidil, a selective alpha-1d oral alphablocking agent for the treatment of LUTS associated with BPH Eight trials were eligible (N = 744 participants). All trials were conducted in Japan. Study duration ranged from 4 to 17 weeks. The mean age of participants was 68 years; pretreatment mean IPSS = 17.8 and mean peak urine flow (Qmax) = 9.5 ml/s (milliliters/second). No trials compared naftopidil to placebo. In 5 trials (N = 419), naftopidil in doses of 25 to 75 mg/d (milligrams/day) showed a mean IPSS improvement similar to low-dose tamsulosin (0.2 mg/d) (8.4 versus 8.9 points). Compared to a phytotherapy preparation (eviprostat), naftopidil significantly improved total IPSS (-5.9 versus 0.4; P < ). In one trial, the addition of anticholinergic drugs (oxybutynin or propiverine hydrochloride) to naftopidil did not offer any significant improvement for IPSS or Qmax in comparison to treatment with naftopidil alone. Although IPSS did not significantly differ between high- (75 mg/d) and low-dose (25 mg/d) naftopidil, high dose significantly improved Qmax compared to low dose (1.2 ml/s versus 0.2 ml/s). Adverse events reported were few, mild and similar to those seen with 0.2 mg/d tamsulosin. Level of Study Ding H, Du W, Hou ZZ, et al. Silodosin is effective for treatment of LUTS in men with BPH: a systematic review. Asian J Androl 2013;15:

70 전립선비대증진료권고안 Systematic review and Meta-analysis 4 studies, 2,504 patients To review the evidence on the efficacy and safety of silodosin treatments on lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) from randomized controlled trials At the follow-up end points, the pooled results showed that the change from baseline for the silodosin group was significantly higher than the placebo group for the IPSS, QoL score and Q(max)(mean difference (MD)=-2.78, P< ; MD=-0.42, P=0.004; MD=1.17, P< , respectively) and patients felt more satisfied with QoL related to urinary symptoms in the silodosin group than the placebo group. Ejaculation disorder was the most commonly reported adverse effect. The pooled results also showed that the silodosin group was superior to the 0.2 mg tamsulosin group with respect to the IPSS and QoL score (IPSS: MD=-1.14, P=0.02; QoL score: MD=-0.26, P=0.02) and inferior to the 0.2 mg tamsulosin group with respect to Q(max) (MD=-0.85, P=0.01). In contrast, there was no significant difference in the incidence of ejaculation disorder and dizziness between the silodosin and 0.2 mg tamsulosin groups. The current meta-analysis suggested that silodosin is an effective therapy for LUTS in men with BPH and is not inferior to 0.2 mg tamsulosin. Level of Study Rittmaster RS, Norman RW, Thomas LN, et al. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab 1996;81: Randomized, placebo-controlled trial 26 patients To determine the mechanism by which finasteride reduces prostate size The mean epithelial cell width in control prostates (mean +/- SEM, 21 +/- 0.7 microns) decreased with duration of treatment to 19 +/- 1 microns in group 1, 15 +/- 2 microns in group 2, and 8 +/- 0.3 microns in group 3. Mean duct width decreased from 135 +/- 6 microns in the control prostates to 128 +/- 10 microns in group 1, 103 +/- 3 microns in group 2, and 63 +/- 6 microns in group 3. To assess whether prostate cell death was occurring, sections were in situ end labeled for DNA breaks and immunostained for tissue transglutaminase (ttg), a marker of apoptosis (programmed cell death). The percentage of epithelial cells staining for DNA breaks was 0.4 +/- 0.2 in control prostates, 2.8 +/- 0.9 in group 1, 1.7 +/- 0.5 in group 2, and 0.7 +/- 0.3 microns in group 3. AntitTG staining of epithelial cells was graded on a scale of 0-4. In control prostates, 3 +/- 1% of the ducts were grade 3 or 4 (> 50% of epithelial cells staining). In finasteride-treated prostates, 2 +/- 2% of the prostates in group 1, 13 +/- 4% of the prostates in group 2, and 0.5 +/- 0.5% of the prostates in group 3 were grade 3-4. These results indicate that a progressive decrease in epithelial cell size and function occurs during the first several months in the prostates of men treated with finasteride. Level of Study Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335:

71 Korean clinical practice guideline for benign prostate hyperplasia Randomized, placebo-controlled trial 1,229 patients To compare the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in men with BPH The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. Level of Study Kirby R, Roehrborn CG, Boyle P, et al; Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003;61: Randomized, placebo-controlled trial 1,095 patients To evaluate the efficacy and tolerability of the selective alpha(1)-adrenergic antagonist doxazosin and the 5-alpha-reductase inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P<0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. Level of Study Andersen JT, Ekman P, Wolf H, et al. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH Study Group. Urology 1995;46: Randomized, placebo-controlled trial 707 patients To study if placebo-induced improvement in men with symptomatic benign prostatic hyperplasia (BPH) is maintained over 2 years, and to study the efficacy and safety from intervention with finasteride 5 mg for 24 months 70

72 전립선비대증진료권고안 In finasteride-treated patients the total symptom score improved throughout the study, with a significant difference between the two groups at 24 months (P < or = 0.01), whereas in placebotreated patients, there was an initial improvement in the symptom score but no change from baseline at 24 months. The maximum urinary flow rate decreased in the placebo group, but improved in the finasteride group, resulting in a between-group difference of 1.8 ml/s at 24 months (P < or = 0.01). The mean change in prostate volume was +12% in the placebo group versus -19% in the finasteride-treated group (P < 0.01). Finasteride was generally well tolerated throughout the 2-year study period. Level of Study Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomised controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ 1996;155: Randomized, placebo-controlled trial 613 patients To evaluate the efficacy and safety of 2 years' treatment of moderate benign prostatic hyperplasia (BPH) with finasteride In the efficacy analyses the mean BPH symptom scores decreased 2.1 points (from 15.8 to 13.7) in the finasteride group, as compared with a decrease of 0.7 points (from 16.6 to 15.9) in the placebo group (P < or = 0.01). The maximum urinary flow rate increased by a mean of 1.4 ml/s (from 11.1 to 12.5 ml/s) in the finasteride group, as compared with an increase of 0.3 ml/s (from 10.9 to 11.2 ml/s) in the placebo group (p < or = 0.01). The mean prostate volume decreased by 21% (from a mean volume of 44.1 cm3 at baseline) in the treatment group; it increased by 8.4% (from a mean volume of 45.8 cm3 at baseline) in the placebo group (p < or = 0.01). In the safety analysis, the proportion of patients who experienced any adverse event was similar in the two groups (81.0% in the treatment group and 81.2% in the placebo group). However, the incidence of adverse events related to sexual dysfunction were significantly higher in the finasteride group than in the placebo group (ejaculation disorder 7.7% v. 1.7% and impotence 15.8% v. 6.3%; p < or = 0.01 for both parameters). Level of Study McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338: Randomized, placebo-controlled trial 3,040 patients To evaluate the extent to which the benefit is sustained and whether finasteride reduces the incidence of related events, including the need for surgery and the development of acute urinary retention 71

73 Korean clinical practice guideline for benign prostate hyperplasia During the four-year study period, 152 of the 1,503 men in the placebo group (10 percent) and 69 of the 1,513 men in the finasteride group (5 percent) underwent surgery for benign prostatic hyperplasia (reduction in risk with finasteride, 55 percent; 95 percent confidence interval, 41 to 65 percent). Acute urinary retention developed in 99 men (7 percent) in the placebo group and 42 men (3 percent) in the finasteride group (reduction in risk with finasteride, 57 percent; 95 percent confidence interval, 40 to 69 percent). Among the men who completed the study, the mean decreases in the symptom score were 3.3 in the finasteride group and 1.3 in the placebo group (P<0.001). Treatment with finasteride also significantly improved urinary flow rates and reduced prostate volume (P<0.001). Level of Study Marberger MJ, on behalf of the PROWESS Study Group. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. Urology 1998;51: Randomized, placebo-controlled trial 3,270 patients To compare the long-term effects of finasteride (5 mg/day) and placebo in patients with moderate symptoms of benign prostatic hyperplasia (BPH) Of the 3,270 men enrolled, 3,168 contributed data to the safety analysis, and 2,902 to the efficacy evaluation. Significantly greater improvement with finasteride compared to placebo was observed at 12 and 24 months for total symptom score (mean -2.9 versus -1.9 at 12 months, P < or =0.001; -3.2 versus -1.5 at 24 months, P < or =0.001), obstructive symptom score (mean -1.9 versus -1.3 at 12 months, P < or =0.001; -2.1 versus -1.1 at 24 months, P < or =0.001), maximal urinary flow rate (mean +1.2 versus +0.6 ml/s at 12 months, P = 0.010; +1.5 versus +0.7 ml/s at 24 months, P = 0.002), and prostate volume (mean versus +5.4% at 12 months, P < or =0.01; versus +8.9% at 24 months, P < or =0.001). Greater improvements in placebo-adjusted total symptom score occurred in men with large prostates than in men with small prostates (mean -2.4 versus -1.1 at 12 months; -3.2 versus -1.3 at 24 months, placebo-adjusted data, P = 0.053). Fifteen of 1,450 men (1.0%) in the finasteride group experienced an acute urinary retention event, compared with 37 of 1,452 (2.5%) in the placebo group, and the corresponding figures for surgery were 51 of 1,450 (3.5%) and 86 of 1,452 (5.9%), respectively. The hazard rate for occurrence, computed using the log-rank statistic, decreased by 57% for acute urinary retention and by 40% for surgery accompanied by finasteride therapy compared to placebo. Level of Study McConnell JD, Roehrborn CG, Bautista O, et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Randomized, placebo-controlled trial 3,047 patients Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5alpha-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. 72

74 전립선비대증진료권고안 The risk of overall clinical progression--defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection--was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. Level of Study Roehrborn CG, Boyle P, Nickel JC, et al; ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60: Randomized, placebo-controlled trial 4,325 patients To study the efficacy and safety of dutasteride, a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II At 24 months, serum dihydrotestosterone was reduced from baseline by a mean of 90.2% (median -93.7%; P<0.001), and the total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (P<0.001). The symptom score was improved by as early as 3 months, with pooled significance from 6 months onward (P<0.001) and a reduction of 4.5 points (21.4%) at 24 months (P<0.001). The maximal flow rate improved significantly from 1 month (P<0.01), with an increase of 2.2 ml/s reported at 24 months (P<0.001). Hence, the risk reduction of acute urinary retention was 57% and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48% compared with placebo. The drug was well tolerated. Level of Study Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179: Randomized, parallel group trial 4,844 patients To investigate whether combination therapy with dutasteride and tamsulosin is more effective than either monotherapy alone for improving symptoms and long-term outcomes in men with moderate to severe lower urinary tract symptoms and prostatic enlargement (30 cc or greater) (Preplanned 2-year analyses) 73

75 Korean clinical practice guideline for benign prostate hyperplasia Combination therapy resulted in significantly greater improvements in symptoms vs dutasteride from month 3 and tamsulosin from month 9, and in benign prostatic hyperplasia related health status from months 3 and 12, respectively. There was a significantly greater improvement from baseline in peak urinary flow for combination therapy vs dutasteride and tamsulosin monotherapies from month 6. There was a significant increase in drug related adverse events with combination therapy vs monotherapies, although most did not result in the cessation of therapy. Level of Study Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombATstudy. Eur Urol 2010;57: Randomized, parallel group trial 4,844 patients To investigate whether combination therapy is more effective than either monotherapy in reducing the relative risk for acute urinary retention (AUR), BPH-related surgery, and BPH clinical progression over 4 yr in men at increased risk of progression Combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery. Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression. Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr. Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies, with the exception of an imbalance in the composite term of cardiac failure among the three study arms. The lack of placebo control is a study limitation. Level of Study Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The influence of baseline parameters on changes in International Prostate Symptom Score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and enlarged prostate: 2-year data from the CombAT Study. Eur Urol 2009;55: Randomized, parallel group trial 4,844 patients To examine the influence of baseline parameters on changes in International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Q(max)) in men with BPH receiving dutasteride, tamsulosin, or a combination of the two using 2-yr Combination of Avodart and Tamsulosin (CombAT) study data Combination therapy was more effective than either monotherapy after 24 mo in improving IPSS in all baseline subgroups, with benefit onset varying by baseline prostate volume. Combination therapy was also more effective in improving Q(max) versus tamsulosin in all subgroups and versus dutasteride in 10 of 18 subgroups. At 24 mo, dutasteride monotherapy resulted in significantly greater IPSS improvements versus tamsulosin in men with lower age, worse symptoms, worse QoL, less bother, higher BMI, greater Q(max), higher prostate volume, and higher PSA at baseline. Post hoc analyses, the lack of placebo control, and the exclusion of men with unsuccessful medical BPH treatment are study limitations. 74

76 전립선비대증진료권고안 Level of Study Roehrborn CG. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int 2008;101(Suppl.3): Systematic review 4 studies, 15,929 patients To know effects of alpha-blocker, 5ARI and combination therapy on BPH progression In selected patients, combination of an alpha(1)-blocker and a 5alpha-reductase inhibitor is the most effective form of BPH medical therapy to reduce the risk of clinical progression and relieve LUTS. Monotherapy also significantly reduces the risk of BPH clinical progression, mainly through a reduction of LUTS deterioration for alpha(1)-blockers while 5alpha-reductase inhibitors also reduce the risk of AUR and need for BPH-related surgery. Enlarged prostate and high serum prostate-specific antigen levels have been consistently found to be good clinical predictors of AUR and BPH-related surgery in longitudinal population-based studies and placebo arms of controlled studies. High post-void residual urine (PVR) is also associated with an increased risk of LUTS deterioration and should thus be reconsidered in practice as a predictor of BPH progression. Conversely, baseline LUTS severity and low peak flow rate, initially identified as predictors of unfavourable outcomes in community setting, behave paradoxically in controlled trials, probably as a consequence of strict inclusion criteria and subsequent regression to the mean and glass ceiling effects. Lastly, there is increasing evidence that dynamic variables, such as LUTS and PVR worsening, and lack of symptomatic improvement with alpha(1)-blockers are important predictors of future LUTS/BPH-related events, allowing better identification and management of patients at risk of BPH progression. Level of Study Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomised clinical trials. Urology 1996;48: Meta-analysis 6 studies, 2,601 patients Six randomized clinical trials have compared at least 1 year of 5 mg finasteride to placebo in the treatment of clinical benign prostatic hyperplasia (BPH). The findings for the 2601 men in these trials provide an opportunity to investigate the heterogeneity of the effects seen in the individual studies and to identify pretreatment predictors of outcomes as expressed by symptoms or peak urinary flow rates. The effect of finasteride treatment on improvements in total symptom severity, frequency score, and peak urinary flow rate was consistent across all six trials and similar among men with similar prostate volumes at baseline. Symptom severity improved by 1.8 points (95% confidence interval [CI], 0.7 to 2.9) in men with prostate volumes less than 20 cc (n = 72), while the improvement was 2.8 points (95% CI, 2.1 to 3.5) for men with volumes greater than 60 cc (n = 272) on the Quasi-IPSS Scale (range 0 to 30). Similarly, improvements in peak urinary flow rate ranged from 0.89 ml/s (95% CI, to 1.83) for men with prostate volumes less than 20 cc to 1.84 ml/s (95% CI, 1.37 to 2.30) in men with volumes greater than 60 cc. The difference in the magnitude of improvement between finasteride and placebo becomes significant (that is, 75

77 Korean clinical practice guideline for benign prostate hyperplasia no overlap in 95% CI) for men with a baseline prostate volume assessed by either transrectal ultrasonography or magnetic resonance imaging of greater than 40 cc, which encompasses approximately 50% of the entire population. Baseline prostate volume is a key predictor of treatment outcomes: approximately 80% of the variation in the treatment effects noted between studies could be attributed to differences in mean prostate volumes at baseline. Variation in entry criteria results in large differences in baseline symptom severity status, prostate volume, and consequently apparent inconsistencies in the overall outcomes of these trials. Level of Study Roehrborn CG, Boyle P, Bergner D, et al. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urol 1999;54: Non-randomized controlled cohort/follow-up study 3,040 patients To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. Baseline PSA and prostate volume are good predictors of long-term symptomatic and flow rate changes. Baseline PSA levels of 1.4 ng/ml or greater and enlarged prostate glands predict the best long-term response to finasteride compared with placebo. Level of Study Roehrborn CG, Lukkarinen O, Mark S, et al. Long-term sustained improvement in symptoms of benign protatic hyperplasia with the dual 5a-reductase inhibitor dutasteride: results of 4-year studies. BJU Int 2005;96: Randomized, placebo-controlled trial 4,325 patients To report additional analyses of efficacy over the initial 2 years and during a 2-year open-label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5alpha-reductase, was shown to be effective and well tolerated There was a clinically meaningful improvement in AUA-SI in patients on dutasteride in the double-blind phase, but not in those on placebo. At 48 months, patients on dutasteride in both study phases had greater improvements in AUA-SI score and individual question scores than those on dutasteride in the open-label phase only. The proportion of patients with severe symptoms declined in both study groups, although these changes were more profound in those receiving dutasteride for the 4-year duration of the study. In men with symptomatic benign prostatic hyperplasia, long-term (4-year) treatment with the dual isozyme 5alpha-reductase inhibitor dutasteride resulted in sustained and continued improvements in symptoms and flow rate. For 4 vs 2 years, longer dutasteride therapy resulted in greater symptom improvement. Level of Study 2 76

78 전립선비대증진료권고안 39. Gittelman M, Ramsdell J, Young J, et al. Dutasteride improves objective and subjective disease measures in men with benign prostatic hyperplasia and modest or severe prostateenlargement. J Urol 2006;176: Randomized, placebo-controlled trial 4,325 patients To determine whether the effect of dutasteride for benign prostatic hyperplasia is influenced by baseline prostate volume using data from 3 phase III clinical trials In patients treated with dutasteride throughout the study (dutasteride/dutasteride group) the mean reduction in prostate volume from baseline to month 48 was 30.3% in those with a baseline prostate volume of 30 to less than 40 cc and 26.2% in those with a prostate volume of 40 cc or greater. Mean improvements in peak urinary flow from baseline to month 48 were 2.7 ml per second regardless of baseline prostate volume. Improvements in the American Urological Association symptom index score were 6.3 in men with a prostate volume of 30 to less than 40 cc and 6.5 in those with a prostate volume of 40 cc or greater. No significant relationships between treatment effect and baseline prostate volume were observed for these parameters. In dutasteride/dutasteride treated patients the risk of acute urinary retention was decreased by 60% in those with a prostate volume of 30 to less than 40 cc and 55% in those with a prostate volume of 40 cc or greater vs values in placebo/dutasteride treated patients (p = and <0.001, respectively). The corresponding values for benign prostatic hyperplasia related surgery were 27% and 48% (p = 0.35 and <0.001, respectively). Level of Study Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5α-reductase inhibitors for the enlarged prostate. Clin Ther 2007;29: Systematic review Not specified in detail To review the natural history of enlarged prostate and the data supporting management of this condition with alpha-blocker and 5ARI therapy, either as monotherapy or combination therapy, for symptomatic relief and a reduction in long-term disease progression Clinical trials of alpha-blockers in men with enlarged prostate have reported improvements in total symptom scores of 10% to 20% compared with placebo; however, these agents were not shown to reduce the risk of long-term complications or disease progression. Studies of the 5ARIs have reported significant reductions compared with placebo in the relative risk for AUR and enlarged prostate-related surgery, slowing of disease progression, and relief of symptoms. In studies of dutasteride, improvements in symptom scores were greater after 4 years of therapy compared with 2 years (-6.4 vs -4.3 points, respectively) and flow rates were better (2.6 vs 2.3 ml/sec). Six-year data for finasteride showed maintenance of the decreased risk for AUR and enlarged prostate-related surgery. Use of combination therapy with an alpha-blocker and a 5ARI may be of benefit in patients who require immediate relief of symptoms, with discontinuation of the alpha-blocker after several months of therapy. 5ARIs were generally well tolerated, with sexual dysfunction the most frequently reported adverse effect, although in only a small proportion of men (1-8%). Level of Study 1 77

79 Korean clinical practice guideline for benign prostate hyperplasia 41. Chung BH, Hong SJ, Cho JS, Seong DH. Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: a multicentre study. BJU Int 2006;97: Non-randomized controlled cohort/follow-up study 5,716 patients To evaluate the relationship between prostate specific antigen (PSA) and prostate volume (PV) in Korean men, as PV is a key predictor of both disease progression and response to medical therapy in patients with benign prostatic hyperplasia (BPH), and PSA has been suggested as a proxy marker to estimate the total PV, mainly in Caucasians. The PSA-PV relationship in Korean men is similar to that in Caucasians, but Korean men have a slightly lower PSA level and a smaller PV than Caucasians. The approximate age-specific criteria for detecting Korean men with a PV of >40 ml were a PSA level of >1.3 ng/ml, >1.7 ng/ ml and >2.0 ng/ml for men with BPH in their sixth, seventh and eighth decade, respectively. Level of Study Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 2005;174: Open label, prospective study 43 patients To determine the efficacy and tolerability of tolterodine extended release (ER) in men with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) in whom previous alpha-blocker therapy had failed A total of 39 men (91%) with a mean age of 61 years completed the 6-month trial. Mean 24- hour micturition frequency decreased from 9.8 to 6.3 voids and nocturia decreased from 4.1 to 2.9 episodes nightly. Significant changes in mean American Urological Association symptom scores (-6.1), the peak urinary flow rate (1.9 ml per second) and post-void residual volume (-22 ml) were also observed. Of the men 27 (63%) were potent at baseline and 29 (67%) were potent after 6 months of tolterodine ER treatment. Mean International Index of Erectile Function erectile function domain scores increased (6.9). Four men (9%) discontinued therapy because of intolerable dry mouth. There were no reports of urinary retention. Level of Study Höfner K, Burkart M, Jacob G, et al. Safety and efficacy of tolertodine extended release in men with overactive bladder symptoms and presumed non-obstructive benign prostatic hyperplasia. World J Urol 2007;25: Prospective, observational non-interventional study 741 patients To generate real-life efficacy and safety data in patients with presumed non-obstructive BPH (Q (max)>or= 15 ml/s) treated with tolterodine ER 4 mg/day for OAB symptoms, alone or added to unsuccessful alpha-blocker treatment of >or=6 weeks duration 78

80 전립선비대증진료권고안 Mean PVR did not increase (25.4 +/ vs / ml at baseline). AUR requiring catheterization occurred in two patients, acute UTI in four patients. Median IPSS total scores decreased from 17 to 10, IPSS QoL scores from 4 to 2, OAB-q symptom bother scores from 50.0 to 22.5 and OAB-q HRQL scores increased from 59.2 to In men with OAB symptoms and presumed non-obstructive BPH, tolterodine ER provided considerable symptomatic and QoL improvements with a low risk of AUR, acute UTI, or increased PVR. Level of Study Kaplan SA, Roehrborn CG, Chancellor M, et al. Extended-release tolterodine with or without tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score. BJU Int 2008;102: Randomized, placebo-controlled trial 851 patients To evaluate the efficacy of tolterodine extended-release (ER) plus tamsulosin on lower urinary tract symptoms (LUTS) as assessed by changes in the International Prostate Symptom Score (IPSS) in men who met symptom entry criteria for both overactive bladder (OAB) and benign prostatic hyperplasia (BPH) trials receiving tolterodine ER + tamsulosin had significantly greater improvements than those taking placebo on IPSS storage subscale scores and scores for all three individual storage items included on the IPSS (urinary frequency, urgency, and nocturnal micturitions) by 12 weeks. Storage subscale and urgency scores were significantly improved vs placebo at 1 and 6 weeks, whereas frequency scores were significantly improved at 6 weeks. Changes in IPSS storage subscale and individual storage item scores in the tolterodine ER and tamsulosin monotherapy groups were not significantly different from placebo at most time points. IPSS voiding subscale scores and scores for three of four individual voiding items (sensation of incomplete emptying, intermittency, and weak stream) were significantly improved by 12 weeks for patients receiving tamsulosin monotherapy vs placebo. Voiding subscale and intermittency scores were significantly improved vs placebo at 1 week; weak stream scores were significantly improved at 1 and 6 weeks. The IPSS voiding subscale and individual voiding item scores in the tolterodine ER + tamsulosin and tolterodine ER groups were not significantly different from placebo at most time points. Level of Study Kaplan SA, Roehrborn CG, Dmochowski R, et al. Tolterodine extended release improves overactive bladder symptoms in men with overactive bladder and nocturia. Urology 2006;68: Post-hoc analysis of data from randomized, placebo-controlled trial 745 patients To evaluate the efficacy and safety of nighttime dosing with tolterodine extended release (TER) in men with overactive bladder (OAB) and nocturia 79

81 Korean clinical practice guideline for benign prostate hyperplasia A total of 745 men (mean age 64 years) were randomized to placebo (n = 374) or TER (n = 371). Of the 745 men, 73% reported no incontinence episodes in a 7-day diary at baseline. At week 12, the weekly values for nighttime severe OAB micturitions and 24-hour and daytime total, OAB, and severe OAB micturitions were significantly reduced in the TER group versus the placebo group. The TER-treated men also reported a significant reduction in the mean urgency rating versus placebo. Adverse events associated with TER were low and comparable to those in the placebo group, with the exception of dry mouth (11% versus 4%). Withdrawals because of adverse events were infrequent (3% TER, 4% placebo). Five men were withdrawn for symptoms suggestive of urinary retention (3 TER, 2 placebo). Level of Study Dmochowski R, Abrams P, Marschall-Kehrel D, et al. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urol 2007;51: Post-hoc analysis of data from randomized, placebo-controlled trial 1,698 patients To evaluate the efficacy and tolerability of tolterodine extended release (ER) in men and women with overactive bladder (OAB) At baseline, 73% (547 of 745) of men and 57% (539 of 953) of women were continent. By week 12, tolterodine ER (n=848) reduced OAB and severe OAB micturitions during 24-h, daytime, and nocturnal intervals in both sexes compared with placebo (n=850). Adverse event rates were low and similar across treatment and gender. Level of Study Abrams P, Kaplan S, De Koning Gans HJ, et al. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006;175: Randomized, placebo-controlled trial 222 patients To evaluate the safety of tolterodine vs placebo in men with OAB and BOO Median treatment differences in Qmax (-0.7 ml per second, 95% CI -1.6 to 0.4) and pdetqmax (-7 cm H2O, 95% CI -3 to 11) were comparable. Tolterodine significantly reduced the BOOI vs placebo (-9 vs 0, p < 0.02). There were significant treatment differences in volume to first detrusor contraction (+59 ml, 95% CI ) and maximum cystometric capacity (+67 ml, 95% CI ), favoring tolterodine over placebo (p < 0.003). Change in PVR was significantly greater among patients treated with tolterodine (+25 ml) than placebo (0 ml, p < 0.004). There were no significant between-group differences in the incidence of adverse events. Urinary retention was reported by 1 patient treated with placebo. Level of Study Kaplan SA, Roehrborn CG, Rovner ES, et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 2006;296:

82 전립선비대증진료권고안 Randomized, placebo-controlled trial 879 patients To evaluate the efficacy and safety of tolterodine extended release (ER), tamsulosin, or both in men who met research criteria for both overactive bladder and benign prostatic hyperplasia A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (P<.001), 146 (71%) receiving tamsulosin (P=.06 vs placebo), or 135 (65%) receiving tolterodine ER (P=.48 vs placebo). receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (-0.88 vs -0.31, P=.005), urgency episodes without incontinence (-3.33 vs -2.54, P=.03), micturitions per 24 hours (-2.54 vs -1.41, P<.001), and micturitions per night (-0.59 vs -0.39, P.02). receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (-8.02 vs placebo, -6.19, P=.003) and QOL item (-1.61 vs -1.17, P=.003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%). Level of Study Disantostefano RL, Biddle AK, Lavelle JP. An evaluation of the economic costs and patientrelated consequences of treatments for benign prostatic hyperplasia. BJU Int 2006;97: Decision analysis using published data including systematic reviews Not specified in detail To compare the costs and effectiveness of treatments for benign prostatic hyperplasia (BPH), including watchful waiting, pharmaceuticals (alpha-blockers, 5-alpha-reductase inhibitors, combined therapy), transurethral microwave thermotherapy (TUMT), and transurethral resection of the prostate (TURP) What is the 'best' treatment depends on the value that an individual and society place on costs and consequences. Alpha-blockers are less expensive than the alternatives, and are effective at relieving patient-reported symptoms. Unfortunately, they have little effect on clinical outcomes and have the highest BPH progression rate. Other treatments have lower disease progression and better clinical outcomes, but are more expensive and entail more invasive treatments, and/ or more uncertainty. Treatment decisions are made using a variety of information, including the cost and consequences of treatment. The best treatment depends on the patient's preference and the outcome considered most important. alpha-blockers are very effective at treating urinary symptoms but do not improve clinical outcomes, including disease progression, relative to other treatments. TURP remains the 'gold standard' for surgical procedures. The desire to avoid TURP or the 2 weeks of catheterization associated with TUMT might affect a patient's treatment decision when symptoms are severe. Therefore, more information about patient preferences and risk aversion is needed to inform treatment decision-making for BPH. Level of Study 2 81

83 Korean clinical practice guideline for benign prostate hyperplasia 참고문헌 1. Djavan B, Chapple C, Milani S, et al. State of the art on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 2004;64: McConnell JD, Roehrborn CG, Bautista O, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Jardin A, Bensadoun H, Delauche-Cavallier MC, et al. Alfuzosin for treatment of benign prostatic hypertrophy. The BPH-ALF Group. Lancet 1991;337: Buzelin JM, Roth S, Geffriaud-Ricouard C, et al. Efficacy and safety of sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. ALGEBI Study Group. Eur Urol 1997;31: van Kerrebroeck P, Jardin A, Laval KU, et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus afluzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol 2000;37: MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 2005;66: Kirby RS, Andersen M, Gratzke P, et al. A combined analysis of double-blind trials of the efficacy and tolerability of doxazosingastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int 2001;87: Chapple CR, Wyndaele JJ, Nordling J, et al. Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A metaanalysis of two randomised, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group. Eur Urol 1996;29: Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 1998;51: Wilt TJ, Mac Donold R, Rutks I. Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2003;(1):CD Brawer MK, Adams G, Epstein H. Terazosin in the treatment of benign prostatic hyperplasia. Terazosin Benign Prostatic Hyperplasia Study Group. Arch Fam Med 1993;2: Roehrborn CG, Oesterling JE, Auerbach S, et al. The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator Group. Urology 1996;47: Wilt TJ, Howe RW, Rutks I, et al. Terazosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002;(4):CD Michel MC, Mehlburger L, Bressel HU, et al. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prost Dis 1998;1: Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related safety profile and efficacy of a-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract 2008;62: Barendrecht MM, Koopmans RP, de la Rosette JJ, et al. Treatment for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: the cardiovascular system. BJU Int 2005;95(Suppl.4): Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg 2005;31: Michel MC, Okutsu H, Noguchi Y, et al. In vivo studies on the effects of a1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits. Naunyn-Schmiedeberg s Arch Pharmacol 2006;372: van Dijk MM, de la Rosette JJ, Michel MC. Effects of a1-adrenoceptor antagonists on male sexual function. Drugs 2006;66:

84 전립선비대증진료권고안 20. Kawabe K, Yoshida M, Homma Y; Silodosin Clinical Study Group. Silodosin, a new a1a-adrenoceptorselective antagonist for treating benign prostatic hyperplasia: a results of a phase III randomised, placebo-controlled, double-blind study in Japanese men. BJU Int 2006;98: Garimella PS, Fink HA, Macdonald R, et al. Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. Cochrane Database Syst Rev 2009;(4):CD Ding H, Du W, Hou ZZ, et al. Silodosin is effective for treatment of LUTS in men with BPH: a systematic review. Asian J Androl 2013;15: Rittmaster RS, Norman RW, Thomas LN, et al. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab 1996;81: Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335: Kirby R, Roehrborn CG, Boyle P, et al; Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003;61: Andersen JT, Ekman P, Wolf H, et al. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebocontrolled study. The Scandinavian BPH Study Group. Urology 1995;46: Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomised controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ 1996;155: McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338: Marberger MJ, on behalf of the PROWESS Study Group. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. Urology 1998;51: McConnell JD, Roehrborn CG, Bautista O, et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The longterm effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Roehrborn CG, Boyle P, Nickel JC, et al; ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60: Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179: Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombATstudy. Eur Urol 2010;57: Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The influence of baseline parameters on changes in International Prostate Symptom Score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and enlarged prostate: 2-year data from the CombAT Study. Eur Urol 2009;55: Roehrborn CG. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int 2008;101(Suppl.3): Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomised clinical trials. Urology 1996;48:

85 Korean clinical practice guideline for benign prostate hyperplasia 37. Roehrborn CG, Boyle P, Bergner D, et al. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urol 1999;54: Roehrborn CG, Lukkarinen O, Mark S, et al. Long-term sustained improvement in symptoms of benign protatic hyperplasia with the dual 5a-reductase inhibitor dutasteride: results of 4-year studies. BJU Int 2005;96: Gittelman M, Ramsdell J, Young J, et al. Dutasteride improves objective and subjective disease measures in men with benign prostatic hyperplasia and modest or severe prostateenlargement. J Urol 2006;176: Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5α-reductase inhibitors for the enlarged prostate. Clin Ther 2007;29: Chung BH, Hong SJ, Cho JS, Seong DH. Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: a multicentre study. BJU Int 2006;97: Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol. 2005;174: Höfner K, Burkart M, Jacob G, et al. Safety and efficacy of tolertodine extended release in men with overactive bladder symptoms and presumed non-obstructive benign prostatic hyperplasia. World J Urol 2007;25: Kaplan SA, Roehrborn CG, Chancellor M, et al. Extended-release tolterodine with or without tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score. BJU Int 2008;102: Kaplan SA, Roehrborn CG, Dmochowski R, et al. Tolterodine extended release improves overactive bladder symptoms in men with overactive bladder and nocturia. Urology 2006;68: Dmochowski R, Abrams P, Marschall-Kehrel D, et al. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urol 2007;51: Abrams P, Kaplan S, De Koning Gans HJ, et al. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006;175: Kaplan SA, Roehrborn CG, Rovner ES, et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 2006;296: Disantostefano RL, Biddle AK, Lavelle JP. An evaluation of the economic costs and patient-related consequences of treatments for benign prostatic hyperplasia. BJU Int 2006;97:

86 전립선비대증진료권고안 KQ 8. 전립선비대증환자에서병용요법이알파차단제단독사용보다치료효과를 높일수있는가? 권고사항권고수준근거수준 8-1. 전립선비대증환자에서알파차단제와 5α 환원효소억제제병용요법은알파 차단제단독요법보다하부요로증상완화에효과적인치료방법이다. Strong A 8-2. 알파차단제와항콜린제병용요법은중등도이상의하부요로증상을가진 환자에서알파차단제단독요법의효과가불충분할경우에시행한다. Strong A 8-3 알파차단제와항콜린제병용요법은배뇨후잔뇨량이많고방광출구폐색이 의심되는남성에서는신중하게시행한다. Strong A 8-4. PDE5 억제제와알파차단제의병용투여는중등도이상의하부요로증상을 감소시키는데있어알파차단제단독요법보다효과적이다. Weak A α 환원효소억제제병용요법 전립선비대증환자에서알파차단제와 5α환원효소억제제의병용요법은전립선비대의성장을억제하는 5α환원효소억제제의효과와방광경부와전립선요도의평활근을이완하는알파차단제의효과를이중으로얻을수있는이상적인치료법이다. 알파차단제 (terazosin doxazosin, alfuzosin, tamsulosin, silodosin, naftopidil) 는수시간에서수일내에하부요로증상완화효과를나타내고, 5α환원효소억제제 (finasteride, dutasteride) 는의미있는임상효과를나타내는데수개월이필요하다. 두약물의병용요법에대한장기추적연구에서는병용요법이알파차단제단독요법이나 5α환원효소억제제단독요법보다증상감소및최고요속개선에있어서효과적이었고, 급성요폐및수술의필요성감소에서는알파차단제단독요법보다우월하였다. Finasteride 와알파차단제의병용요법의효과를알아보기위한 MTOPS (medical therapy of prostatic symptoms) 연구에서전립선비대증의임상적진행에대한위약, doxazosin, finasteride 단독요법, 병용요법의효과를비교하기위하여남성 3,047 명을대상으로장기이중맹검연구를하였다. 전반적인전립선비대증진행가능성은위약에비해 66% 감소하여 doxazosin (39% 감 85

87 Korean clinical practice guideline for benign prostate hyperplasia 소 ) 과 finasteride (34% 감소 ) 에비해유의하게감소하였다. 급성요폐발생과수술적치료의빈도는병용요법과 finasteride 단독요법에서는유의하게감소하였다. CombAT (Combination of Avodart and Tamsulosin) 연구는병용요법이증상개선및 Qmax 관점에서치료시작 9개월째부터각각의단독요법보다우월하고급성요폐및수술의필요성감소측면에선 8개월째부터알파차단제보다우월함을보였다 [1,2]. 병용요법은전체임상적진행 ( 적어도 4점이상의 IPSS 증가, 급성요폐, 요로감염, 요실금, 또는기저치대비 50% 이상의혈청크레아티닌의증가 ) 을억제하는데있어 MTOPS 및 CombAT 연구에서단독요법보다우월하였다. 5α환원효소억제제와알파차단제병용요법은최소한 1년이상의기간을유지해야효과가나타날수있고규칙적인전립선특이항원확인이필요하였다. SMART-1 연구 (Symptom Management after Reducing Therapy Study) 는 24주간 dutasteride 와 tamsulosin 병용요법후 tamsulosin 을중단하였을때증상개선효과가유지될수있는지알아보기위해진행되었다. 주관적증상은 30주째에서병용요법군의 9%, 단독요법군의 23% 에서악화되었고, 36주째에는각각 4%, 7% 에서악화되어, 알파차단제를중단한후에는증상이악화될수있으나장기간사용하면개선될수있다고보고하였다 [3]. 알파차단제단독요법과알파차단제와 5α환원효소억제제의병용요법의메타분석비교를보면단독요법에대한병용요법의 mean difference 가 IPSS는 (95% 신뢰구간 ) 로단독요법보다병용요법이증상개선에효과적이었으나통계적인유의성은없었고, 최고요속 (Q-max) 의 mean difference 는 0.88 (95% 신뢰구간 ) 로최고요속의개선폭이단독요법보다병용요법이더컸으며통계적유의성도확인하였다. 문헌고찰과메타분석결과를토대로보았을때, 알파차단제와 5α환원효소억제제의병용요법은단독요법에비하여전립선비대증의진행을효과적으로예방하며증상개선에나은효능을보였다. 86

88 전립선비대증진료권고안 그림 8-1. 알파차단제단독요법군과알파차단제와 5α 환원효소억제제의병용요법군에서효과에대한숲그림 (forest plot) (A) IPSS Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI finasteride Debruyne FM % 0.20 [-0.45, 0.85] Kirby R 2003a % [-0.93, 0.53] Lepor H % [-0.76, 0.56] McConnell JD 2003a % [-1.55, -0.65] Subtotal (95% CI) % [-0.98, 0.31] Heterogeneity: Tau z = 0.33; Chi z = 13.38, df = 3 (P = 0.004); I z = 78% Test for overall effect: Z = 1.00 (P = 0.32) dutasteride Roehrborn CG 2010a % [-1.36, -0.64] Subtotal (95% CI) % [-1.36, -0.64] Heterogeneity: Not applicable Test for overall effect: Z = 5.45 (P < ) Total (95% CI) % [-1.01, 0.02] Heterogeneity: Tau z = 0.26; Chi Z = 18.10, df = 4 (P = 0.001); I Z = 78% Test for overall effect: Z = 1.88 (P = 0.06) Test for subgroup differences: Chi Z = df = 1 (P = 0.08). I Z = 68.2% Favours [experimental] Favours [control] (B) Q-max Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI finasteride Debruyne FM % 0.40 [-0.05, 0.85] Kirby R 2003a % 0.50 [-0.13, 1.13] Lepor H % 0.50 [0.18, 0.82] McConnell JD 2003a % 1.20 [1.01, 1.39] Subtotal (95% CI) % 0.68 [0.20, 1.16] Heterogeneity: Tau Z = 0.19; Chi Z = 21.15, df = 3 (P < ); I Z = 86% Test for overall effect: Z = 2.79 (P = 0.005) dutasteride Roehrborn CG 2010a % 1.60 [1.42, 1.78] Subtotal (95% CI) % 1.60 [1.42, 1.78] Heterogeneity: Not applicable Test for overall effect: Z = (P < ) Total (95% CI) % 0.88 [0.40, 1.35] Heterogeneity: Tau Z = 0.26; Chi Z = 53.71, df = 4 (P < ); I Z = 93% Test for overall effect: Z = 3.62 (P = ) Test for subgroup differences: Chi Z = df = 1 (P = ). I Z = 92.0% Favours [experimental] Favours [control] Debruyne FM 1998 [5], Kirby R 2003a [6], Lepor H 1996 [4], McConnell JD 2003a [1], Roehrborn CG 2010a [2] 87

89 Korean clinical practice guideline for benign prostate hyperplasia 근거표 KQ 8-1 Treatment (daily dose) Change in Change Level (n) symptoms in Qmax of (% IPSS) (ml/s) Study Lepor et al. (1996) randomized controlled trial Placebo Terazocin Finasteride Terazocin 1 x 10mg + Finasteride 1 x 5mg a -37.7a,b,d -19.8a -39a, b,d b,d b,d 2 Debruyne et al. (1998) randomized controlled trial Alfuzosin 2 x 5 mg Finasteride 1 x 5 mg Alfuzosin 2 x 5 mg + finasteride 1 x 5 mg d d Kirby et al. (2003) randomized controlled trial Placebo Doxazosin 1 x 1-8 mg Finasteride 1 x 5 mg Doxazosin 1 x 1-8 mg + finasteride 1 x 5 mg b,d b,d b,d d 2 McConnell et al. (2003) randomized controlled trial Placebo Doxazosin 1 x 1-8 mg Finasteride 1 x 5 mg Doxazosin 1 x 1-8 mg + finasteride 1 x 5 mg a -35.3a,b,d -28.4a,b -41.7a,b,c,d +1.4a +2.5a,b +2.2a,b +3.7a,b,c,d 2 Roehrborn et al. (2008) randomized controlled trial Tamsulosin 1 x 0.4 mg Dutasteride 1 x 0.5 mg Tamsulosin 1 x 0.4 mg + dutasteride 1 x 0.5 mg c,d c,d 2 Roehrborn et al. (2010) randomized controlled trial Tamsulosin 1 x 0.4 mg Dutasteride 1 x 0.5 mg Tamsulosin 1 x 0.4 mg + dutasteride 1 x 0.5 mg c,d c 2 참고문헌 1. McConnell JD, Roehrborn CG, Bautista O, et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The longterm effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010;57: Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S, vanvierssen Trip OB. Alpha-blocker therapy can be withdrawn inthe majority of men following initial combination therapy withthe dual 5alpha-reductase inhibitor dutasteride. Eur Urol 2003;44:

90 전립선비대증진료권고안 4. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335: Debruyne FM, Jardin A, Colloi D, et al; on behalf of the European ALFIN Study Group. Sustained release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol 1998;34: Kirby R, Roehrborn CG, Boyle P, et al; Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003;61: 항콜린제병용요법전립선비대증환자는일반적으로많은비율에서과민성방광증상을동반하게된다. 전립선비대증으로인한폐색이존재하는경우 50-75% 에서과민성방광이동반되며, 폐색을치료한후에도과민성방광이 38% 정도에서보이는것으로알려져있다 [1]. 일반적으로연령이증가할수록전립선비대에의한폐색의발생률이증가하고과민성방광이동반되는경우도증가하게되는데전립선비대증으로인한하부요로폐색이심할수록과민성방광의발생률도비례하여증가한다. 실제로환자에게빈뇨, 요절박과같은자극증상이폐색증상보다더큰괴로움을준다고알려져있고, 치료시이러한점들을충분히감안하여야한다. 과민성방광을동반한전립선비대증의경우알파차단제만으로는증상개선에한계가있으며이러한과민성방광으로인한자극증상을치료하기위하여항콜린제 (anti-cholinergic agent) 를사용할수있다. 항콜린제는불수의적방광수축을보이는환자에서방광수축이일어날때최초방광용적을증가시키고, 수축력을감소시키며, 최대방광용량을증가시킨다. 그러므로요절박, 절박성요실금등의증상을보이는과민성방광의치료에항콜린제가주로사용되고있으며, 현재임상적으로그약효가증명된항콜린제는 darifencacin, fesoterodine, Imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine 그리고 trospium chloride 이다. 전립선비대증에서알파차단제와항콜린제의병용요법은주로알파차단제를사용한환자에서지속적으로남아있는자극증상의호전을위해선택적으로사용되는경우가많았다. 이러한병용요법은알파차단제또는위약단독요법과비교하여절박뇨뿐만아니라절박성요실금에피소드를유의하게감소시키며, 삶의질을증가시켰다 [2]. 여러임상시험에서알파차단제로치료하는동안하부요로증상이지속되는환자를대상으로기존의알파차단제에항콜린제를추가하여병용요법의효능을평가하였다. 병용요법군에서전반 89

91 Korean clinical practice guideline for benign prostate hyperplasia 적인증상개선정도는혈청전립선특이항원농도에관계없이위약군보다유의하게높은반면, tolterodine 단독요법은전립선특이항원농도가 1.3 ng/ml 미만인환자에서주로증상을개선하였다 [3]. 또한관련된임상시험에서지속되는대부분하부요로증상이배뇨근과활동과관련된경우에있어서항콜린제의추가에의해서의미있게감소될수있음을보여주었다 [4-6]. Medline, EMbase, Cochrane, KoreaMed 에서검색식을적용하여검색하였을때, 총 573 개의문헌이검색되고, 중복배제후기간을 1990년 1월 1일부터 2014 년 7월 1일로제한하였을때, 430 개의문헌이추출되었고, 이중관련논문인총 13개의문헌을근거로사용하였다. 단독요법과병용요법의증상개선비교결과를보면병용요법의 mean difference 가 IPSS는 (95% 신뢰구간 ) 정도로증상개선에좀더효과적이었으며통계적으로유의하였다. 최대요속은병용요법군이알파차단제단독요법군에비해 mean difference (95% 신뢰구간 ) 로수치상감소된효과를보이지만통계적으로유의하지는않았다. 각군에포함된연구결과의이질성은없어보이며또한약제에따라일부효과의차이가있어보이지만약제각각에포함된연구의수가많지않아약제에따른약효의차이를결론내리기는어려웠다. 문헌고찰과메타분석결과를토대로보았을때, 알파차단제와항콜린제의병용요법은임상적으로알파차단제요법에비하여미비하게최고요속을감소시킬수있으나의미있는감소는아니며증상개선측면에서유의한우위를보여주었다. 결론적으로임상적으로중등도이상에서, 특히자극증상을주로호소하는환자의경우병용요법의유효성과안정성이증명되었다. 다만남성에서방광출구폐색이있는경우에는항콜린제로인한요폐색의합병증을증가시킬수있으므로주의가필요하다 [7]. 90

92 전립선비대증진료권고안 그림 8-2. 알파차단제단독요법군과알파차단제와항콜린제의병용요법군에서효과에대한숲그림 (forest plot) (A) IPSS Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI tolterodine Athanasopoulos % [-5.64, -2.36] Gan % [-2.66, -1.74] Mohanty % [-3.71, -2.29] Wu % 0.70 [-2.04, 3.44] Yang % [-5.57, -2.03] Subtotal (95% CI) % [-3.64, -1.79] Heterogeneity: Tau Z =0.65; Chi Z =14.05, df=4 (P = 0.007); I Z = 72% Test for overall effect: Z = 5.76 (P < ) solifenacin GAO Zhong-wei. 2014_moderater % 1.20 [0.14, 2.26] Kerrebroeck % 0.00 [-1.13, 1.13] Seo % 1.57 [-1.74, 4.88] Yamaguchi % 0.00 [-0.85, 0.85] Subtotal (95% CI) % 0.42 [-0.27, 1.10] Heterogeneity: Tau Z = 0.12; Chi Z = 3.99, df = 3 (P = 0.26); I Z = 25% Test for overall effect: Z = 1.19 (P = 0.23) propiverine Lee % [-2.10, 1.90] Subtotal (95% CI) % [-2.10, 1.90] Heterogeneity: Not applicable Test for overall effect: Z = 0.10 (P = 0.92) festoterodine Konstantinidis % [-2.641, -0.76] Subtotal (95% CI) % [-2.641, -0.76] Heterogeneity: Not applicable Test for overall effect: Z = 3.55 (P = ) oxybutynin MacDiarmdi % [-2.93, -0.47] Subtotal (95% CI) % [-2.93, -0.47] Heterogeneity: Not applicable Test for overall effect: Z = 2.71 (P = 0.007) Total (95% CI) % [-2.16, -0.32] Heterogeneity: Tau Z = 2.06; Chi Z = 92.06, df = 11 (P < ); I Z = 88% Test for overall effect: Z = 2.65 (P = 0.008) Test for subgroup differences: Chi Z = 33.79; df = 4 (P < ); I Z = 88.2% Favours [experimental] Favours [control] Athanasopoulos [4], Gan [15], Mohanty [11], Wu [12], Yang [6], GAO Zhong-wei. 2014_moderater [18], Kerrebroeck 2013 [17], Seo [14], Yamaguchi [13], Lee [8], Konstantinidis [16], MacDiarmdi [10] 91

93 Korean clinical practice guideline for benign prostate hyperplasia (B) Q-max Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI tolterodine Athanasopoulos % 0.16 [-0.29, 0.61] Chapple % [-2.38, 0.38] Gan % 0.10 [-0.36, 0.56] Mohanty % [-1.10, -0.10] Wu % [-3.36, 1.76] Yang % 0.10 [-1.14, 1.34] Subtotal (95% CI) % [-0.52, 0.21] Heterogeneity: Tau Z = 0.07; Chi Z = 7.80, df = 5 (P = 0.17); I Z = 36% Test for overall effect: Z = 0.82 (P = 0.41) solifenacin GAO Zhong-wei. 2014_mild % [-2.05, -0.55] GAO Zhong-wei. 2014_moderater % [ ] Seo % [-3.68, 1.18] Yamaguchi % 1.10 [-0.91, 3.11] Subtotal (95% CI) % [-1.56, 0.29] Heterogeneity: Tau Z = 0.40; Chi Z = 5.80, df = 3 (P = 0.12); I Z = 48% Test for overall effect: Z = 1.34 (P = 0.18) propiverine Lee % [-2.05, 0.65] Subtotal (95% CI) % [-2.05, 0.65] Heterogeneity: Not applicable Test for overall effect: Z = 1.01 (P = 0.31) festoterodine Konstantinidis % 0.40 [-0.19, 0.99] Subtotal (95% CI) % 0.40 [-0.19, 0.99] Heterogeneity: Not applicable Test for overall effect: Z = 1.32 (P = 0.19) oxybutynin MacDiarmdi % [-1.39, 0.79] Subtotal (95% CI) % [-1.39, 0.79] Heterogeneity: Not applicable Test for overall effect: Z = 0.54 (P = 0.59) Total (95% CI) % [-0.60, 0.09] Heterogeneity: Tau Z = 0.16; Chi Z = 23.31, df = 12 (P = 0.03); I Z = 49% Test for overall effect: Z = 1.47 (P = 0.14) Test for subgroup differences: Chi Z = 4.98; df = 4 (P = 0.29); I Z = 19.6% Favours [experimental] Favours [control] 92

94 전립선비대증진료권고안 근거표 KQ 8-2 Treatment (daily dose) Athanasopoulos et al. (2003) Lee et al. (2005) Yang et al. (2007) Chapple et al. (2008) MacDiarmid et al. (2008) Mohanty et al. (2009) Wu et al. (2009) Yamaguchi et al. (2011) Seo. et al. (2011) Gan et al. (2011) Konstantinidis et al. (2012) Kerrebroeck. (2013) GAO Zhong- wei et al. (2014) randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial randomized controlled trial Tamsulosin Tamsulosin + tolterodine Doxazosin Doxazosin + propiverine Terazosin Terazosin + tolterodine Tamsulosin Tamsulosin + tolterodine Tamsulosin Tamsulosin + oxybutynin Tamsulosin Tamsulosin + tolterodine Tamsulosin Tamsulosin + tolterodine Tamsulosin Tamsulosin + solifenacin Tamsulosin Tamsulosin + solifenacin Doxazosin Doxazosin + tolterodine Tamsulosin Tamsulosin + fesoterodine Tamsulosin Tamsulosin + solifenacin Tamsulosin Tamsulosin + solifenacin (n) Change in symptoms (% IPSS) Change in Qmax (ml/s) 참고문헌 1. Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchuelz A. The pharmacokinetics of oxybutynin in man. Eur J Clin Pharmacol 1988;35: Kaplan SA, Roehrborn CG, Rovner ES, et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder. JAMA 2006;296: Roehrborn CG, Kaplan SA, Kraus SR, et al. Effects of serum PSA on efficacy of tolterodine extended release with or without tamsulosin in men with LUTS, including OAB. Urology 2008;72:

95 Korean clinical practice guideline for benign prostate hyperplasia 4. Athanasopoulols A, Gyftopoulos K, Giannitsas K, et al. Combination treatment with an a-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomised, controlled study. J Urol 2003;169: Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 2005;174: Yang Y, Zhao SF, Li HZ, et al. Efficacy and safety of combined therapy with terazosin and tolterodine for patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective study. Chin Med J 2007;120: Hao N, Tian Y, Liu W, Wazir R, Wang J, Liu L, et al. Antimuscarinics and α-blockers or α-blockers monotherapy on lower urinary tract symptoms--a meta-analysis.urology 2014;83: Lee KS, Choo MS, Kim DY, et al. Combination treatment withpropiverine hydrochloride plus doxazosin controlled release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign prostatic obstruction: a prospective, randomized, controlled multicenter study. J Urol 2005;174: Chapple C, Herschorn S, Abrams P, et al. Tolterodine treatmentimproves storage symptoms suggestive of overactive bladder in men treated with alpha-blockers. Eur Urol 2009;56: MacDiarmid SA, Peters KM, Chen A, et al. Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc 2008;83: Mohanty NK, Kumar A, Jain M, et al. Efficacy and safety of an alpha-blocker with and without anticholinergic agent in the management of lower urinary tract symptoms with detrusor overactivity. Urotoday Int J 2009; Wu ZL, Geng H. Combination of tolterodine and tamsulosin for benign prostatic hyperplasia. Zhonghua Nan Ke Xue 2009;15: Yamaguchi O, Kakizaki H, Homma Y, et al. Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms-assist, randomized controlled study. Urology 2011;78: Seo DH, Kam SC, Hyun JS. Impact of lower urinary tract symptoms/benign prostatic hyperplasia treatment with tamsulosin and solifenacin combination therapy on erectile function. Korean J Urol 2011;52: Gan W, Zhang SF, Jia HT, et al. Tolterodine tartrate combined with alpha-receptor blocker for benign prostatic hyperplasia with detrusor overactivity. Zhonghua Nan Ke Xue 2011;17: Konstantinidis C, Samarinas M, Andreadakis S, Xanthis S, Skriapas K. Lowerurinary tract symptoms associated with benign prostatic hyperplasia: combined treatment with fesoterodine fumarate extended-release and tamsulosin a prospective study. Urol Int 2013;90: Van Kerrebroeck P, Haab F, Angulo JC, Vik V, Katona F, Garcia-Hernandez A, et al. Efficacy and safety of solifenacin plus tamsulosin OCAS in men with voiding and storage lower urinary tract symptoms: results from a phase 2, dose-finding study (SATURN). Eur Urol 2013;64: Gao ZW, Xin SY, Zhang JG, Ren XQ, Shang YF, Zhang W, et al. Efficacy of combination therapy of tamsulosin and solifenacin for mild and moderate benign prostatic hyperplasia with overactive bladder. Zhonghua Nan Ke Xue 2014;20: PDE5 억제제병용요법 발기과정에가장핵심적인역할을하는 nictric oxide synthase (NOS) 혹은 nitric oxide (NO) 는음경에존재하는평활근의수용성 guanylate cyclase 을활성화시킴으로써세포내의 cgmp 94

96 전립선비대증진료권고안 를증가시키고, 증가된세포내 cgmp가평활근을이완시켜음경발기를유발하게된다. 또한 NO 는척수내반사경로를억제함으로써배뇨주기에관여하고, 요도, 전립선또는방광내신경전달에도관여한다. Phosphodiesterase (PDE) 억제제는세포내 cgmp의농도를증가시키고이의활동을연장시킴으로써배뇨근, 전립선및요도의평활근긴장도를줄여주는효과가있다. 골반강내 NO 체계의변화로발기부전이발생하고전립선비대증의이행대는평활근이감소한상태이므로조직내 NO가감소하여하부요로증상이생긴다고보았을때임상적으로 PDE5 inhibitor (PDE5I) 를사용하는경우배뇨증상이개선될수있다. 지금까지 11개의 PDE가알려져있으며, PDE 4와 5가인체전립선의이행대, 방광및요도에서주된형태이다. 또한 PDE4 형과 5형이다른기관에서보다전립선에상대적으로많이발현되므로, 전립선에 NO가특징적으로작용한다고볼수있는데최근저용량의 PDE5I 의매일복용에대한연구가진행되면서 PDE5I 와알파차단제의병용투여시배뇨증상과성기능에긍정적인효과를나타낼수있다는연구들이발표되었다 [1]. PDE5 억제제는위장관에서흡수되고, 혈장에서높은단백결합력을보이며간에서일차적으로대사되어대변으로배설된다. 그러나그들의반감기는현저하게차이가있다. 현재사용가능한선택적경구 PDE5 억제제는 sildenafil, tadalafil, vardenafil, udenafil 및 mirodenafil의다섯가지로, PDE5 억제제는발기부전환자에서필요에따라투여되지만, tadalafil 은필요에따른투여보다낮은용량 (5 mg) 의매일투여용법으로허가되어있다. 최초개발되었던 sildenafil 의경우발기부전환자에서 PDE5 억제제가 IPSS 설문지에의해측정된하부요로증상을유의하게감소시키고방광증상관련삶의질을향상시킴을보여주었다 [2,3]. 이후다양한 PDE5 억제제의효능에대한무작위, 위약대조임상시험결과들이발표되었고증상의변화 (IPSS), 최대요속 (Qmax) 및배뇨후잔뇨량을조사해보았을때거의모든 PDE5 억제제는 IPSS를유의하게감소시켰다. 방광저장및배뇨증상모두 PDE5 억제제로치료하는동안동일하게감소하였으나배뇨후잔뇨량은대부분의임상시험에서변화가없었다 [4-6]. PDE5 억제제는질산염을복용하는환자에서는금기시되는데, 추가혈관확장으로인해저혈압, 관상동맥질환자에서심근허혈, 뇌졸중을유발할수있기때문이다 [7]. 혈관확장제효과를가지는알파아드레날린차단제, PDE5 억제제의병용투여는일부환자에서증상을동반하는저혈압을유발할수있기때문에조심해야하는데, doxazocin( 매일 4, 8 mg) 과 tadalafil( 매일 5 mg 또는간헐적 20 mg) 의병용투여는혈압을더욱많이낮추며, 이들의병 95

97 Korean clinical practice guideline for benign prostate hyperplasia 용투여는일부환자에서위험할수도있기때문에피하는것이좋다. Vardenafil 은 tamsulosin 과는언제든지병용투여해도되지만 vardenafil 과 terazosin 을동시에투여받는남성은저혈압이더자주발생함을보고하고있다 [8]. 이런저혈압효과는 vardenafil 과 terazosin 을 6시간이상의간격으로분할투여함으로써최소화된다. PDE5 억제제는일반적으로두통, 홍조, 현기증, 소화불량, 비충혈, 근육통, 저혈압, 실신, 이명, 결막염또는시각이상등을초래할수있다. 그러나부작용의빈도는개개의 PDE5 억제제에따라다르며지속발기증또는급성요폐의발생가능성은아주적은것으로알려져있다 [7]. 모든 PDE5 억제제는불안정협심증, 최근심근경색 ( 이전 3 개월 ) 또는뇌졸중 ( 이전 6개월 ), 심부전, 저혈압, 조절되지않는혈압, 의미있는간또는신부전환자, 또는갑작스런시각소실을동반한비동맥염성전방허혈성시신경병증이있거나이전에 PDE5 억제제사용후부작용을경험했던환자에서는투여하지않는것이좋다. 알파차단제와병용한 PDE5 억제제의효능을비교한임상시험들은소수의환자를대상으로 6-12 주의제한된기간동안진행된것들이대부분이다. Medline, EMbase, Cochrane, KoreaMed 에서위검색식을적용하여검색하였을때, 총 935 개의문헌이검색되고, 이를기간을 1990년 1월 1일부터 2014 년 7월 1일로제한하였을때, 629개의문헌이추출되었고, 이중관련논문만을총 10개의문헌을근거로사용하였다. 메타분석상의알파차단제와 PDE5 억제제의병용요법과의비교결과를보면단독요법에대한병용요법의 mean difference 가 IPSS는 (95% 신뢰구간 ) 정도로증상개선에좀더효과적이었으며 Q-max 의 mean difference 는 0.71 (95% 신뢰구간 ) 로최고요속의개선폭이병용요법에서더컸으며두인자모두통계적으로유의하였다. 또한발기능의지표인 IIEF 점수에있어서병용요법이 mean difference 3.99 (95% 신뢰구간 ) 로발기능의개선이의미있게컸다. 통계적으로유의하지는않았지만잔뇨량의감소폭도병용요법에서더높았다. 문헌고찰과메타분석결과를토대로보았을때, 알파차단제와 PDE5 억제제의병용요법은임상적으로알파차단제요법에비하여성기능개선효과는명확하나증상개선이나요역동학적인자들에관련된여러임상지표에서결정적우위를보이지는못했다. 하지만여러연구에서 PDE5 억제제는알파차단제와의복합요법에서발기부전여부와관계없이하부요로증상의호전을보여, 성기능개선뿐아니라배뇨장애증상호전에유의한효과를보여주고있다. 96

98 전립선비대증진료권고안 그림 8-3. 알파차단제단독요법군과알파차단제와 PED5 억제제의병용요법군에서효과에대한숲그림 (forest plot) (A) IPSS Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Sildenafil Abolyosr A et al % [-3.59, -0.61] Kaplan et al % [-3.97, 0.77] Tuncel A et al % [-2.92, 0.92] Öztürk Mi et al % [-4.67, 3.27] Subtotal (95% CI) % [-2.62, -0.59] Heterogeneity: Tau Z = 0.00; Chi Z = 1.00, df = 3 (P = 0.80); I Z = 0% Test for overall effect: Z = 3.09 (P = 0.002) tadalafil Bechara et al % [-4.79, -0.21] Kumar, S et al % [-4.09, -1.31] Liguori G et al % [-3.06, 0.86] Regadas RP et al % [-6.16, -1.44] Singh DV et al % [-2.62, 0.62] Subtotal (95% CI) % [-3.10, -1.14] Heterogeneity: Tau Z = 0.36; Chi Z = 5.61, df = 4 (P = 0.23); I Z = 29% Test for overall effect: Z = 4.24 (P < ) Vardenafil Gacci et al % [-4.23, 0.03] Subtotal (95% CI) % [-4.23, 0.03] Heterogeneity: Not applicable Test for overall effect: Z = 1.94 (P = 0.05) Total (95% CI) % [-2.54, -1.32] Heterogeneity: Tau Z = 0.00; Chi Z = 7.22, df = 9 (P = 0.61); I Z = 0% Test for overall effect: Z = 6.24 (P < ) Test for subgroup differences: Chi Z = 0.55; df = 2 (P = 0.76); I Z = 0% Favours [experimental] Favours [control] (B) Q-max Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Sildenafil Abolyosr A et al % 0.70 [-0.12, 1.52] Kaplan et al % 0.90 [-0.47, 2.27] Tuncel A et al % 2.50 [0.83, 4.17] Öztürk Mi et al % 0.20 [-0.68, 1.08] Subtotal (95% CI) % 0.86 [0.09, 1.63] Heterogeneity: Tau Z = 0.29; Chi Z = 5.74, df = 3 (P = 0.12); I Z = 48% Test for overall effect: Z = 2.18 (P = 0.03) tadalafil Bechara et al % [-2.30, 0.50] Kumar, S et al % 1.20 [-1.08, 3.48] Liguori G et al % 1.40 [-0.62, 3.42] Regadas RP et al % [-1.61, 0.81] Singh DV et al % 0.60 [-0.80, 2.00] Subtotal (95% CI) % 0.14 [-0.69, 0.97] Heterogeneity: Tau Z = 0.25; Chi Z = 5.60, df = 4 (P = 0.23); I Z = 29% Test for overall effect: Z = 0.33 (P = 0.74) Vardenafil Gacci et al % 2.80 [0.78, 4.82] Subtotal (95% CI) % 2.80 [0.78, 4.82] Heterogeneity: Not applicable Test for overall effect: Z = 2.72 (P = 0.007) Total (95% CI) % 0.71 [0.08, 1.33] Heterogeneity: Tau Z = 0.48; Chi Z = 18.47, df = 9 (P = 0.03); I Z =51% Test for overall effect: Z = 2.22 (P = 0.03) Test for subgroup differences: Chi Z = 6.06; df = 2 (P = 0.05); I Z = 67.0% Favours [experimental] Favours [control] Abolyosr A et al 2013 [16], Kaplan et al [9], Tuncel A et al 2010 [12], Öztürk Mi et al 2012 [14], Bechara et al [10], Kumar, S et al 2014 [17], Liguori G et al [11], Regadas RP et al 2013 [15], Singh DV et al 2014 [16], Gacci et al 2012 [13] 97

99 Korean clinical practice guideline for benign prostate hyperplasia (C) PVR Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Sildenafil Abolyosr A et al % [-11.48, -9.12] Kaplan et al % 2.00 [-7.68, 11.68] Tuncel A et al % [-14.06, -0.14] Öztürk Mi et al % [-12.56, 9.96] Subtotal (95% CI) % [-11.48, -0.02] Heterogeneity: Tau Z = 21.02; Chi Z = 9.10, df = 3 (P = 0.0.3); I Z = 67% Test for overall effect: Z = 1.97 (P = 0.05) tadalafil Bechara et al % 3.50 [-6.81, 13.81] Kumar, S et al % [-54.55, ] Singh DV et al % [-52.88, -9.72] Subtotal (95% CI) % [-45.97, 8.30] Heterogeneity: Tau Z = ; Chi Z = 14.25, df = 2 (P = ); I Z = 86% Test for overall effect: Z = 1.36 (P = 0.17) Vardenafil Gacci et al % [-25.15, 14.55] Subtotal (95% CI) % [-25.15, 14.55] Heterogeneity: Not applicable Test for overall effect: Z = 0.52 (P = 0.60) Total (95% CI) % [-13.15, -1.04] Heterogeneity: Tau Z = 41.39; Chi Z = 23.85, df = 7 (P = 0.001); I Z = 71% Test for overall effect: Z = 2.30 (P = 0.02) Test for subgroup differences: Chi Z = 0.86; df = 2 (P = 0.65). I Z = 0% Favours [experimental] Favours [control] (D) IIEF Experimental Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Sildenafil Abolyosr A et al % 2.60 [0.99, 4.21] Kaplan et al % 6.60 [3.88, 9.32] Tuncel A et al % 6.70 [4.78, 8.62] Öztürk Mi et al % 6.30 [3.58, 9.02] Subtotal (95% CI) % 5.43 [3.10, 7.76] Heterogeneity: Tau Z = 4.32; Chi Z = 13.75, df = 3 (P = 0.003); I Z = 78% Test for overall effect: Z = 4.57 (P < ) tadalafil Bechara et al % 6.30 [3.83, 8.77] Kumar, S et al % 2.00 [-1.96, 5.96] Liguori G et al % 0.70 [-1.38, 2.78] Singh DV et al % 2.40 [0.65, 4.15] Subtotal (95% CI) % 2.85 [0.46, 5.24] Heterogeneity: Tau Z = 4.30; Chi Z = 11.96, df = 3 (P = 0.008); I Z = 75% Test for overall effect: Z = 2.33 (P = 0.02) Vardenafil Gacci et al % 2.50 [0.18, 4.82] Subtotal (95% CI) % 2.50 [0.18, 4.82] Heterogeneity: Not applicable Test for overall effect: Z = 2.11 (P = 0.03) Total (95% CI) % 3.99 [2.42, 5.56] Heterogeneity: Tau Z = 4.30; Chi Z = 35.14, df = 8 (P < ); I Z = 77% Test for overall effect: Z = 4.98 (P < ) Test for subgroup differences: Chi Z = 3.62; df = 2 (P = 0.16); I Z = 44.7% Favours [experimental] Favours [control] 98

100 전립선비대증진료권고안 근거표 KQ 8-3 Trials Kaplan et al. (2007) Bechara et al. (2008) Liguori G et al. (2009) Tuncel A et al. (2010) Gacci et al. (2012) Öztürk Mİ et al. (2012) Regadas RP et al. (2013) Abolyosr A et al. (2013) Kumar, S et al. (2014) Singh DV et al. (2014) Duration (wks) 12 randomized controlled trial 6 randomized controlled trial 12 randomized controlled trial 8 randomized controlled trial 12 randomized controlled trial 12 randomized controlled trial 4 randomized controlled trial 16 randomized controlled trial 12 randomized controlled trial 12 randomized controlled trial Treatment IPSS Qmax (ml/s) Alfuzosin 1 x 10 mg/day Alfuzosin 1 x 10 mg/day + Sildenafil 1 x 25 mg/day Tamsulosin 1 x 0.4 mg/day Tamsulosin 1 x 0.4 mg/day + tadalafil 1 x 20 mg/day Alfuzosin 1 x 10 mg/day Alfuzosin 1 x 10 mg/day + tadalafil 20 mg on alternative day Tamsulosin 0.4 mg Tamsulosin 0.4 mg + sildenafil 25 mg. Four times/ week Tamsulosin 0.4 mg + Placebo Tamsulosin 0.4 mg +Vardenafil 10 mg Alfuzosin 1 x 10 mg/day Alfuzosin 1 x 10 mg/day + Sildenafil 1 x 25 mg/day Tamsulosin 0.4 mg + tadalafil 5 mg/day Tamsulosin 0.4 mg Doxazosin 1 x 2 mg Doxazosin 1 x 2 mg + Sildenafil 1 x 50 mg/day Alfuzosin 1 x 10 mg/day Alfuzosin 1 x 10 mg/day + + tadalafil 1 x 10 mg/day Tamsulosin 1 x 0.4 mg/day Tamsulosin 1 x 0.4 mg/day + tadalafil 1 x 10 mg/day (-15.5%) -4.3 (-24.1%) -6.7 (-34.5%) -9.2 (-47.4%) -27.6% -41.6% -36.2% -40.1% -3.7 (18.1%) -5.8 (31.0%) -4.9 (26.8%) -5.8 (28.2%) (47.3%) -6.0 (29.4%) (19.35%) (32.1%) -9.5 (55.5%) (64.0%) % % PVR (ml) LE

101 Korean clinical practice guideline for benign prostate hyperplasia 참고문헌 1. Ückert S, Oelke M, Stief CG, et al. Immunohistochemical distribution of camp- and cgmpphosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 2006;49: Sairam K, Kulinskaya E, McNicholas TA, et al. Sildenafil influences lower urinary tract symptoms. BJU Int 2002;90: Mulhall JP, Guhring P, Parker M, et al. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med 2006;3: McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2007;177: Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and sign and symptoms of benign prostatic hyperplasia. Eur Urol 2009;56: Stief CG, Porst H, Neuser D, et al. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2008;53: Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract 2006;60: Yokoyama O, Yoshida M, Kim SC, et al. Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A randomized placebo- and tamsulosin-controlled 12-week study in Asian men. Int J Urol 2013;20: Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 2007;51: Bechara A, Romano S, Casabé A, et al. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med 2008;5: Liguori G, Trombetta C, De Giorgi G, et al. Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. preliminary report. J Sex Med 2009;6: Tuncel A, Nalcacioglu V, Ener K, Aslan Y, Aydin O, Atan A. Sildenafil citrate and tamsulosin combination is not superior tomonotherapy in treating lower urinary tract symptoms and erectile dysfunction. World J Urol 2010;28: Gacci M, Vittori G, Tosi N, Siena G, et al. A randomized, placebo-controlled study to assess safety and efficacy of vardenafil 10 mg and tamsulosin 0.4 mg vs. tamsulosin 0.4 mg alone in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med 2012;9: Öztürk Mİ, Kalkan S, Koca O, Güneş M, Akyüz M, Karaman MI. Efficacy of alfuzosin and sildenafil combination in male patients with lower urinary tract symptoms. Andrologia 2012;44 Suppl 1: Regadas RP, Reges R, Cerqueira JB, Sucupira DG, Josino IR, Nogueira EA, et al. Urodynamic effects of the combination oftamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial.int Urol Nephrol 2013;45: Abolyosr A, Elsagheer GA, Abdel-Kader MS, Hassan AM, Abou-Zeid AM. Evaluation of the effect of sildenafil and/or doxazosin on Benign prostatic hyperplasia-related lower urinary tract symptoms and erectile dysfunction. Urol Ann 2013;5: Kumar S, Kondareddy C, Ganesamoni, R Nanjappa B, Singh SK. Randomized controlled trial to assess the efficacy of the combination therapy of alfuzosin and tadalafil in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. LUTS 2014;6: Singh DV, Mete UK, Mandal AK, Singh SK. A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. J Sex Med 2014;11:

102 전립선비대증진료권고안 KQ 9. 전립선비대증환자에서급성요폐발생시 TWOC (Trial without catheter) 는 수술적치료전에우선적으로고려되어야하는가? 권고사항권고수준근거수준 9-1. 급성요폐발생시 TWOC 는수술적치료전에고려할수있다. Strong A 9-2. 급성요폐를치료하는데있어요도도관유치전후알파차단제사용이도 움이된다. Strong B 9-3. 요도도관은급성요폐후 2-7 일간유치하는것이도움이된다. Strong B 전립선비대증으로인한합병증중급성요폐는가장흔한비뇨기과적응급상황으로서즉시치료를요하는상태이다 [1]. 최근이러한급성요폐를치료하는데있어요도도관유치전후알파차단제를사용하고일정시간이지나면요도도관을제거 ( 급성요폐후 2-7일 ) 한후자가배뇨를시키는방법이제안되고있다 [2,3]. 과거에는전립선비대증에의한급성요폐의일차적치료로조기에경요도전립선절제술이많이시행되었으며이것이하부요로증상의가장뚜렷한호전을가져오는것으로알려져있었다 [4]. 하지만경요도전립선절제술자체가갖고있는합병증및위험성이문제가되었다 [5]. Murray 등 [6] 이급성요폐환자를대상으로요역동학검사를시행한결과 23% 에서전립선절제술이필요하지않았다고기술하였으며, Pickard 등 [7] 은경요도전립선절제술을시행받은환자의약 9.2% 에서술후자가배뇨를하지못해요도도관유치및청결간헐적자가도뇨를시행하여야하고이중 0.9% 가영구적인요도도관유치를해야하는것으로보고하면서급성요폐가있었던환자에서의전립선절제술은술후합병증의위험이크다고보고하였다. 전립선비대증으로인한급성요폐의초기치료로일시적요도도관유치와알파차단제사용후자가배뇨를시키는방법이많이쓰이는것은술기의간단함과경제적이득및조기에경요도전립선절제술을시행함으로써발생할수있는합병증및위험성을피하고자함이다. Manikandan 등 [8] 은영국의비뇨기과의사 264명을대상으로전립선비대증으로인한급성요폐의초기치료에대한설문조사를한결과 98% 가일시적요도도관유치법을사용하는것으로나타났으며 70.5% 가 101

103 Korean clinical practice guideline for benign prostate hyperplasia 요도도관유치와동시에알파차단제를사용하였다고보고하였다. 또한 Taube 와 Gajraj [9] 의연구그리고 Kumer 등 [10] 의연구에서는급성요폐의초기치료로서요도도관을유치하고자가배뇨가성공한경우적은수의환자들에서만급성요폐가재발하는것으로보고하고있다. 따라서급성요폐환자에서요도도관유치후자가배뇨가성공했다면전립선비대증의수술적치료를지연시키거나피할수있을것이라보고하였다. 급성요폐시요도도관제거시도의성패에영향을미치는인자로서환자의정체소변량이적은경우 [11], 전립선크기가작은경우및급성요폐전알파차단제를복용한적이없는경우에 TWOC 의더높은성공률을기대할수있다고보고하였다 [12,13]. 또한 Kim 등은 58세이하의젊은환자에서급성요폐가발생했을때일차적으로 TWOC 를고려해볼수있을것이라보고하였다 [14]. TWOC 의실패인자로고령의연령, 이전의척추수술을보고한국내연구도있다 [15]. 근거표 KQ 9 1. Kurita Y, Masuda H, Terada H, Suzuki K, Fujita K. Transition zone index as a risk factor for acute urinary retention in benign prostatic hyperplasia. Urology 1998;51: Retrospective 331 To examine the efficacy of various parameters obtained by transrectal ultrasonography (TRUS) as predictors of the onset of acute urinary retention in patients with benign prostatic hyperplasia (BPH). There were significant differences in the American Urological Association (AUA) symptom score, total prostate volume, TZ volume, TZ index, and PCAR between patients with and without acute urinary retention, but no significant differences in age and quality of life score. In patients with acute urinary retention, the area under the ROC curve was for the TZ index, for the TZ volume, for the PCAR, for the total prostate volume, and for the AUA symptom score. Level of Study 4 2. Lucas MG, Stephenson TP, Nargund V. Tamsulosin in the management of patients in acute urinary retention from benign prostatic hyperplasia. BJU Int 2005;95: RCT

104 전립선비대증진료권고안 To evaluate the efficacy of tamsulosin compared to placebo for treating catheterized patients with acute urinary retention (AUR) caused by benign prostatic hyperplasia (BPH), by comparing the numbers of patients who voided successfully after removing their catheter. In all, 149 men (mean age 69.4 years) were randomly assigned to receive tamsulosin (75) or placebo (74); eight were not evaluable, so the intent-to-treat population was 141 men. Thirtyfour men taking tamsulosin and 18 taking placebo did not require re-catheterization on the day of the trial without catheter (48% and 26% respectively, P = 0.011; odds ratio 2.47, 95% confidence interval, CI, ). Success using free-flow variables was also higher in the men who received tamsulosin, at 37 (52%) vs 24 (34%) on placebo (P = 0.019; odds ratio 2.34, 95% CI ). Withdrawals were high (120 men, 81%), mostly because of a need for recatheterization (89 men, 60%). Dizziness and somnolence occurred in seven (10%) and four (6%) men who received tamsulosin, and two (3%) who received placebo, but overall the incidence of adverse events was similar in the two groups. One patient died from carcinomatosis. Level of Study 2 3. McNeill SA, Hargreave TB, Roehrborn CG. Alfaur study group. Alfuzosin 10 mg once daily in the management of acute urinary retention: Results of a double-blind placebo-controlled study. Urology 2005;65:83-9. RCT 360 To study the impact of alfuzosin 10 mg once daily (OD) on the outcome of a trial without catheter (TWOC) after a first episode of acute urinary retention (AUR) related to benign prostatic hyperplasia (BPH) and the subsequent management of BPH in these patients. Alfuzosin significantly increased the successful TWOC rate (146 of 236, 61.9%) compared with placebo (58 of 121, 47.9%; P = 0.012). In the second phase, 14 (17.1%) of the 82 alfuzosin-treated patients versus 20 (24.1%) of the 83 placebo-treated patients required BPH surgery, 5 (36%) of 14 versus 13 (65%) of 20 within 1 month, and 8 (57%) of 14 versus 17 (85%) of 20 within 3 months of treatment. Emergency surgery because of AUR relapse was the main cause of failure in both groups (11 [78.6%] of 14 in the alfuzosin group and 16 [80.0%] of 20 in the placebo group). Compared with placebo, alfuzosin improved the Kaplan-Meier survival rates by 9.6% (P = 0.04), 11.4% (P = 0.04), and 8.3% (P = 0.20), with surgical risk reductions of 61%, 52%, and 29% at 1, 3, and 6 months of treatment, respectively. High prostate-specific antigen values and the post- TWOC residual urine volume significantly increased the risk of AUR relapse and BPH surgery. Alfuzosin 10 mg OD was well tolerated. Level of Study 2 4. The pathophysiology of lower urinary tract symptoms in the ageing male population. Br J Urol 1998;81(Suppl 1): retrospective 3,885 To evaluate the immediate and postoperative complication of transurethral resection of prostate 103

105 Korean clinical practice guideline for benign prostate hyperplasia The mortality rate for transurethral prostatectomy was 0.2 per cent in 3,885 patients reviewed retrospectively. The immediate postoperative morbidity rate was 18 per cent. Increased morbidity was found in patients with a resection time of more than 90 minutes, gland size of more than 45 gm., acute urinary retention and patient age greater than 80 years, and in the black population. Of the patients 77 per cent had significant pre-existing medical problems. Operative mortality, significant morbidity and hospital stay were reduced in comparison to studies done 15 and 30 years ago. Level of Study 4 6. Murray K, Massey A, Feneley RC. Acute urinary retention-a urodynamic assessment. Br J Urol 1984;56: Prospective 30 Thirty male patients with acute urinary retention were studied by standard urodynamic techniques on admission to hospital. Ten individuals also underwent cystography and sequential urodynamic testing over 96 h. Twenty-three per cent of patients did not require subsequent prostatectomy. Inability to initiate a voiding contraction during cystometry at the time of admission was associated with a prolonged duration of retention and a greater retained volume. The internal urethral meatus is closed in retention, and release of the retention results in an increase in profile length and maximum urethral closure pressure and a decrease in maximum urethral pressure. Free catheter drainage was associated with a reduction in bladder capacity and the appearance of detrusor instability. Level of Study 3 7. Pickard R, Emberton M, Neal DE. The management of men with acute urinary retention. National Prostatectomy Audit Group. Br J Urol 1998;81: Prospective study 3,966 To determine the outcome of men with acute urinary retention undergoing prostatectomy and to assess whether discharge with a catheter before subsequent planned re-admission for prostatectomy had an adverse effect on outcome. Compared with those who underwent elective prostatectomy for symptoms alone, men presenting with acute retention had an excess risk of death at 30 days (relative risk [RR], 26.6, 95% confidence interval [CI], ) and at 90 days after operation (RR 4.4, 95% CI ), and an increased risk of perioperative complications. Although men with retention were older, had larger glands and had more comorbidity, these factors did not totally explain the excess risk. The final symptomatic outcome of men with acute retention was no different from that of men presenting for elective treatment. Men with retention who were managed by initial catheterization, sent home and subsequently re-admitted for planned operation had similar pretreatment characteristics, postoperative complications and outcomes to those who were kept in hospital throughout, although the men kept in hospital had a total increased length of stay. 104

106 전립선비대증진료권고안 Level of Study 3 8. Manikandan R, Srirangam SJ, O'Reilly PH, Collins GN. Management of acute urinary retention secondary to benign prostatic hyperplasia in the UK: a national survey. BJU Int 2004;93:84-8. Retrospective 270 To analyse current practice in the management of acute urinary retention (AUR) secondary to benign prostatic hyperplasia (BPH) in the UK, and to assess how much of this is evidence-based We received 270 (66%) replies, of which six were excluded because they were from subspeciality interests (e.g. paediatric urology) or had ambiguous answers; 264 (64%) were therefore available for analysis. Urethral catheterization was the initial management of choice (98%), failing which a suprapubic catheter was inserted. Two-thirds (65.5%) admitted the patient after catheterization. Most consultants initiated alpha-blockers (70.5%), with 64% (118) of these using a TWOC 2 days after starting them. One failed TWOC was an indication for transurethral resection of the prostate for 192 (72.8%), with 136 (49.8%) re-admitting the patient for surgery later. Routine follow-up after a successful TWOC was advocated by 77.3%. Just over half the respondents (52.6%) felt that there was no need for uniform guidelines in the management of AUR secondary to BPH. Level of Study 5 9. Taube M, Gajraj H. Trial without catheter following acute retention of urine. Br J Urol 1989;63: prospective 60 A total of 60 patients with acute urinary retention were studied to establish whether a trial without a catheter was justified and to identify subgroups of patients most likely to benefit from this practice 17 patients urinated satisfactorily after removal of the catheter. Re-establishment of micturition was not associated with the length of history or severity of symptoms of prostatism, with age or the presence of urinary tract infection. The mean retained volume of urine in patients with a satisfactory result was 786 ml and 1,069 ml in the failures. Of the 34 patients with retained volumes of less than 900 ml, 15 were successful in re-establishing micturition compared with 2 of 26 of those with retained volumes greater than 900 ml. The time of catheter removal was not important. The 17 successful patients were reviewed 6 months later. None reported further urinary retention; 6 had required prostatectomy for severe symptoms, 6 had minor symptoms and 5 were symptomless. It was concluded that a trial without a catheter is worthwhile, since 11 of 60 patients had not required surgery, but it should be avoided in patients with a residual volume exceeding 900 ml. Level of Study Kumar V, Marr C, Bhuvangiri A, Irwin P. A prospective study of conservatively managed acute urinary retention: prostate size matters. BJU Int 2000;86:

107 Korean clinical practice guideline for benign prostate hyperplasia Prospective 40 To evaluate in a prospective study the medium- to long-term outcome of a policy of conservatively managing acute urinary retention (AUR), arising solely by bladder outlet obstruction caused by benign prostatic enlargement (BPE), and to identify the factors favouring a positive outcome of a trial without catheter (TWOC). Of the 40 men with AUR, 22 (55%) voided spontaneously after removing the catheter and continued to do so with mean peak flow rates of 12.2 ml/s and mean PVRs of 69.6 ml over a follow-up of 8-24 months. These patients remained asymptomatic, with a mean IPSS of 5.2 and quality-of-life score of 0.9. These men had a mean prostatic size of 15.9 g and a mean catheterized residual volume of 814 ml, while in those who had an unsuccessful TWOC the mean prostate size was 27.5 g (P = 0.006) and a mean catheterized residual volume of 1062 ml (P = 0.09). Prostate size as assessed by the DRE was the most significant factor in predicting the outcome of a TWOC. Level of Study Ko YH, Kim JW, Kang SG, Jang HA, Kang SH, Park HS, et al. The efficacy of in-and-out catheterization as a way of trial without catheterization strategy for treatment of acute urinary retention induced by benign prostate hyperplasia: variables predicting success outcome. Neurourol Urodyn 2012;31: retrospective 515 To evaluate the efficacy and proper use of in-and-out catheterization as a strategy for trial without catheterization (TWOC) for treatment of acute urinary retention (AUR) TWOC success rate was 25.1% for Group 1 and 30.3% for Group 2. In successful cases, age, retention volume, and prostate sizes were significantly lower than those of failure counterparts in both Groups 1 and 2. Among these, age and retention volume were finally selected for LDA. When comparing successful cases, these two were significantly lower in Group 1 than Group 2. LDA showed an 81.6% hit ratio for cases with successful TWOC. In a prospective trial of 28 patients, using an equation from LDA, five of seven patients in Group 1 (71.4%) and 16 of 21 patients (76.2%) in Group 2 succeeded in their initial TWOC. Level of Study Park SH, Kwon TG, Kim DY, Park CH, Seo JH, Lee JH, et al. The factors that influence the clinical outcomes after trial without catheter for acute urinary retention due to benign prostatic hyperplasia: a multicenter trial. Kor J Uro 2006;47: Retrospective 455 Benign prostatic hyperplasia (BPH) is a common problem that's experienced by aging men, and it can lead to serious outcomes, including acute urinary retention (AUR). We studied the factors that influence the clinical outcomes after trial without catheter (TWOC) for AUR due to BPH. 106

108 전립선비대증진료권고안 From the 292 cases of group I and the 163 cases of group II, the multivariate analysis revealed statistically significant differences in the retention volume (p-0.01), the prostate volume (p-0.01) and the previous use of α-blockers before AUR (p-0.01). The prostate volume, retention volume and previous use of α-blockers before AUR were thought to influence the clinical outcomes of TWOC for the BPH patients with AUR, and these factors should be considered in future treatment planning Level of Study Park KS, Kim SH, Ahn SG, Lee SJ, Ha US, Koh JS, et al. Analysis of the treatment of two types of acute urinary retention. Korean J Urol 2012;53: retrospective This study analyzed the type of acute urinary retention (AUR) and evaluated the treatments used, including trial without catheter (TWOC) Of 299 men with AUR, 160 (54%) had spontaneous AUR and 139 (46%) had precipitated AUR. Compared with group P, patients in group S were more likely to be treated by surgery, either immediately (16.9% vs. 3.6%, p<0.05) or after prolonged catheterization (42.2% vs. 29.1%, p<0.05). The success rate of TWOC was lower in men of older ages ( 70 years) and in those with enlarged prostates ( 50 ml), higher PSA levels ( 3 ng/ml), and a large drained volume at catheterization ( 1,000 ml). Level of Study Kim MJ, Lee JG, Cheon J. The factors that influence the success rate of treatment without using a catheter for the management of acute urinary retention: comparison of in-and-out catheterization and foley indwelling catheterization. Korean J Urol 2008;49: retrospective Acute urinary retention (AUR) is a serious outcome of benign prostatic hyperplasia (BPH). Although Foley indwelling catheterization is a standard treatment for the conservative management of AUR, we studied the success rate of in-and-out catheterization and the factors that favor a positive outcome of a trial treatment without using a catheter (TWOC) Of the 62 patients who underwent in-and-out catheterization, 30 had no further episodes of AUR during 1-year follow up (group I) and the other patients had repeated episodes (group II). For the clinical parameters, only the retained urine volume was significantly difference between the two groups. The multivariate analysis revealed that the statistically significant influencing factor was urinary retention volume (p<0.01). Level of Study Lee KS, Lim KH, Kim SJ, Choi HJ, Noh DH, Lee HW, et al. Predictors of successful trial without catheter for postoperative urinary retention following non-urological surgery. Int Neurourol J 2011;15:

109 Korean clinical practice guideline for benign prostate hyperplasia 104 retrospective To investigate the success rate of trial without catheter (TWOC) for postoperative urinary retention (POUR) after non-urological surgery and to determine predictors of successful TWOC. The mean age of the patients was 65.2 (range, 23 to 92) years. There were 45 male and 59 female patients. Intraoperative indwelling catheterization was performed in 69 (66.3%) patients. Mean duration of indwelling catheterization for POUR was 5.0 (range, 3.0 to 7.0) days and 83 (79.8%) patients received medication with an alpha-blocker. A successful TWOC was observed in 70 (67.4%) patients. The mean age of the patients with failure of TWOC was significantly higher than that of the patients with successful TWOC. The percentages of female patients, spinal surgery, and prone position during surgery in patients with unsuccessful TWOC were higher than in those with successful TWOC. In the multivariate logistic regression analysis, age and location of surgery (spine vs. non-spine) were the independent predictors of successful TWOC for POUR. Level of Study 4 참고문헌 1. Kurita Y, Masuda H, Terada H, Suzuki K, Fujita K. Transition zone index as a risk factor for acute urinary retention in benign prostatic hyperplasia. Urology 1998;51: Lucas MG, Stephenson TP, Nargund V. Tamsulosin in the management of patients in acute urinary retention from benign prostatic hyperplasia. BJU Int 2005;95: McNeill SA, Hargreave TB, Roehrborn CG. Alfaur study group. Alfuzosin 10 mg once daily in the management of acute urinary retention: Results of a double-blind placebo-controlled study. Urology 2005;65: Lepor H. The pathophysiology of lower urinary tract symptoms in the ageing male population. Br J Urol 1998;81(Suppl 1): Mebust WK, Holtgrewe HL, Cockett AT, Peters PC. Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 1989;141: Murray K, Massey A, Feneley RC. Acute urinary retention-a urodynamic assessment. Br J Urol 1984;56: Pickard R, Emberton M, Neal DE. The management of men with acute urinary retention. National Prostatectomy Audit Group. Br J Urol 1998;81: Manikandan R, Srirangam SJ, O Reilly PH, Collins GN. Management of acute urinary retention secondary to benign prostatic hyperplasia in the UK: a national survey. BJU Int 2004;93: Taube M, Gajraj H. Trial without catheter following acute retention of urine. Br J Urol 1989;63: Kumar V, Marr C, Bhuvangiri A, Irwin P. A prospective study of conservatively managed acute urinary retention: prostate size matters. BJU Int 2000;86: Ko YH, Kim JW, Kang SG, Jang HA, Kang SH, Park HS, et al. The efficacy of in-and-out catheterization as a way of trial without catheterization strategy for treatment of acute urinary retention induced by benign prostate hyperplasia: variables predicting success outcome. Neurourol Urodyn 2012;31: Park SH, Kwon TG, Kim DY, Park CH, Seo JH, Lee JH, et al. The factors that influence the clinical outcomes after trial without 108

110 전립선비대증진료권고안 catheter for acute urinary retention due to benign prostatic hyperplasia: a multicenter trial. Kor J Uro 2006;47: Park KS, Kim SH, Ahn SG, Lee SJ, Ha US, Koh JS, et al. Analysis of the treatment of two types of acute urinary retention. Korean J Urol 2012;53: Kim MJ, Lee JG, Cheon J. The factors that influence the success rate of treatment without using a catheter for the management of acute urinary retention: comparison of in-and-out catheterization and foley indwelling catheterization. Korean J Urol 2008;49: Lee KS, Lim KH, Kim SJ, Choi HJ, Noh DH, Lee HW, et al. Predictors of successful trial without catheter for postoperative urinary retention following non-urological surgery. Int Neurourol J 2011;15:

111 Korean clinical practice guideline for benign prostate hyperplasia KQ 10. 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서 우선적으로고려되어야하는가? 권고사항권고수준근거수준 경요도전립선절제술은전립선비대증수술에우선적으로고려하여야한다. Strong C g 이상의큰전립선비대증환자에서경요도를통한내시경수술은개복 전립선수술과함께 1 차수술법으로고려할수있다. Strong A 경요도전립선절제술은전립선막힘으로인한하부요로증상에대한가장대표적인수술적치료방법이다 년대에개발된이후장비와술기의발전을거듭하여왔으며, 그동안많은약물치료법과여러수술적치료법이개발되었지만아직도양성전립선비대증의수술치료중가장기본이되는방법 (gold standard) 으로여겨지고있다 [1-3]. 중등도이상의하부요로증상이있는경우수술을고려할수있으며경요도전립선절제술후환자의 78-96% 에서증상이호전되었고, 85% 에서증상점수가감소하였다. 경요도절제기구와술기의발달로경요도전립선절제술후의출혈등합병증이현저히감소하였다. 개복전립선절제술은 TURP에비해서재치료율이낮고전립선선종을좀더완전하게제거할수있으며, TURP 환자의약 2% 에서발생하는희석성저나트륨혈증의발생도피할수있다는장점이있다 [4-6]. 단점이라면절개를해야하므로경요도전립선절제술보다입원및회복기간이길고수술전후출혈의가능성도높다는점이다. 개복전립선절제술은폐색조직의크기가클경우 (75 g 이상 ) 뿐아니라, 큰방광게실이동반된경우, 큰방광결석이있어서요도를통해서제거가곤란한경우, 정형외과적인문제로경요도전립선절제술의자세를취할수없는경우등에서고려할수있다. 최근 Giulianelli 등 [7] 은 100 g이넘는큰전립선크기에서도양극성경요도전립선절제술이개복전립선절제술과비슷한정도의치료효과가있음을보고하였다 [8-10]. 또한최근홀뮴레이저를이용한 enucleation이 70 g 이상의큰전립선비대증에효과가있음이보고되었다 [11]. 비록큰전립선비대증환자에서경요도전립선절제술과개복전립선절제술중어느것이우월한지에대한자료는부족한실정이나전립선비대증의일차적수술치료로우선적으로경요도를통한내시경수술을고 110

112 전립선비대증진료권고안 려해야할것이다 [12]. 근거표 KQ Baazeem A, Elhilali MM. Surgical management of benign prostatic hyperplasia: current evidence. Nat Clin Pract Urol 2008;5: Review Benign prostatic hyperplasia (BPH) is one of the most common male urological disorders. The surgical management of BPH is evolving at a rapid rate, with several new procedures available that challenge transurethral resection of the prostate as the standard treatment in the surgical management of small to medium sized glands. The new procedures aim to achieve results comparable to transurethral resection of the prostate while minimizing morbidity and cost. In this Review, we discuss some of the current surgical options for the treatment of BPH that seem popular in the literature. Level of Study 5 3. Borboroglu PG, Kane CJ, Ward JF, et al. Immediate and postoperative complications of transurethral prostatectomy in the 1990s. J Urol 1999;162: Retrospective study 520 We compare the morbidity, mortality, hospitalization and urethral catheter time of contemporary transurethral prostatectomy to historical series, and evaluate recent trends in hospitalization and urethral catheter time during the last 8 years A total of 520 patients were identified with an average age of 67 years (range 44 to 89). Significant co-morbidity (2 or more co-morbid disease processes) was identified preoperatively in 30.3% of the patients. The most common indications for transurethral prostatectomy were lower urinary tract symptoms (80.9%) and urinary retention (15.2%). Average preoperative International Prostate Symptom Score was Average weight of resected tissue was 18.8 gm. There was no perioperative patient mortality. Blood transfusion rate was 0.4%. The rate of intraoperative and immediate postoperative complications was 2.5% and 10.8%, respectively. Average hospital stay was 2.4 days, and 1.1 from 1997 through The rate of late postoperative complication was 8.5% and the average postoperative symptom score was 6.4 with an average followup of 42 months (range 6 to 84). Level of Study 4 4. Tubaro A, Carter S, Hind A, et al. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. J Urol 2001;166:

113 Korean clinical practice guideline for benign prostate hyperplasia prospective 32 We investigate the safety and efficacy of suprapubic transvesical prostatectomy, and the change in bladder wall thickness after surgery. An average of 63 gm. prostate adenoma were enucleated at surgery. An indwelling catheter was required for an average plus or minus standard deviation of 5.4 +/- 2.6 days after treatment. The International Prostate Symptom Score decreased from /- 4.4 to 1.5 +/- 2.7 and the quality of life score decreased from 4.9 +/- 1.0 to 0.2 +/- 0.4 at year 1, respectively. Maximum flow rate improved from 9.1 +/- 5.3 to /- 8.9 ml. per second. Residual urine decreased from 128 +/- 113 to 8 +/- 18 ml. Before surgery 30 patients had obstruction and 2 were in the equivocal zone of the International Continence Society nomogram. At 6 months after prostatectomy 30 patients did not have obstruction, and 2 who were subsequently operated on for bladder neck sclerosis were equivocal and had obstruction, respectively. No patient had significant postoperative bleeding and no heterologous blood transfusions were required. There were 4 men who had urinary tract infection and 1 who had wound infection. A slight decrease in erectile function was observed 6 weeks postoperatively, and no change in patient libido and quality of sex life was reported. The total complication rate was 31.3%. The bladder was unstable in 7 men before and 3 after surgery. A significant decrease in bladder wall thickness was observed from 5.2 +/- 0.7 at baseline to 2.9 +/- 0.9 mm. at year 1 postoperatively. Level of Study 3 5. Mearini E, Marzi M, Mearini L, et al. Open prostatectomy in benign prostatic hyperplasia: 10- year experience in Italy. Eur Urol 1998;34: review This study reports the experience of 47 Italian urology units together with the urology unit at the University of Perugia concerning open surgery in the management of benign prostatic hyperplasia (BPH). Until years ago, open surgery was the most common approach. In the late 1970s the development of endoscopes and their methodology has led to a gradual reduction in open surgery operations, which decreased rapidly with the introduction of mini-invasive endoscopic techniques. Therefore, open surgery for BPH is declining, though still performed. Skill in traditional surgery is mandatory because, until an alternative is devised, indications for open surgery still exist and cannot be ignored. The survey shows the indications and contraindications, complications and results of a 10-year nationwide experience. Guidelines for open surgery in patients with BPH have been drawn up. Level of Study 5 6. Serretta V, Morgia G, Fondacaro L, et al. Open prostatectomy for benign prostatic enlargement in southern Europe in the late 1990s: a contemporary series of 1800 interventions. Urology 2002;60: retrospective 112

114 전립선비대증진료권고안 5,636 Contemporary series of open prostatectomies from Western countries are rare. Frequently, the analysis of the outcome of open prostatectomy refers to old experiences or to series from developing countries. Any comparison with transurethral resection of the prostate can be invalidated by complications of open surgery because of the lack of an adequate healthcare system and technology. Twenty-six units (72.3%) replied. Of 31,558 patients treated for symptomatic benign prostatic hyperplasia, 5636 underwent surgery. Open prostatectomy (n = 1804) accounted for 32% of all surgical treatment. The median prostate volume was 75 cm(3) and the median serum prostatespecific antigen level was 3.7 ng/ml. The postoperative median hospitalization time was 7 days. Concomitant low urinary tract disease was present in 25% of the patients. Severe bleeding occurred in 11.6% of open prostatectomies. Blood transfusions were given in 8.2% of cases. Sepsis was reported in 8.6% of the patients. Reinterventions, within 2 years, mainly due to bladder neck stenosis, were reported in 3.6% of cases. Level of Study 5 7. Giulianelli R, Brunori S, Gentile BC, Vincenti G, Nardoni S, Pisanti F, et al. Comparative randomized study on the efficaciousness of treatment of BOO due to BPH in patients with prostate up to 100 gr by endoscopic gyrus prostate resection versus open prostatectomy. Preliminary data. Arch Ital Urol Androl 2011;83: RCT 140 Aim of this study was to evaluate efficacy and safety of Bipolar TURP (Gyrus electro surgical system) versus standard open prostatectomy in patients with lower urinary tract symptoms (LUTS) due to bladder outlet obstruction (BOO) with markedly enlarged glands refractory to medical therapy. Comparative data on IPSS symptom score, IIEF-5 and Qol, PSA, peak urinary flow rates and post-void residual urine volume in the 2 groups were similar but showed a significative improvement with respect to baseline value. Postoperative haemoglobin levels, postoperative catheterization, hospital stay and 3-yr overall surgical re-treatment-free rate were significantly better in the Bipolar group. Level of Study 2 8. Kuntz RM, Lehrich K, Ahyai SA. Holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial. European Urology 2008;53: RCT 46 To report 5-year follow-up results of a randomised clinical trial comparing holmium laser enucleation of the prostate (HoLEP) with open prostatectomy (OP). 113

115 Korean clinical practice guideline for benign prostate hyperplasia Five years postoperatively, a total of 46 patients (38.3%) were lost to follow-up or had to be excluded from the study. All the remaining 74 patients (42 HoLEP vs. 32 OP patients, p=0.11) had undergone the 5-yr follow-up assessments. Mean AUA-SS was 3.0 in both groups (p=0.98), mean Qmax was 24.4 ml/s in both groups (p=0.97) and PVRU volume was 11 ml in the HoLEP and 5 ml in the OP group (p=0.25). Late complications consisted of urethral strictures and bladderneck contractures; reoperation rates were 5% in the HoLEP and 6.7% in the OP group (p=1.0). No patient developed benign prostatic hyperplasia recurrence. Level of Study 2 9. Naspro R, Suardi N, Salonia A, Scattoni V, Guazzoni G, Colombo R, et al. Holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24-month follow-up. European Urology 2006;50: RCT 80 Prospectively evaluate perioperative outcomes and 2-yr follow-up after holmium laser enucleation (HoLEP) and standard open prostatectomy (OP) for treating benign prostatic hyperplasia-related obstructed voiding symptoms, with prostates >70 g. Operating room time was significantly shorter for the OP group (72.09+/ min vs / min, p<0.0001); catheter removal (1.5+/-1.07 d and 4.1+/-0.5 d, p<0.001) and hospital stay (2.7+/-1.1 d vs. 5.4+/-1.05 d, p<0.001) were shorter in the HoLEP group. Blood loss was less and blood transfusions fewer in the HoLEP group (p<0.001). In both groups urodynamic and uroflowmetry findings improved from baseline, were still evident at the 24-mo follow-up, and were comparable between the two groups. Late complications were also comparable. Level of Study Skolarikos A, Papachristou C, Athanasiadis G, Chalikopoulos D, Deliveliotis C, Alivizatos G. Eighteen-month results of a randomized prospective study comparing transurethral photoselective vaporization with transvesical open enucleation for prostatic adenomas greater than 80 cc. Journal of Endourology 2008;22: RCT 125 This is a prospective randomized study showing that for large prostatic adenomas, photoselective vaporization of the prostate requires less blood transfusions, shorter catheterization time and shorter hospital stay compared to open prostatectomy, while achieving similar functional results at the same time Longer length of operation time, shorter length of catheterization and hospital stay were experienced by patients who underwent PVP. Although patients who underwent OP showed a higher transfusion rate, adverse events in general were minor and of similar profile in both groups. All functional parameters improved significantly compared to baseline values in both groups. There was no difference in IPSS between the two groups at 3, 6, 12, and 18 months postoperatively. who underwent OP scored better in the IPSS-Quality of life score at 18 months postoperatively. 114

116 전립선비대증진료권고안 At 18 months there were no significant differences between the two groups in the Qmax, post void residual urine volume and in the International Index for Erectile function-5 questionnaire. At three months prostate volume was significantly lower in the OP group and remained as such throughout follow-up. Level of Study Chen H, Tang P, Ou R, Deng X, Xie K. Holmium laser enucleation versus open prostatectomy for large volume benign prostatic hyperplasia: a meta-analysis of the therapeutic effect and safety. Nan Fang Yi Ke Da Xue Xue Bao 2012;32: Metanalysis To compare holmium laser enucleation (HoLEP) versus open prostatectomy (OP) for large volume benign prostatic hyperplasia. Three RCTs were included in the analysis. No significant differences were found in IPSS or Qmax between HoLEP and OP (P>0.05). Compared with OP, HoLEP was associated with significantly less blood loss, a shorter catheterization time and a shorter hospital stay, but a longer operating time. HoLEP and OP were similar in terms of urethral stricture, stress incontinence, transfusion requirement and the rate of reintervention. Level of Study Lee SW, Choi JB, Lee KS, Kim TH, Son H, Jung TY, et al. Transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement: a quality and metaanalysis. Int Neurourol J. 2013;17: meta-analysis Thanks to advancements in surgical techniques and instruments, many surgical modalities have been developed to replace transurethral resection of the prostate (TURP). However, TURP remains the gold standard for the surgical treatment of benign prostatic hyperplasia (BPH). We conducted a meta-analysis on the efficacy and safety of minimally invasive surgical therapies for BPH compared with TURP. Only 2 articles (5.56%) were assessed as having a low risk of bias by use of the Cochrane collaboration risk of bias tool. On the other hand, by use of the Jadad scale, there were 26 highquality articles (72.22%). Furthermore, 28 articles (77.78%) were assessed as high-quality articles by use of the van Tulder scale. Holmium laser enucleation of the prostate (HoLEP) showed the highest reduction of the International Prostate Symptom Score compared with TURP (P<0.0001). Bipolar TURP, bipolar transurethral vaporization of the prostate, HoLEP, and open prostatectomy showed superior outcome in postvoid residual urine volume and maximum flow rate. The intraoperative complications of the minimally invasive surgeries had no statistically significant inferior outcomes compared with TURP. Also, there were no statistically significant differences in any of the modalities compared with TURP. Level of Study 1 115

117 Korean clinical practice guideline for benign prostate hyperplasia 참고문헌 1. Fitzpatrick JM. Minimally invasive and endoscopic management of benign prostatic hyperplasia. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh Urology. 10th Ed. Philadelphia: Elsevier Saunders; 2012; Baazeem A, Elhilali MM. Surgical management of benign prostatic hyperplasia: current evidence. Nat Clin Pract Urol 2008;5: Borboroglu PG, Kane CJ, Ward JF, et al. Immediate and postoperative complications of transurethral prostatectomy in the 1990s. J Urol 1999;162: Tubaro A, Carter S, Hind A, et al. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. J Urol 2001;166: Mearini E, Marzi M, Mearini L, et al. Open prostatectomy in benign prostatic hyperplasia: 10-year experience in Italy. Eur Urol 1998;34: Serretta V, Morgia G, Fondacaro L, et al. Open prostatectomy for benign prostatic enlargement in southern Europe in the late 1990s: a contemporary series of 1800 interventions. Urology 2002;60: Giulianelli R, Brunori S, Gentile BC, Vincenti G, Nardoni S, Pisanti F, et al. Comparative randomized study on the efficaciousness of treatment of BOO due to BPH in patients with prostate up to 100 gr by endoscopic gyrus prostate resection versus open prostatectomy. Preliminary data. Arch Ital Urol Androl 2011;83: Kuntz RM, Lehrich K, Ahyai SA. Holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial. European Urology 2008;53: Naspro R, Suardi N, Salonia A, Scattoni V, Guazzoni G, Colombo R, et al. Holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24-month follow-up. European Urology 2006;50: Skolarikos A, Papachristou C, Athanasiadis G, Chalikopoulos D, Deliveliotis C, Alivizatos G. Eighteen-month results of a randomized prospective study comparing transurethral photoselective vaporization with transvesical open enucleation for prostatic adenomas greater than 80 cc. Journal of Endourology 2008;22: Chen H, Tang P, Ou R, Deng X, Xie K. Holmium laser enucleation versus open prostatectomy for large volume benign prostatic hyperplasia: a meta-analysis of the therapeutic effect and safety. Nan Fang Yi Ke Da Xue Xue Bao 2012;32: Lee SW, Choi JB, Lee KS, Kim TH, Son H, Jung TY, et al. Transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement: a quality and meta-analysis. Int Neurourol J. 2013;17:

118 전립선비대증진료권고안 KQ11. 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경우 에는어떠한치료가권장되는가? 권고사항권고수준근거수준 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경 우간헐적자가도뇨또는도뇨관유치를권장한다. Strong B 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경 우 TUMT 또는 TUNA 를고려할수있다. 그러나장기적인치료효과 ( 재치료및 증상개선정도 ) 는 TURP 에비해좋지않다. Strong A 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경 우전립선내약물주입이시도되고있으나임상적용은권고하지않는다. Strong A 전립선비대증의수술적치료는약물치료에도불구하고하부요로증상이호전되지않는환자, 약물치료를원하지않고적극적인치료를원하는중등도이상의하부요로증상을호소하는환자, 불응성혹은재발성요폐환자, 일상생활에지장을줄정도의심한하부요로증상환자, 전립선비대증으로인한신기능의저하, 5α환원효소억제제를이용한약물치료에도불구하고지속되는혈뇨환자, 그리고방광결석환자가그적응이되고있다. 그러나, 심각한기저질환이있거나이로인한약물치료를중단하기어려운경우 ( 예, 항혈소판제제, 항응고제 ), 수술적치료로인한부작용을원치않은경우, 극히고령의환자인경우에는수술적치료를시행하기어렵거나선뜻수술적치료를결정하기어렵다. 이러한환자들을대상으로몇가지방법이소개되거나현재시도되고있으며, 대표적인방법으로도뇨관을이용한배뇨 [1-5], 경요도극초단파온열요법 (TUMT) 이나경요도침소작술 (TUNA) 등의최소침습적치료, stent의삽입그리고 ethanol 이나 botulinum toxin 등의전립선내약물주입등이있다. 우선도뇨관을이용하는경우환자및보호자의삶의질이나만족도, 그리고감염등의부작용측면에서간헐적도뇨를우선선택하는것이유리하다 [2-4]. 그러나환자스스로이를시행하기어렵거나소변으로인한위생악화그리고피부질환등이문제가되는경우에는요도및치골상부 117

119 Korean clinical practice guideline for benign prostate hyperplasia 를통한도뇨관유치를고려할수있다. 최소침습적치료 ( 예, TUMT, TUNA) 를고려하는경우기존경요도전립선절제술 (TURP) 에비해합병증이적고, 국소마취하에서도시술이가능하며, 치료효과또한 TURP와비교하여별다른차이가없다고보고되었으나재치료율등장기적인치료효과측면에서다소미흡한점이있음을고려해야한다 [6-11]. 최근다른최소침습적치료로전립선내 enthanol [12], botulinum toxin [13-15], NX-1203 [16], PRX-302 [17] 등의약물주입이나전립선동맥색전술 [18] 등이시행된연구결과가보고되고있으나, 임상적적용에는좀더많은연구가필요한실정이다. Stent 의삽입을고려하는경우임시적혹은영구적인삽입이가능하며, 특히기저질환이급성악화를보이며도뇨관의유치를원하지않을경우임시적인 stent 삽입을고려할수있다. 추가로요도를통해장기간도뇨관을유치하는경우이를대신해시행할수있다. 그러나유치된 stent의이동, 요도상피의증식에의한폐색, 회음부의불편감및저장증상의악화등부작용이발생할수있음을고려해야한다 [19-20]. 근거표 KQ Ghalayini IF, Al-Ghazo MA, Pickard RS. A prospective randomized trial comparing transurethral prostatic resection and clean intermittent self-catheterization in men with chronic urinary retention. BJU Int 2005;96:93-7. RCT 41 patients To determine whether a preliminary period of clean intermittent self catheterization (CISC) before transurethral resection of the prostate (TURP) improves bladder contractility and surgical outcome in men with chronic urinary retention (CUR), and whether pressure-flow studies (PFS) before TURP predict the outcome. Of the 41 patients, 17 (mean age 67 years, range 52 84) were randomized to immediate TURP and 24 (mean age 69 years, range 55 85) to CISC. There was a significant improvement in IPSS and quality of life at 6 months in both groups (P<0.001). In the CISC group there was a significant improvement in voiding and end-filling pressures, indicating recovery of bladder function (P<0.001 for each). Of the 41 men, nine (22%) with voiding pressures of 45 cmh2o had no significant improvement in symptoms or urodynamic variables. Detrusor overactivity was found in 17 (41%) patients, of whom six had upper tract dilatation which 118

120 전립선비대증진료권고안 Level of Study 2 2. Logan K, Shaw C, Webber I, Samuel S, Broome L. experiences of learning clean intermittent self-catheterization: A qualitative study. J Adv Nurs 2008;62: Qualitative study 15 patients To explore the experiences of learning to carry out clean intermittent self-catheterization and user views of service provision. Themes identified were psychological issues, physical problems and service interaction. The communication skills of nurses helped facilitate the learning experience. In conjunction with nurses' skills, a friendly relaxed approach alleviated embarrassment and anxiety, thus facilitating information exchange and retention of information. Level of Study 3 3. Saint S, Lipsky BA, Baker PD, McDonald LL, Ossenkop K. Urinary catheters: What type do men and their nurses prefer? J Am Geriatr Soc1999;47: Qualitative study-interviews 104 patients, 99 nursing staff members Urinary catheters are used frequently, but the relative risks and benefits of different types of devices are not clear. We sought to determine the beliefs of both older male patients and nursing staff about the relative merits and problems of condom and indwelling catheters. were mostly older and predominantly hospitalized on the medical service. Compared with those using an indwelling catheter, patients using a condom catheter were more likely to believe that their catheter was comfortable (86 vs 58%, P =.04) and less likely to believe it was painful (14 vs 48%, P =.008) or to restrict their activity (24 vs 61%, P =.002). The nursing staff had a mean of 13 years nursing experience, and the majority worked in the nursing home unit. Most of the nursing staff respondents believed that condom catheters were less painful and restrictive for patients and were easier to apply, but they also believed that they fell off and leaked more often and required more nursing time. Level of Study 3 4. Shaw C, Logan K, Webber I, Broome L, Samuel S. Effect of clean intermittent selfcatheterization on quality of life: A qualitative study. J Adv Nurs 2008;61: Quallitative study 15 patients to describe the experience of people carrying out clean intermittent self-catheterization and the impact on their quality of life 119

121 Korean clinical practice guideline for benign prostate hyperplasia The core category consisted of two subcategories of positive and negative impacts. Positive impacts were related to improvement in lower urinary tract symptoms, whereas the negative impacts resulted from the practical difficulties encountered, and the psychological and cultural context of worry and stigma. The factors influencing variations in quality of life impacts were sex, lifestyle, frequency and duration of carrying out self-catheterization, technical difficulties, type of catheter, comorbidities and individual predispositions. Level of Study 3 5. Jakobsson L. Indwelling catheter treatment and health-related quality of life in men with prostate cancer in comparison with men with benign prostatic hyperplasia. Scand J Caring Sci 2002;16: Cohort study 108 patients The aim of this study was to investigate what was felt of uneasiness when having an indwelling urinary catheter installed and while wearing it, and the problems related to catheter handling in men with prostate cancer in comparison with men with BPH. The aim was also to investigate the association between health-related quality of life (HRQOL) and SOC in the two groups Men with catheter experience (prostate cancer n = 71, BPH n = 37) were selected from a larger questionnaire study. Assessment was made with study-specific questions together with the QLQ C-30 assessing HRQOL and the SOC questionnaire measuring sense of coherence. Data reduction method was applied to study specific variables to determine problem patterns. Correlation between HRQOL and SOC was determined. Results showed similar problem patterns in men with prostate cancer and BPH: discomfort in wearing catheter (e.g. uneasiness 48.2%), practical and psychosocial difficulties in handling and wearing catheter (e.g. attaching catheter 32.4%) and discomfort at installation (e.g. pain 29.7%). There was lack of knowledge about wearing and practical handling of the catheter. Having a cancer diagnosis did not add to uneasiness or practical problems. Life quality was correlated to SOC (p <or= 0.001). Level of Study 3 6. D Ancona FC, van der Bij AK, Francisca EA, Kho H, Debruyne FM, Kiemeney LA, et al. Results of high-energy transurethral microwave thermotherapy in patients categorized according to the ameerican society of anesthesiologists operative risk classification. Urology 1999;53: Cohort study 246 patients To evaluate the relation between the American Society of Anesthesiologists (ASA) classification and response to transurethral microwave thermotherapy (TUMT) in patients with lower urinary tract symptoms and benign prostatic hyperplasia (BPH). There was a significant improvement in objective and subjective parameters at 12, 26, and 52 weeks of follow-up in both ASA 1 and 2 patients and ASA 3 and 4 patients. There was no difference in objective and subjective improvement between both groups at each point of follow-up. Objective and subjective improvement in ASA 3 and 4 patients with cardiovascular disease and ASA 3 and 4 patients with noncardiovascular disease was the same, although patients with cardiovascular disease received less energy during TUMT. Using logistic regression analysis, ASA classification was not predictive of response after high-energy TUMT. 120

122 전립선비대증진료권고안 Level of Study 3 7. de la Rosette JJ, Laguna MP, Gravas S, de Wildt MJ. Transurethral microwave thermotherapy: The gold standard for minimally invasive therapies for patients with benign prostatic hyperplasia? J Endourol 2003;17: Meta-analysis 4 studies Describes the status of TUMT in the treatment of lower urinary tract symptoms related to BPH, focusing on variations in the outcomes with different devices, the durability of treatment outcomes, morbidity, selection criteria, and cost. The relation of TUMT to medical management and TURP also is addressed. The literature supports TUMT as the only viable treatment among the minimally invasive options for BPH that have appeared during the past decade. The clinical trials report durable and significant symptomatic and objective improvement with minimum morbidity. In sum, TUMT is anesthesia free, safe and effective. Also, economic considerations favor this truly outpatientbased procedure. Level of Study 1 8. Hill B, Belville W, Bruskewitz R, Issa M, Perez-Marrero R, Roehrborn C, et al. Transuethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective, randomized, multicenter clinical trial. J Urol 2004;171: RCT 121 patients the 5-year efficacy and safety of transurethral needle ablation of the prostate (TUNA) compared to transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Improvement from baseline for TUNA and TURP retained statistical significance at each interval for International Prostate Symptom Score, quality of life and peak flow rate. Post-void residual volume was statistically significant at all time points for TURP and at year 5 for TUNA. The TURP group reported 41% retrograde ejaculation, while the TUNA group reported none. The incident of erectile dysfunction, incontinence and stricture formation was also greater in TURP than in TUNA cases with significantly fewer adverse events for TUNA than for TURP. Level of Study 2 9. Mattiasson A, Wagrell L, Schelin S, Nordling J, Richthoff J, Magnusson B, et al. Five- year follow-up of feedback microwave thermotherapy versus TURP for clinical BPH: A prospective randomized multicenter study. Urology 2007;69:91-6. RCT 154 patients 121

123 Korean clinical practice guideline for benign prostate hyperplasia Level of Study 2 Level of Study 1 To compare the efficacy and safety of transurethral microwave thermotherapy (TUMT) with ProstaLund Feedback Treatment, using the CoreTherm device, with transurethral resection of the prostate (TURP) 5 years after treatment. Of the 154 patients, 66% completed the 60 months of follow-up. Statistically significant improvements in the TUMT and TURP groups were observed for IPSS, QOL, and Qmax at 60 months. The average values for the TUMT group were an IPSS of 7.4, QOL score of 1.1, and Qmax of 11.4 ml/s. The values for the TURP group were IPSS of 6.0, QOL score of 1.1, and Qmax of 13.6 ml/s. No statistically significant differences were found in any of these variables between the two treatment groups. In the TUMT group, 10% needed additional treatment versus 4.3% in the TURP group. 10. Bouza C, Lopez T, Magro A, Navalpotro L, Amate JM. Systemic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia. BMC Urol 2006;6:14. Systemic review and meta-analysis 35 studies To ascertain the efficacy and safety of TUNA in the treatment of BPH. 35 studies (9 comparative, 26 non-comparative) were included. Although evidence was limited by methodological issues, the analysis of relevant outcomes indicates that while TUNA significantly improves BPH parameters with respect to baseline, it does not reach the same level of efficacy as TURP in respect to all subjective and objective variables. Further, its efficacy declines in the long-term with a rate of secondary-treatment significantly higher than of TURP [OR: 7.44 (2.47, 22.43)]. Conversely, TUNA seems to be a relatively safe technique and shows a lower rate of complications than TURP [OR:0.14 (0.05, 0.14)] with differences being particularly noteworthy in terms of postoperative bleeding and sexual disorders. Likewise, TUNA has fewer anesthetic requirements and generates a shorter hospital stay than TURP [WMD: -1.9 days (-2.75, -1.05)]. Scarce data and lack of replication of comparisons hinder the assessment of TUNA vs. other local therapies. No comparisons with medical treatment were found. 11. Hoffman RM, Monga M, Elliott SP, Macdonald R, Langsjoen J, Tacklind J, et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012:CD Systemic review 15 studies, 1,585 patients To assess the therapeutic efficacy and safety of microwave thermotherapy techniques for treating men with symptomatic benign prostatic obstruction. In this update, we identified no new randomized comparisons of TUMT that provided evaluable effectiveness data. Fifteen studies involving 1,585 patients met the inclusion criteria, including six comparisons of microwave thermotherapy with TURP, eight comparisons with sham thermotherapy procedures, and one comparison with an alpha-blocker. Study durations ranged from 3 to 60 months. The mean age of participants was 66.8 years and the baseline symptom scores and urinary flow rates, which did not differ across treatment groups, demonstrated moderately severe lower urinary tract symptoms. The pooled mean urinary symptom scores decreased by 65% with TUMT and by 77% with TURP. The weighted mean difference (WMD) with 95% confidence interval (CI) for the International Prostate Symptom Score (IPSS) was (95% CI to -0.03), favoring TURP. The pooled mean peak urinary flow increased by 122

124 전립선비대증진료권고안 Level of Study 1 Level of Study 2 Level of Study 3 70% with TUMT and by 119% with TURP. The WMD for peak urinary flow was 5.08 ml/s (95% CI 3.88 to 6.28 ml/s), favoring TURP. Compared to TURP, TUMT was associated with decreased risks for retrograde ejaculation, treatment for strictures, hematuria, blood transfusions, and the transurethral resection syndrome, but increased risks for dysuria, urinary retention, and retreatment for BPH symptoms. Microwave thermotherapy improved IPSS symptom scores (WMD -5.15, 95% aci to -6.04) and peak urinary flow (WMD 2.01 ml/s, 95% CI 0.85 to 3.16) compared with sham procedures. Microwave thermotherapy also improved IPSS symptom scores (WMD -4.20, 95% CI to -5.25) and peak urinary flow (WMD 2.30 ml/s, 95% CI 1.47 to 3.13) in the one comparison with alpha-blockers. No studies evaluated the effects of symptom duration, patient characteristics, prostate-specific antigen levels, or prostate volume on treatment response. 12. Li Y, Zhao Q, Dong L. Efficacy and safety of ultrasound-guided transrectal ethanol injection for the treatment of benign prostatic hyperplasia in patients with high-risk comorbidities: A longterm study at a single tertiary care institution. Urology 2014;83: Prospective cohort study 70 patients To evaluate the efficacy and safety of ultrasound-guided transrectal ethanol injection for the treatment of benign prostatic hyperplasia (BPH) in patients with high-risk comorbidities. After 24 months of treatment, prostate volume, international prostate symptom score, quality of life score, and postvoid residual of patients were significantly reduced when compared with the pretreatment values (55.9 ± 16.7 vs 46.8 ± 8.1 ml, 29.3 ± 6.7 vs 9.8 ± 2.4 points, 5.3 ± 1.7 vs 1.9 ± 0.7 points, and ± 71.5 vs 25.9 ± 12.0 ml, respectively, P <.05). Qmax significantly increased to 15.3 ± 3.2 ml/s than the pretreatment Qmax of 4.7 ± 3.1 ml/s (P =.001). Four of 36 patients who received a high dose of ethanol developed liquefaction necrosis and urinary tract injury (2 patients each). However, the subsequent 34 patients received a reduced dose of ethanol and had no complications. 13. Kuo H-C. Prostate botulinum A toxin injection-an alternative treatment for benign prostatic obstruction in poor surgical candidates. Urology 2005;65: Prospective cohort study 10 patients To evaluate, in a prospective study, the effectiveness of prostate injection of botulinum A toxin in patients who were poor surgical candidates. with benign prostatic hyperplasia (BPH) are usually successfully treated with medical treatment or transurethral resection. However, some patients with chronic urinary retention or a large postvoid residual urine volume due to BPH are poor surgical candidates or are patients in whom medical treatment has failed. All patients had an improvement in spontaneous voiding after treatment. Of them, 8 had an excellent result (80%) and 2 had an improved result. Both voiding pressure and postvoid residual volume were significantly decreased after treatment. The total prostate volume was significantly reduced, and the maximal flow rate was significantly increased after treatment. The maximal effects of botulinum A toxin appeared at about 1 week and were maintained at 3 and 6 months after treatment. At 6 to 12 months (mean 9) of follow-up, no patient had had recurrence of urinary retention and the voiding condition in all patients remained at the posttreatment status. No adverse effect was noted. 123

125 Korean clinical practice guideline for benign prostate hyperplasia 14. Silva J, Silva C, Saraiva L, Silva A, Pinto R, Dinis P, et al. Intraprostatic botulinum toxin type a injection in patients unfit for surgery presenting with refractory urinary retention and benign prostatic enlargement. Effect on prostate volume and micturition resumption. Eur Urol 2008;53: Prospective cohort study 21 patients To evaluate the effect of intraprostatic injection of botulinum toxin A (BoNTA) on prostate volume and refractory urinary retention in patients with benign prostatic enlargement. had a mean age of 80 _ 2 yr. Injections were done without anaesthetic support as an outpatient procedure. No significant local effects occurred. Baseline prostate volume of 70 _ 10 ml decreased to 57 _ 10 ml (p < ) at 1mo and to 47 _7ml (p =0.03 against 1 mo) at 3 mo. At 1 mo, 16 patients (76%) could resume voiding with a mean Qmax of 9.0 _ 1.2 ml/s. At 3 mo, 17 patients (81%) voided with a meanqmax of 10.3 _ 1.4 ml/s. Residual urine was 80 _ 19 ml and 92 _ 24 ml at the two time points, respectively. Mean serum total PSA decreased from 6.0 _ 1.1 ng/ ml at baseline to 5.0 _ 0.9 ng/ml at 3 mo (p = 0.04). Level of Study Marchal C, Perez JE, Herrera B, Machuca FJ, Redondo M. The use of botulinum toxin in benign prostatic hyperplasia. Neurourol Urodyn 2012;31: Meta-analysis 24 studies To summarize the action mechanisms of BoNT/A on experimental animals and to analyze its effectiveness according to published clinical studies We located 24 papers on the treatment of HBP with BoNT/A. The doses applied ranged from 100 (OnabotA) to 600 U (OnabotA and AbobotA). The IPSS score presented a mean posttreatment reduction, for all series, of 10.8 þ 2.66 points. Other significant results included the overall mean reduction in QoL score of 2.1 _ 0.62 points, and the pre and post-treatment differences in prostate volume (22.43 _ 20.2 cm 3 ), post-voiding residue (76.77 þ cm 3 ) and PSA (1.15 þ 0.93 ng/ml). However, only two clinical trials were on sufficient quality to be selected for meta-analysis, and it was observed that the difference of the means, preand post-treatment of maximum flow, prostate volume, IPSS and PSA were not statistically significant (P ¼ 0.18). Neither was there any statistically significant difference between pre- and post-treatment post-voiding residue(p ¼ 0.65). In conclusion, BoNT/A alleviates lower urinary tract symptoms due to HBP, but different studies present considerable variations regarding the dose administered, inclusion criteria and follow-up time, as well as poorly defined retreatment, losses to follow up and, above all, a high degree of variability in the communication of results (with large standard deviations). Level of Study Andersson KE. Intraprostatic injections for lower urinary tract symptoms treatment. Curr Opin Urol 2014;24:

126 전립선비대증진료권고안 Systemic review 2 RCT Patient : 85 The purpose of this study is to review and discuss recently published ( ) experimental and clinical studies of intraprostatic injection therapy as an alternative treatment of lower urinary tract symptoms (LUTS). Recent focus has been on intraprostatic injection of botulinum toxin both with regard to mechanism of action and efficacy. In contrast to the promising findings in several previous studies, a recent large, randomized, placebo-controlled trial found no differences between onabotulinumtoxin A treatment and placebo. There is little new information on the use of anhydrous ethanol and agents such as NX-1207 and PRX302, which previously have been reported to have promising effects. Level of Study Denmeade SR, Egerdie B, Steinhoff G, Merchant R, Abi-Habib R, Pommerville P. Phase 1 and 2 studies demonstarate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2011;59: Studies without consistently applied reference standards Phase 1: 15 patients, Phase 2: 18 patients To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH. Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had 30% improvement compared to baseline in IPSS out to day 360. also experienced improvement in QoL and reduction in prostate volume out to day 360. receiving 1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size. Level of Study Pisco JM, Rio Tinto H, Campos Pinheiro L, Bilhim T, Duarte M, Fernandes L, et al. Embolisation of prostatic arteries as treatment of moderate to severe lower urinary symptoms (LUTS) secondary to benign hyperplasia: Results of short- and mid-term follow-up. Eur Radiol 2013;23: Cohort study 255 patients To evaluate the short- and medium-term results of prostatic arterial embolisation (PAE) for benign prostatic hyperplasia (BPH). PAE was technically successful in 250 patients (97.9 %). Mean follow-up, in 238 patients, was 10 months (range 1-36). Cumulative rates of clinical success were 81.9 %, 80.7 %, 77.9 %, 75.2 %, 72.0 %, 72.0 %, 72.0 % and 72.0 % at 1, 3, 6, 12, 18, 24, 30 and 36 months, respectively. There was one major complication. Level of Study 3 125

127 Korean clinical practice guideline for benign prostate hyperplasia 19. Masood S, Djaladat H, Kouriefs C, Keen M, Palmer JH. The 12-year outcome analysis of an endourethral wallstent for treating benign prostatic hyperplasia. BJU Int 2004;94: Cohort study 62 patients To evaluate the long-term results of using the Urolume(TM) endourethral prosthesis (American Medical Systems, Minnetonka, MN, USA) for managing benign prostatic hyperplasia (BPH), an alternative minimally invasive option. Twenty-two and 11 patients completed the 5- and 12-year follow-up, respectively. Twenty-one (34%) patients died with the stent in situ from causes unrelated to BPH and Urolume insertion. Twenty-nine (47%) stents were removed; 18 in the first 2 years, seven at 3-5 years and four at 9-10 years. Early stent explantation was primarily a result of poor case selection, or stent malposition/migration. Four stents were removed because the patient was dissatisfied. Late stent explantation was for symptom progression. At 5 years, the symptom score and PFR were 6.82 an 11.7 ml/s, respectively, compared with 20.4 and 9 ml/s at basleine (P < 0.05); at 12 years, the symptom score, PFR and PVR were 10.82, 11.5 ml/s and 80 ml, respectively. The mean quality of life score was 2 and no patient opted for any further treatment. Level of Study Armitage JN, Cathcart PJ, Rashidian A, De Nigris E, Emberton M, van der Meulen JH. Epithelializing stent for benign prostatic hyperplasia: A systematic review of the literature. J Urol 2007;177: Systemic review 20 studies, 990 patients To review the literature on the effectiveness, durability and safety of the UroLume stent for men with benign prostatic hyperplasia. A total of 20 case series evaluated the UroLume stent in a total of 990 patients with benign prostatic hyperplasia. Of the patients 84% who were catheter dependent voided spontaneously after stent insertion. Ten studies assessed symptoms before stent insertion and at some point within 1 year after stent insertion. All reported decreases in symptom scores, including Madsen- Iversen by 7.9 to 14.3 points and International Prostate Symptom Score by 10 to 12.4 points. Peak urine flow rates increased by 4.2 to 13.1 ml per second. A total of 104 stents (16%) failed in 606 patients who were evaluable at 1 year and migration was the commonest cause of failure (38 stents or 37%). Most patients initially experienced perineal pain or irritative voiding symptoms following stent placement. Level of Study 1 참고문헌 1. Ghalayini IF, Al-Ghazo MA, Pickard RS. A prospective randomized trial comparing transurethral prostatic resection and clean intermittent self-catheterization in men with chronic urinary retention. BJU Int 2005;96: Logan K, Shaw C, Webber I, Samuel S, Broome L. experiences of learning clean intermittent self-catheterization: A 126

128 전립선비대증진료권고안 qualitative study. J Adv Nurs 2008;62: Saint S, Lipsky BA, Baker PD, McDonald LL, Ossenkop K. Urinary catheters: What type do men and their nurses prefer? J Am Geriatr Soc 1999;47: Shaw C, Logan K, Webber I, Broome L, Samuel S. Effect of clean intermittent self-catheterization on quality of life: A qualitative study. J Adv Nurs 2008;61: Jakobsson L. Indwelling catheter treatment and health-related quality of life in men with prostate cancer in comparison with men with benign prostatic hyperplasia. Scand J Caring Sci 2002;16: D Ancona FC, van der Bij AK, Francisca EA, Kho H, Debruyne FM, Kiemeney LA, et al. Results of high-energy transurethral microwave thermotherapy in patients categorized according to the ameerican society of anesthesiologists operative risk classification. Urology 1999;53: de la Rosette JJ, Laguna MP, Gravas S, de Wildt MJ. Transurethral microwave thermotherapy: The gold standard for minimally invasive therapies for patients with benign prostatic hyperplasia? J Endourol 2003;17: Hill B, Belville W, Bruskewitz R, Issa M, Perez-Marrero R, Roehrborn C, et al. Transuethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective, randomized, multicenter clinical trial. J Urol 2004;171: Mattiasson A, Wagrell L, Schelin S, Nordling J, Richthoff J, Magnusson B, et al. Five- year follow-up of feedback microwave thermotherapy versus TURP for clinical BPH: A prospective randomized multicenter study. Urology 2007;69: Bouza C, Lopez T, Magro A, Navalpotro L, Amate JM. Systemic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia. BMC Urol 2006;6: Hoffman RM, Monga M, Elliott SP, Macdonald R, Langsjoen J, Tacklind J, et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012:CD Li Y, Zhao Q, Dong L. Efficacy and safety of ultrasound-guided transrectal ethanol injection for the treatment of benign prostatic hyperplasia in patients with high-risk comorbidities: A long-term study at a single tertiary care institution. Urology 2014;83: Kuo H-C. Prostate botulinum A toxin injection-an alternative treatment for benign prostatic obstruction in poor surgical candidates. Urology 2005;65: Silva J, Silva C, Saraiva L, Silva A, Pinto R, Dinis P, et al. Intraprostatic botulinum toxin type a injection in patients unfit for surgery presenting with refractory urinary retention and benign prostatic enlargement. Effect on prostate volume and micturition resumption. Eur Urol 2008;53: Marchal C, Perez JE, Herrera B, Machuca FJ, Redondo M. The use of botulinum toxin in benign prostatic hyperplasia. Neurourol Urodyn 2012;31: Andersson KE. Intraprostatic injections for lower urinary tract symptoms treatment. Curr Opin Urol 2014;24: Denmeade SR, Egerdie B, Steinhoff G, Merchant R, Abi-Habib R, Pommerville P. Phase 1 and 2 studies demonstarate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2011;59: Pisco JM, Rio Tinto H, Campos Pinheiro L, Bilhim T, Duarte M, Fernandes L, et al. Embolisation of prostatic arteries as treatment of moderate to severe lower urinary symptoms (LUTS) secondary to benign hyperplasia: Results of short- and mid-term followup. Eur Radiol 2013;23: Masood S, Djaladat H, Kouriefs C, Keen M, Palmer JH. The 12-year outcome analysis of an endourethral wallstent for treating benign prostatic hyperplasia. BJU Int 2004;94: Armitage JN, Cathcart PJ, Rashidian A, De Nigris E, Emberton M, van der Meulen JH. Epithelializing stent for benign prostatic hyperplasia: A systematic review of the literature. J Urol 2007;177:

129 Korean clinical practice guideline for benign prostate hyperplasia KQ 12. 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇 이며, 추적관찰의기간은어떻게설정하여야하는가? 권고사항권고수준근거수준 전립선비대증치료후추적관찰간격과검사의종류는개별환자의중증 도와임상지표를고려하여임상의사의경험이나판단에따른다. Strong C 전립선비대증의진행을확인하기위해서는국제전립선증상점수, 직장수 지검사, 혈청전립선특이항원검사, 요속검사, 잔뇨량측정그리고전립선초음파 등을시행한다. Strong C 추적관찰 전립선비대증을진단받은모든환자는증상의진행이있는지, 치료방침의변화가필요한지, 또는추가적인검사가필요한지확인하기위해추적관찰이필요하다. 추적관찰간격은치료종류에따라차이가있으며, 적절한간격에대한근거는아직부족한실정이어서임상의사의경험이나판단에따른다. 1. 대기요법또는행동요법대기요법또는행동요법을시행하는환자들은첫 6개월째, 그이후에는 1년마다재평가를통해증상의변화여부및수술적치료가필요한지를확인한다. 권장하는검사는국제전립선증상점수, 직장수지검사, 요속검사그리고잔뇨량측정이다. 2. 알파차단제알파차단제를투여하는경우, 투여시작후 2-6주에추적관찰을하여증상호전이있거나알파차단제로인한부작용이없는경우치료를지속할수있다. 이후에는 6-12개월간격으로추적관찰하도록한다 [1-4]. 권장하는검사는국제전립선증상점수, 직장수지검사, 요속검사그리고잔뇨량측정이다. 128

130 전립선비대증진료권고안 3. 5α환원효소억제제 5α환원효소억제제의효과는 주에나타나므로투여시작후 주에추적관찰하여치료반응을확인하고부작용여부를확인한다 [3,5,6]. 그이후에는 6-12 개월간격으로추적하도록한다. 5α환원효소억제제를투여하는환자의여명이 10년이상인경우, 전립선암이발견되어치료방침이바뀔수있는경우에는 5α환원효소억제제투여 6개월째전립선특이항원수치를측정하고이를새로운기준점으로잡고이후연속적인전립선특이항원수치측정을통해증가여부를확인하도록한다. 권장하는검사는국제전립선증상점수, 직장수지검사, 요속검사, 잔뇨량측정, 혈청전립선특이항원검사그리고전립선초음파등이다. 4. 항콜린제, 데스모프레신항콜린제를투여하는경우에는증상이안정화될때까지는 4-6주간격으로추적하며효과및부작용여부를확인한다. 증상이안정화된이후에는 6-12 개월간격으로추적관찰을권장한다. 데스모프레신을투여하는경우투여시작후 3일, 7일, 그리고 1달째혈중나트륨수치를측정하고이후매 3개월마다재확인하도록한다. 또한배뇨일지를작성하여치료반응을확인하도록한다. 5. 수술치료수술치료이후, 도뇨관을제거하고 4-6 주뒤치료결과와조직검사결과확인을위해추적관찰하여야한다 [6-8]. 치료에실패한환자들은압력요류검사를포함한요역동학검사를시행하여야한다. 권장하는검사는국제전립선증상점수, 직장수지검사, 요속검사그리고잔뇨량측정이다. 6. 보완대체요법아직보완대체요법들의효과와지속성에대한확실한증거가미약하기때문에장기추적관찰이필요하다. 추적관찰간격은치료방법에따라달라질수있으며보통은 6주, 3개월, 6개월간격으로추적하도록한다. 권장하는검사는국제전립선증상점수, 직장수지검사, 요속검사그리고잔뇨량측정이다. 129

131 Korean clinical practice guideline for benign prostate hyperplasia 근거표 KQ Chung BH. Medical management for benign prostatic hyperplasia. Korean J Urol 2007;48: Review To summarize our current management for benign prostatic hyperplasia Level of Study 5 2. Joung JY, Park JK, Park CH, Lee JG, Chung BH, Hong SJ, et al. The role of alpha 1 (A) adrenoceptor antagonist tamsulosin for the treatment of patients with benign prostatic hyperplasia:the effect on lower urinary tract symptoms and nocturia. Korean J Urol 2006;47:1-6. Case-control study 268 patients with BPH treated with tamsulosin at a dose of 0.2 mg/day. effectiveness of administering alpha 1 (A)-adrenoceptor antagonist tamsulosin for the patients with benign prostatic hyperplasia The change of nocturnal frequency was 2.2 at baseline to 1.4 after 12 weeks of treatment. Level of Study 4 3. Jeong DH, Park YI. Clinical experience of symptomatic management of BPH with terazosin, doxazosin or combination of terazosin and finasteride. Korean J Urol 1998;39: Single blind case-control study 60 patients were divided 3 groups (terazosin group, doxazosin group, terazosin with finasteride group. To compare the efficacy of terazosin, doxazosin and terazosin (alpha-1 adrenoreceptor antagonist) with finasteride (5-alpha reductase inhibitor) in the treatment of patient with benign prostatic hyperplasia At baseline, 1-PSS, QOL index and Qmax were 18.8+/-4.3, 3.7+/-1.0, 8.6+/-1.7 in terazosin group, 19.3+/-3.9, 3.6+/-1.0, 7.8+/-1.8 in doxazosin group, 20.1+/-4.4, 3.8+/-1.0, 72 +/-1.6 in combination group, respectively. After 12 weeks trial, 1-PSS, QOL index and Qmax were 12.0+/-2.8, 1.9+/-0.9, 11.4+/-2.8 respectively in terazosin group, 11.3+/-3.0, 1.7+/- 0.7, 10.6+/-2.6 in doxazosin group, 10.9+/-4.0, 1.8+/-0.9, 9.8+/-1.0 in combination group, respectively. Level of Study 4 130

132 전립선비대증진료권고안 4. Chung BH, Chung HJ, Hong SJ. Long-term efficacy and safety of terazosin in the symptomatic treatment of benign prostatic hyperplasia. Korean J Androl 1999;17: Case-control study 228 male patients aged 50 years or older who had clinical evidence of BPH To evaluate the long-term efficacy and safety of terazosin, a selective alpha-1 blocker, in the treatment of benign prostatic hyperplasia The mean IPSS was reduced by 35% or greater. In the hypertensive patients, the mean systolic BP was reduced by 11.9% (-18 mmhg) and the mean diastolic BP by 16.8% (-17 mmhg), whereas in normotensive patients, the reductions were 4.0% (-5 mmhg) and 1.2% (-1 mmhg), respectively. There were no significant differences in the IPSS improvement in these two groups. Level of Study 4 5. Cho SH, Lee SK. The experience with combination of finasteride and tamsulosin on benign prostatic hyperplasia. Korean J Urol 2003;44: Case-control study 210 men with symptomatic benign prostatic hyperplasia who were treated with a combination of finasteride and tamsulosin for 12 months. To evaluate the sustained efficacy and the safety of finasteride and tamsulosin in combination in the treatment of benign prostatic hyperplasia Finasteride plus tamsulosin combination therapy produced statistically significant improvements in the urinary obstructive symptoms score and led to overall reduction from baseline of 9.8% in prostatic volume and 55% in serum PSA at the end of a 12-month trial. In men with prostatic volume greater than 30ml (n=28), a decrease in prostatic volume was higher than that less than 30ml (n=31) (13.1% vs. 6.9% from baseline respectively, p=0.0001, p=0.02). Level of Study 4 6. Noh JH, Oh BR, Park YI. The efficacy of combination therapy of 5alpha-reductase inhibitor and of -adrenergic blocker in benign prostate hyperplasia. Korean J Urol 1998;39: Case-control study 85 patients with BPH divided into three groups: Group 1 (doxazosin 3 mg/day), Group 2 (finasteride 5 mg) and Group 3 (combination of both drugs). 6 months followup. To evaluate the efficacy of the combination of 5 alpha -reductase inhibitor (finasteride) and alpha1-adrenergic blocker (doxazosin) In Group 1 and 3, IPSS were more decreased than In Group 2 immediately (p < 0.001). In Group 1 and 3, maximal flow rate was more increased than in group 2 immediately (p < 0.001) Level of Study 4 131

133 Korean clinical practice guideline for benign prostate hyperplasia 7. Yu HS, Kim WT, Ham WS, Choi YD. Transurethral resection of prostate in benign prostatic hyperplasia patients with large prostate volume. Korean J Urol 2008;49: Case-control study 211 patients treated with TURP in BPH with large prostate. Each group was divided by prostate volume (group 1; , group 2; , group 3; , group 4; , group 5; >100 cc of prostate volume) To investigate the safety and efficacy of transurethral resection of the prostate in benign prostatic hyperplasia more than 60 cc Prostate volume, adenoma volume, resection time, Resection volume, irrigation volume of each groups were different significantly. But, resection volume/resection time and irrigation volume/ resection time were not different significantly Level of Study 4 8. Kim HG, Lee BK, Paick SH, Lho YS. Efficacy of bipolar transurethral resection of the prostate: comparison with standard monopolar transurethral resection of the prostate. Korean J Urol 2006;47: Case-control study 25 patients with symptomatic benign prostatic hyperplasia (BPH) who underwent TURP compared with standard monopolar TURP. to assess the efficacy of bipolar transurethral resection of the prostate (TURP) compared with standard monopolar TURP The mean weight of resection was 29.7 g for the bipolar TURP and 22.5 g for the monopolar TURP. The operative time was shorter (82.5 vs 98.1 minutes, respectively), the estimated blood loss was less (252 vs 268 cc, respectively) and the mean post-operative hospital stay was shorter (5.3 vs 5.7 days, respectively) in the bipolar TURP group. However, these differences were not statistically significant. The acute complications were significant hyponatremia in one patient and clot retention in one patient after monopolar TURP, but no complications occurred after bipolar TURP. The maximal flow rate increased from 6.4 to 14.7 ml/sec in the bipolar TURP group, and it increased from 6.7 to 15.2 ml/sec in the monopolar TURP group Level of Study 4 참고문헌 1. Chung BH. Medical management for benign prostatic hyperplasia. Korean J Urol 2007;48: Joung JY, Park JK, Park CH, Lee JG, Chung BH, Hong SJ, et al. The role of alpha 1 (A) adrenoceptor antagonist tamsulosin for the treatment of patients with benign prostatic hyperplasia: the effect on lower urinary tract symptoms and nocturia. Korean J Urol 2006;47:

134 전립선비대증진료권고안 3. Jeong DH, Park YI. Clinical experience of symptomatic management of BPH with terazosin, doxazosin or combination of terazosin and finasteride. Korean J Urol 1998;39: Chung BH, Chung HJ, Hong SJ. Long-term efficacy and safety of terazosin in the symptomatic treatment of benign prostatic hyperplasia. Korean J Androl 1999;17: Cho SH, Lee SK. The experience with combination of finasteride and tamsulosin on benign prostatic hyperplasia. Korean J Urol 2003;44: Noh JH, Oh BR, Park YI. The efficacy of combination therapy of 5alpha-reductase inhibitor and of -adrenergic blocker in benign prostate hyperplasia. Korean J Urol 1998;39: Yu HS, Kim WT, Ham WS, Choi YD. Transurethral resection of prostate in benign prostatic hyperplasia patients with large prostate volume. Korean J Urol 2008;49: Kim HG, Lee BK, Paick SH, Lho YS. Efficacy of bipolar transurethral resection of the prostate: comparison with standard monopolar transurethral resection of the prostate. Korean J Urol 2006;47:

135 Korean clinical practice guideline for benign prostate hyperplasia KQ 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰 해야하는경우는무엇인가? 권고사항권고수준근거수준 전립선비대증환자에서하부요로증상이 1 차약물치료로호전되지않는경 우에는비뇨기과의사에게의뢰해야한다. Strong B 전립선비대증환자에서요로감염, 혈뇨, 반복적인요폐색과같은하부요 로증상의객관적인이상이나악화소견이동반될때비뇨기과의사에게의뢰해 야한다. Strong A 전립선비대증환자에서혈청전립선특이항원검사가정상범위를벗어나거 나직장수지검사에서이상소견이관찰되는경우전립선암과의감별을위해비 뇨기과의사에게의뢰해야한다. Strong A 전립선비대증과이로인한하부요로증상의경우 1차적인약물치료로많은수의환자들이증상의호전을보일수있다. 특히다뇨증이없는경우에 1차약제로추천되는알파차단제를기본으로한약물치료에중장기적인호전을보이는경우가많은데, 만약 1차약물치료로호전이되지않고약물증량이나수술적치료가필요하다고판단되면비뇨기과의사에게의뢰해야한다 [1]. 전립선비대증의증상이심한경우약물치료의호전이없을수있으며약물용량의조절, 약물의추가, 그리고비뇨기과적검사 (uroflowmetry, PVR, Urethrocystoscopy, TRUS 등 ) 가추가로필요하므로비뇨기과의사에게의뢰해야한다. 또한반복적인요로감염이나혈뇨, 높은수치의전립선특이항원검사결과를보이거나, 직장수지검사에서이상소견을보이는경우에도추가적인비뇨기과검사및조직검사등이필요할수있으므로우선적인의뢰를고려해야한다 [2-5]. 이외에약물치료중에도반복적으로요폐색이오거나 [6], 요실금이발생하는경우, 방광기능의장애가의심되는경우에도추가적인비뇨기과적검사및처치가필요하다 [7-10]. 비록전립선비대증이전립선암으로진행하는전구단계는아니지만전립선비대증환자중에서전립선암으로진단받는경우가많고일부에서는전립선암의증상과전립선비대증의증상이혼동 134

136 전립선비대증진료권고안 되기도한다. 따라서주기적인혈액검사에서전립선특이항원수치가높거나 [11-12], 직장수지검사에서이상소견이있는경우에는비뇨기과전문의에게의뢰해야한다. 또한환자의기저질환혹은기저질환과관련된약제들이하부요로증상을일으킬만한원인을갖고있을때, 하부요로증상과함께비뇨기과적증상이동반되어있어비뇨기과적신체검사가필요한경우, 하부요로증상으로인해삶의질이현저히악화되는경우에도비뇨기과전문의의진찰이권장된다. 특히전립선특이항원수치의비정상적인상승이나직장수지검사에서이상소견이관찰되는경우에는전립선암과의감별진단이필요하므로비뇨기과전문의에게의뢰하는것이필요하다 [14]. 근거표 KQ Abrams P, Chapple C, Khoury S, et al. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2009;181: Expert opinion The 6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases met from June 24-28, 2005 in Paris, France to review new developments in benign prostatic disease. The Consultation endorsed the appropriate use of the current terminology lower urinary tract symptoms/benign prostatic hyperplasia/benign prostate enlargement and benign prostatic obstruction, and recommended that terms such as "clinical benign prostatic hyperplasia" or "the benign prostatic hyperplasia patient" be abandoned, and asked the authorities to endorse the new nomenclature. The diagnostic evaluation describes recommended and optional tests, and in general places the focus on the impact (bother) of lower urinary tract symptoms on the individual patient when determining investigation and treatment. The importance of symptom assessment, impact on quality of life, physical examination and urinalysis is emphasized. The frequency volume chart is recommended when nocturia is a bothersome symptom to exclude nocturnal polyuria. The recommendations are summarized in 2 algorithms, 1 for basic management and 1 for specialized management of persistent bothersome lower urinary tract symptoms. Level of Study 5 2. Kaplan SA. Update on the American Urological Association guidelines for the treatment of benign prostatic hyperplasia. Rev Urol 2006;8(Suppl.4):S Expert opinion 135

137 Korean clinical practice guideline for benign prostate hyperplasia The updated 2003 American Urological Association (AUA) Guidelines for the treatment of benign prostatic hyperplasia (BPH) are the culmination of an exhaustive effort predicated on scientifically accepted methods of reviewing the medical literature. In this second publication of the guidelines, a multidisciplinary panel reviewed a new meta-analysis of outcome data from the BPH literature from before and after 1994 The major differences between the 2 guidelines are the changes in our understanding of the biology of the prostate and the introduction of new therapies. The vast majority of randomized controlled trials, particularly with respect to minimally invasive therapies and progression of BPH, were performed after the release of the 1994 guidelines. Also, the most recent AUA panel carefully reviewed unpublished data to make the guidelines as timely as possible. Studies that were subsequently published included those on the value of combination medical therapy for BPH. The panel agreed on updated recommendations for the treatment of moderate-to-severe lower urinary tract symptoms associated with BPH, and diagnostic algorithms were revised. The durability and utility of the present guidelines should exceed that of its predecessor. Level of Study 5 3. Grosse H. Frequency, localization and associated disorders in urinary calculi: analysis of 1671 autopsies in urolithiasis. Z Urol Nephrol 1990; 83: Cross sectional study 27,133 In the area of Rügen-Stralsund a maximum value of urolithiasis and cholelithiasis was found. In 27,133 autopsies the frequency of urolithiasis was 6%. Obesity, hypertension and diabetes mellitus may increase the tendency of cholelithiasis patients to develop additional urolithiasis Ureteral and urinary bladder calculi are more frequently among male patients. In cases with benign prostatic hyperplasia the incidence of urolithiasis was not higher than in female patients. In the autopsy material multiple calculi and bilateral cases occur more frequently. Hypertension and increased heart weight did occur more frequently in patients suffering from oxalate lithiasis. Some of the calculi may develop in the terminal age of life Level of Study 3 4. Wasson JH, Reda DJ, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995;332:75 9. RCT 556 Transurethral resection of the prostate is the most common surgical treatment for benign prostatic hyperplasia. We conducted a multicenter randomized trial to compare this surgery with watchful waiting in men with moderate symptoms of benign prostatic hyperplasia. 136

138 전립선비대증진료권고안 Of the men randomly assigned to the surgery group, 249 underwent surgery within two weeks after the assignment. Surgery was not associated with impotence or urinary incontinence. The average follow-up period was 2.8 years. In an intention-to-treat analysis, there were 23 treatment failures in the surgery group, as compared with 47 in the watchful-waiting group (relative risk, 0.48; 95 percent confidence interval, 0.30 to 0.77). Of the men assigned to the watchful-waiting group, 65 (24 percent) underwent surgery within three years after the assignment. Surgery was associated with improvement in symptoms and in scores for urinary difficulties and interference with activities of daily living (P < for all comparisons). The outcomes of surgery were best for the men who were most bothered by urinary symptoms at base line. Level of Study 2 5. Holtgrewe HL, Mebust WK, et al. Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 1989;141: Expert opinion In a national survey of all American urologists transurethral prostatectomy accounted for 38 per cent of the major surgical procedures performed by the respondents. They regarded the operation as complex and they believe achievement of proficiency requires that more be performed during residency training than any other urological operation. Furthermore, they assigned transurethral prostatectomy a significantly higher relative value than have medical economists doing research in the field of physician reimbursement. The effect of recent legislated congressional reductions in the allowable Medicare fees for transurethral prostatectomy is discussed along with the impact of these reductions on urological patient care and the American urologist. Practice patterns and geographic variations in the costs of transurethral prostatectomy also are considered. Level of Study 5 6. McConnell JD, Roehrborn C, et al. The long-term effects of doxazosin, finasteride and the combination on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: RCT 2,872 We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short-Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS-QoL, International Prostate Symptom Score-QoL) during 4 years. Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS-QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group. 137

139 Korean clinical practice guideline for benign prostate hyperplasia Level of Study 2 7. Levin RM, Longhurst PA, et al. Effect of bladder outlet obstruction on the morphology, physiology, and pharmacology of the bladder. Prostate [Suppl] 1990;3:9 26. Observational study Bladder outlet obstruction secondary to benign prostatic hyperplasia induces numerous changes in bladder morphology, physiology, and pharmacology. These changes have been studied experimentally in various animal models, and while each species has advantages and disadvantages, it is unclear which is the most like man. It has been shown that tissue hypertrophy leading to an increase in tissue mass develops rapidly after bladder outlet obstruction. It has been shown that tissue hypertrophy leading to an increase in tissue mass develops rapidly after bladder outlet obstruction. Ischemia induced by the obstruction results in acute muscle dysfunction. The degree of functional impairment is directly related to the degree of tissue hypertrophy. However, the bladder contractile apparatus appears to have a surprising regenerative ability, such that recovery of bladder function becomes obvious 14 days after obstruction. Urodynamic changes include an increase in urinary frequency and voiding pressure and a decrease in voided volume. Clinically, involuntary bladder contractions are often present. Determination of which of these specific aspects of outlet obstruction the investigator is interested in studying will dictate the selection of the most appropriate animal model. Level of Study 5 8. McConnell JD, Barry MJ, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guideline no. 8. Rockville, MD: U.S. Department of Health and Human Services, Agency for Health Care Policy and Research, Public Health Service; 1994; Expert opinion This Quick Guide for Clinicians contains highlights from the Clinical Practice Guideline of Benign Prostatic Hyperplasia: Diagnosis and Treatment. The Benign Prostatic Hyperplasia Guideline Panel, a private-sector panel of health care providers, developed the guideline after comprehensively analyzing the research literature. As a result, this guideline comprises the most current scientific knowledge of the development, diagnosis, and treatment of benign prostatic hyperplasia (BPH). The guideline makes specific recommendations to identify both the most effective methods for diagnosing BPH and the most appropriate treatments for BPH based on patient preference and clinical need. BPH affects quality of life and is very rarely a life-threatening disease. Motivation to seek active treatment will, for most patients, depend on how much their symptoms bother them. Many patients choose a regimen of "watchful waiting." The guideline details the relative benefits and harms associated with all diagnostic and treatment approaches. Treatment options discussed include watchful waiting, alpha blocker and finasteride medications, balloon dilation, and the surgical options of transurethral incision, transurethral resection, and open prostatectomy. 138

140 전립선비대증진료권고안 Level of Study DiPaola RS, Kumar P, et al. State-of-the-art prostate cancer treatment and research. A report from the Cancer Institute of New Jersey. N J Med 2001;98: Expert opinion Prostate cancer is a devastating disease that will be diagnosed in approximately 200,000 men in New methods for screening, prevention, and treatment are being developed Novel agents for the treatment of resistant prostate cancer are being developed in clinical trials. This review summarizes the recent efforts in diet, screening, novel systemic therapies, and alternative medicine for prostate cancer. Level of Study Madersbacher S, Alivizatos G, Nordling J, et al. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol 2004;46: Expert opinion To provide the first update of the EAU guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). During initial assessment the following tests are recommended: medical history, physical examination including digital-rectal examination, International Prostate Symptom Score, urinalysis, serum creatinine and prostate specific antigen measurement, uroflowmetry and postvoid residual volume. All other tests are optional or not recommended. Aim of treatment is to improve LUTS and quality of life and to prevent severe BPE-related complications. Development of a 5alpha-reductase type I and II inhibitor and the data of the MTOPS trial providing scientific evidence for a combination therapy were the most significant innovations since the first version. Finally a more detailed knowledge on the natural history with identification of several risk factors for progression is the basis for a risk-profile orientated (preventive) therapy. Level of Study Roehrborn CG, Malice M, Cook TJ, Girman CJ. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58: Meta analysis 5,355 To comprehensively evaluate clinical predictors of spontaneous acute urinary retention (AUR) across pooled data of placebo-treated patients from clinical trials conducted in men with lower urinary tract symptoms and clinically diagnosed benign prostatic hyperplasia. 139

141 Korean clinical practice guideline for benign prostate hyperplasia The different methods of analysis identified consistent potential predictors of episodes of AUR. When prostate volume was included in the analyses, it was selected as the initial variable discriminating men with and without subsequent AUR. Omitting prostate volume because of its availability in only a subset of men, a logistic model including serum prostate-specific antigen (PSA), urinating more than every 2 hours, symptom problem index, maximum urinary flow rate, and hesitancy of urination had good predictive properties (area under the receiver-operating characteristic curve [AUC] = / ), as did a model with PSA (AUC = / ). A classification and regression decision tree with the same variables predicted AUR (AUC = 0.74, sensitivity = 72%, specificity = 67%) as well as did a tree with PSA alone (AUC = 0.70, sensitivity = 75%, specificity = 64%). Level of Study M. Oelke (chairman), A. Bachmann, A. Descazeaud, M. Emberton, S. Gravas, M.C. Michel, et al. Guidelines on the Management of Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO). EAU2012. Expert opinion To present a summary of the 2013 version of the European Association of Urology guidelines on the treatment and follow-up of male lower urinary tract symptoms (LUTS). Men with mild symptoms are suitable for watchful waiting. All men with bothersome LUTS should be offered lifestyle advice prior to or concurrent with any treatment. Men with bothersome moderate-to-severe LUTS quickly benefit from α1-blockers. Men with enlarged prostates, especially those >40 ml, profit from 5α-reductase inhibitors (5-ARIs) that slowly reduce LUTS and the probability of urinary retention or the need for surgery. Antimuscarinics might be considered for patients who have predominant bladder storage symptoms. The phosphodiesterase type 5 inhibitor tadalafil can quickly reduce LUTS to a similar extent as α1- blockers, and it also improves erectile dysfunction. Desmopressin can be used in men with nocturia due to nocturnal polyuria. Treatment with an α1-blocker and 5-ARI (in men with enlarged prostates) or antimuscarinics (with persistent storage symptoms) combines the positive effects of either drug class to achieve greater efficacy. Prostate surgery is indicated in men with absolute indications or drug treatment-resistant LUTS due to benign prostatic obstruction. Transurethral resection of the prostate (TURP) is the current standard operation for men with prostates ml, whereas open surgery or transurethral holmium laser enucleation is appropriate for men with prostates >80 ml. Alternatives for monopolar TURP include bipolar TURP and transurethral incision of the prostate (for glands <30 ml) and laser treatments. Transurethral microwave therapy and transurethral needle ablation are effective minimally invasive treatments with higher retreatment rates compared with TURP. Prostate stents are an alternative to catheterisation for men unfit for surgery. Ethanol or botulinum toxin injections into the prostate are still experimental. Level of Study Aziz DC, Barathur RB. Prostate-specific antigen and prostate volume: a meta-analysis of prostate cancer screening criteria. J Clin Lab Anal 1993;7:

142 전립선비대증진료권고안 Meta analysis To establish the value of serum prostate-specific antigen (PSA) and prostate-specific antigen per unit volume of prostate gland (PSAD) in detecting prostate carcinoma (CaP) in a hypothetical screening algorithm, a meta-analysis of the sensitivities, specificities, predictive values and likelihood ratios were combined from the published data. Hypothetical cohorts of 1,000 men between the ages of 60 and 70 years were screened using three different screening decision algorithms. Using a serum PSA cutoff of 3.0 ng/ml for referral for transrectal biopsy, 59 of 80 (74%) CaP would be detected and 21 (26%) would be missed. 209 transrectal biopsies would be performed, and 150 (72%) of them would be negative for CaP. Using a serum PSA cutoff of 4.0 ng/ml, 52 of 80 (65%) CaP would be detected and 28 (35%) would be missed. 146 transrectal biopsies would be performed, and 94 (64%) of them would be unnecessary. Using a cutoff of 2.0 ng/ml for serum PSA and 0.1 ng/ml/cc for PSAD, 55 of 80 (69%) of the cancers would be detected and 25 (31%) would be missed. Only 84 transrectal biopsies would be performed, and 29 (35%) of them would be negative for cancer. Level of Study 1 참고문헌 1. Abrams P, Chapple C, Khoury S, et al. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2009;181: Kaplan SA. Update on the American Urological Association guidelines for the treatment of benign prostatic hyperplasia. Rev Urol 2006;8(Suppl.4):S Grosse H. Frequency, localization and associated disorders in urinary calculi: analysis of 1671 autopsies in urolithiasis. Z Urol Nephrol 1990; 83: Wasson JH, Reda DJ, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995;332: Holtgrewe HL, Mebust WK, et al. Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 1989;141: McConnell JD, Roehrborn C, et al. The long-term effects of doxazosin, finasteride and the combination on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Levin RM, Longhurst PA, et al. Effect of bladder outlet obstruction on the morphology, physiology, and pharmacology of the bladder. Prostate [Suppl] 1990;3: McConnell JD, Barry MJ, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guideline no. 8. Rockville, MD: U.S. Department of Health and Human Services, Agency for Health Care Policy and Research, Public Health Service; 1994; Mebust WK, Holtgrewe HL, Cockett AT, Peters PC. Transurethral prostatectomy: immediate and postoperative complications: a cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol 1989;141: DiPaola RS, Kumar P, et al. State-of-the-art prostate cancer treatment and research. A report from the Cancer Institute of New Jersey. N J Med 2001;98:

143 Korean clinical practice guideline for benign prostate hyperplasia 11. Madersbacher S, Alivizatos G, Nordling J, et al. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol 2004;46: Roehrborn CG, Malice M, Cook TJ, Girman CJ. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58: M. Oelke (chairman), A. Bachmann, A. Descazeaud, M. Emberton, S. Gravas, M.C. Michel, et al. Guidelines on the Management of Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO). EAU Aziz DC, Barathur RB. Prostate-specific antigen and prostate volume: a meta-analysis of prostate cancer screening criteria. J Clin Lab Anal 1993;7:

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145 Korean clinical practice guideline for benign prostate hyperplasia

146 부록 권고안요약표용어의정의진료지침평가표 (K-AGREE 2.0 평가결과 ) 권고안매트릭스델파이합의결과표근거검색식문헌고찰에인용한참고문헌근거요약표

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148 전립선비대증진료권고안 1. 권고안요약표 권고사항 권고등급 근거수준 주요참고문헌 ( 중위수 ) 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다진단에도움을주는가? 1-1. 국제전립선증상점수 (IPSS) 는치료에대한반응이나추적관찰중 증상악화를판단하는데있어중요한요소이다. 따라서치료를시작하 고자하는환자들에게치료전 IPSS 를작성하기를권고한다. Strong (9) B 1, 7 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을주는가? 2-1. 배뇨일지가병력청취로부터얻어진정보를명확히하고정확한 진단에도움이된다. Strong (8) B 3, 8 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을주는가? 3-1 하부요로증상이있는전립선비대증환자에게선택적으로요속검사를시행한다. Strong (7) C NA 3-2. 하부요로증상이있는전립선비대증환자에게선택적으로잔뇨량검사를시행한다. Strong (7) C NA 3-3. 하부요로증상이있는전립선비대증환자에서전문의의평가가필요한경우요속검사와잔뇨량측정을시행한다. Strong (8) B NA 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가더정확한평가를할수있는가? 4-1. 정확한전립선의해부학적인평가를위해서는직장수지검사외에 전립선초음파가필요하다. Strong (9) B 6, 7, 8 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? 세이상의하부요로증상을호소하는전립선비대증환자에서전 립선특이항원검사를해야한다. Strong (9) A 7-9, 20, 21, 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? 6-1. 경증의전립선비대증환자는대기요법이적절하다. Strong (7) B 1, 3, 하부요로증상을가진환자에게약물치료전또는약물치료와 동시에생활습관개선에대한교육을시행하여야한다. Strong (9) B 5, 8, 9 147

149 Korean clinical practice guideline for benign prostate hyperplasia 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적으로고려되어야하는가? 7-1. 전립선비대증으로인해중등도이상의증상을보이는경우는약물치료가일차적으로권장된다. 그러나, 방광돌이있는경우, 방광기능장애를동반한방광게실이있는경우, 상부요로의확장으로인한신기능부전이동반된경우, 약물치료에도불구하고요폐, 요로감염, 혈뇨가반복되거나배뇨증상, 배뇨후잔뇨량의호전이없는경우에는수술치료가고려되어야한다 α환원효소억제제는중등도이상의하부요로증상을호소하는환자에서직장수지검사또는전립선초음파검사에서전립선크기가크거나혈청전립선특이항원검사에서전립선비대증의진행가능성이보이는경우장기간처방을고려해야하는치료약물이다 항콜린제는중등도이상의하부요로증상을보이는환자중방광자극증상을주로호소하는환자에서고려될수있으며, 방광출구폐색이심하거나배뇨후잔뇨량이많은경우신중한사용이필요하다 알파차단제는중등도이상의하부요로증상을보이는전립선비대증환자에게우선적으로고려되어야하는치료약물이다. Strong (9) Strong (8) Strong (7) Strong (9) B 49 A 30, 33-36, 40 A 42, 44, 47, 48 A 1, 6, 8, 10, 13, 21, 22, 전립선비대증환자에서병용요법이알파차단제단독사용보다치료효과를높일수있는가? 8-1. 전립선비대증환자에서알파차단제와 5알파환원효소억제제병용요법은알파차단제단독요법보다하부요로증상완화에효과적인치료방법이다 알파차단제와항콜린제병용요법은중등도이상의하부요로증상을갖는환자에서알파차단제단독요법의효과가불충분할경우에시행한다. 8-3 알파차단제와항콜린제병용요법은배뇨후잔뇨량이많고방광출구폐색이의심되는남성에서는신중하게시행한다 PDE5 억제제와알파차단제의병용투여는중등도이상의하부요로증상을감소시키는데있어알파차단제단독요법보다효과적이다. Strong (8) Strong (8) Strong (9) Weak (6) A 1-6 A 4, 6, 8 A 7 A 전립선비대증환자에서급성요폐발생시 TWOC (Trial without catheter) 는수술적치료전에우선적으로고 려되어야하는가? 9-1. 급성요폐발생시 TWOC 는수술적치료전에고려할수있다. Strong (7) A 3, 7-9, 급성요폐를치료하는데있어요도도관유치전후알파차단제사 용이도움이된다. Strong (9) B 2,3 148

150 전립선비대증진료권고안 9-3. 요도도관은급성요폐후 2-7 일간유치하는것이도움이된다. Strong (9) B 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서우선적으로고려되어야하는가? 경요도전립선절제술은전립선비대증수술에우선적으로고려된다 gm 이상의큰전립선비대증환자에서경요도를통한내시경수술은개복전립선수술과함께 1차수술법으로고려할수있다. Strong (9) Strong (8) C 2, 3, 7 A 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경우에는어떠한치료가권장되는가? 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우간헐적자가도뇨또는도뇨관유치를권장한다 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우 TUNA 또는 TUMT 를고려할수있다. 그러나장기적인치료효과 ( 재치료및증상개선정도 ) 는 TURP에비해좋지않다 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우전립선내약물주입이시도되고있으나임상적용은권고하지않는다. Strong (7) Strong (8) Strong (8) B 1-5 A 6-11 A 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇이며, 추적관찰의기간은어떻게 설정하여야하는가? 전립선비대증치료후추적관찰간격과검사의종류는개별환자의중증도와임상지표를고려하여임상의사의경험이나판단에따른다. Strong (7) C NA 전립선비대증의진행을확인하기위해서는국제전립선증상점수, 직장수지검사, 혈청전립선특이항원검사, 요속검사, 잔뇨량측정그리 Strong (8) C NA 고전립선초음파등을시행한다. 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰해야하는경우는무엇인가? 전립선비대증환자에서하부요로증상이 1차약물치료로호전되지않는경우에는비뇨기과의사에게의뢰해야한다 전립선비대증환자에서요로감염, 혈뇨, 반복적인요폐색과같은하부요로증상의객관적인이상이나악화소견이동반될때비뇨기과의사에게의뢰하여야한다 전립선비대증환자에서혈청전립선특이항원검사가정상범위를벗어나거나직장수지검사에서이상소견이관찰되는경우전립선암과의감별을위해비뇨기과의사에게의뢰하여야한다. Strong (9) Strong (9) Strong (9) B 1 A 2, 6 A 11 NA: Not Applicable 149

151 Korean clinical practice guideline for benign prostate hyperplasia 2. 용어의정의 AUA American Urological Association 미국비뇨기과학회 BOO (I) Bladder outlet obstruction (index) 방광출구폐색 ( 지표 ) BPE Benign prostatic enlargement 양성전립선비대 ( 증 ) BPH Benign prostatic hyperplasia 양성전립선증식 ( 증 ) BPO Benign prostatic obstruction 양성전립선폐색 cgmp Cyclic guanosine monophosphate 고리형일인산구노아신 CIC Clean intermittent catheterization 청결간헐적도뇨 CombAT Combination of avodart and tamsulosin DHT Dihydrotestosterone 디히드로테스토스테론 DRE Digital rectal examination 직장수지검사 EAU European Association of Urology 유럽비뇨기과학회 EBM Evidence-based medicine 근거중심의학 ED Erectile dysfunction 발기장애 EjD Ejaculation dysfunction 사정장애 enos Endothelial nitric oxide synthase 내피성산화질소합성효소 HoLAP Holmium laser ablation of the prostate 레이저전립선소작술 HoLEP Holmium laser enucleation of the prostate 레이저전립선적출술 IPP Intravesical protrusion of prostate 방광내전립선돌출 IPSS International prostate symptom score 국제전립선증상점수 KTP Potassium titanyl phosphate LUTS Lower urinary tract symptoms 하부요로증상 MIST Minimal invasive surgery and technique 최소침습치료 MTOPS Medical therapy of prostatic symptoms NO Nitric oxide 산화질소 NOS NO synthases 산화질소합성효소 nnos Neuronal nitric oxide synthase 신경성산화질소합성효소 n.s. Not significant 150

152 전립선비대증진료권고안 OAB Overactive bladder 과민성방광 PA Prostatic adenoma 전립선선종 PDE Phosphodiesterase 포스포디에스테라아제 PFS Pressure-flow study 압력요류검사 Post-TURP Transarethral resection of the prostate 경요도전립선절제술 PSA Prostate specific antigen 전립선특이항원 PV Prostate volume 전립선부피 PVP Photoselective vaporization of the prostate 광선택적전립선기화술 PVR Post-void residual urine 배뇨후잔뇨 Qmax Maximum urinary flow rate during free uroflowmetry 최대요속, 최고요속 QoL Quality of life 삶의질 Randomized control trials 무작위비교연구 RR Relative risk 상대위험도 Residual urine 잔뇨 Retrograde ejaculation 역행성사정 Retrospective cohort study 역방향코호트연구, 후향코호트연구 Retrospective study 역방향연구, 후향연구 Risk factor 위험인자 Sensitivity 민감도 SHBG Sexual hormone binding globulin 성호르몬결합글로불린 Sexual dysfunction 성기능장애 Side effect 부작용 Sigh 징후 Significance 유의성 Single blinding study 단순맹검법 Specificity 특이도 Standardization 표준화 Storage symptom 저장증상 151

153 Korean clinical practice guideline for benign prostate hyperplasia Suprapubic catheterization 치골상부도관삽입 Symptom 증상 Symptom score 증상점수 TUIP Transurethral incision of the prostate 경요도전립선절개술 TUMT Transurethral microwave thermotherapy 경요도저주파온열치료, 경요도극로단파치료 TUNA Transurethral needle ablation 경요도침절제술, 경요도침소작술 Transurethral resection (TUR) syndrome 경요도절제술후증후군 TURP Transurethral resection of the prostate 경요도전립선절제술 TUVP Transurethral vaporization of the prostate 경요도전립선기화술 TWOC Trial without catheter 일시적도뇨법 Ultrasonography 초음파촬영술 Urethral stent 요도스탠트 Urinary retention 요폐 UTI Urinary tract infection 요로감염 Uroflowmetry 요속검사 Voided volume 배뇨량 Voiding diary = micturition diary, bladder diary 배뇨일지 Voiding symptom 배뇨증상 152

154 전립선비대증진료권고안 3. 진료지침평가표 (K -AGREE 2.0 평가결과 ) 가이드라인 발행 년도영역 1. 영역 2. 영역 3. 영역 4. 영역 5. 영역 6. 기관 범위와 이해당사 개발의 표현의 적용성 편집의 목적 자의참여 엄격성 명확성 독립성 1 전립선비대증진료지침 ( 대한전립선학회, 한국 ) 2 남성하부요로증상의치료 ( 임상진료지침센터, 영국 ) 3 하부요로증상 ( 국립보건임상연구원, 영국 ) 4 남성하부요로증상의치료가이드라인 ( 유럽비뇨기과학회 ) 5 전립선비대증치료가이드라인 ( 미국비뇨기과학회 ) 6 전립선비대증치료가이드라인 ( 캐나다비뇨기과학회 ) KPS NCGC NICE EAU AUA CUA ,4,5 번가이드라인채택 (3번영역표준화점수 50% 이상채택 ) KPS (the Korean Prostate Society), 2010 KPS guideline NCGC (the National Clinical Guideline Centre), 2010 NCGC UK full LUTS NICE (the National Institute for Health and Care Excellence), 2010 NICE UK EAU (European Association of Urology), 2012 EAU 12_Male_LUTS_LR AUA (American Urological Association), AUA 2010 Benign-Prostatic- Hyperplasia CUA (Canadian Urological Association), bph_2009_en v2a CUA guideline 153

155 Korean clinical practice guideline for benign prostate hyperplasia 4. 권고안매트릭스 권고사항 NCGC (National Clinical Guideline Centre, 2010) AUA (American Urological Association, 2010) EAU (European Association of Urology, 2012) IPSS 국제전립선증상점수 (IPSS) No clinical evidence was found. Recommendation Recommended# 배뇨일지 배뇨일지 No clinical evidence was found. Recommendation Recommended# 요속검사, 잔뇨량측정 요속검사 All studies were performed at secondary care setting Option Recommended# 잔뇨량검사 with high prevalence and should be used to inform recommendations for this setting. There was no evidence to suggest that this test was useful at initial assessment. 직장수지검사, 전립선초음파검사 직장수지검사 No clinical or economic evidence was found. Recommendation Recommended# 전립선초음파 - Option Optional# PSA( 전립선특이항원수치 ) 전립선특이항원검사 There was no evidence comparing LUTS outcomes for Recommendation Recommended# men that had a PSA test compared to those that had not. The ideal analysis for the prognostic question would be regression analysis identifying the link of baseline PSA levels with progression while controlling for other variables. This was performed in only some of the studies reviewed. Data suggesting that PSA has prognostic value in predicting symptom progression were inconsistent. 생활습관개선 대기관찰요법 No clinical or economic evidence was found Standard 1b/A 생활습관개선 No clinical or economic evidence was found - 1b/A 일차치료법으로약물치료법 알파차단제 The quality of evidence for IPSS and Qmax was moderate Option 1a/A for alpha blocker vs. placebo. 5α 환원효소억제제 The quality of evidence for IPSS and Qmax was moderate Option 1b/A to high for alpha blocker vs. 5ARIs. Fourteen RCTs comparing 5-ARI vs. placebo were found. Most of these studies recruited men with larger prostates and higher PSA values. 154

156 전립선비대증진료권고안 항콜린제 The quality of evidence for these comparisons mostly ranged Option 1b/B from low to very low quality. Only studies conducted in men were included. One RCT with 4 arms (anticholinergics, alpha blockers, combination and placebo) conducted in men with moderate to severe LUTS was found. Only statistical significance of combination versus placebo was reported. The total number of patients was too small to determine adverse events precisely. 급성요폐발생시 TWOC (trial without catheter) TWOC - NA NA 요도도관유치전후 All the studies were imprecise as they crossed the minimally 알파차단제사용 important difference confidence intervals. The re-catheterisation outcome was low quality as there were also limitations in the study design of one of the two studies retrieved. 요도도관유치기간 There is no clear evidence for how long this treatment should continue before TWOC, but it seems likely that this should be at least two days treatment before TWOC 경요도전립선절제술 / 개복전립선절제술경요도전립선절제술 Studies included were on patients having a first (TURP) surgery and without prior catheterisation, therefore not totally generalisable. NA NA Option NA NA 1a/A TUIP This recommendation is based on expert opinion. There is Option 1a/A a high degree of uncertainty with the evidence reviewed (low to very low quality further research is very likely to have an important impact on our confidence of the estimate, or may change the estimate). Only a very small RCT with important study limitations was found. Holmium laser, instead of the usual TUIP procedures were used. Holmium Laser Enucleation (HoLEP) / Holmium Laser Resection of the Prostate (HoLRP) Studies included were on patients having a first surgery and without prior catheterisation, therefore not totally generalisable. Option 1b/A 532 nm laser vaporisation Studies included were on patients having a first surgery and without prior catheterisation, therefore not totally generalisable. 개복전립선절제술 This recommendation is based on expert opinion. One small study found OP to be more effective at improving quality of life than HoLEP at three months but this was not seen at later follow up periods. The GDG were uncertain about these results as patients following OP usually still have pain and continence problems at 3 months. As the GDG was uncertain about these results they recommended OP as an alternative surgery to HoLEP for men with larger prostates. Option 3/B Option 1b/A 155

157 Korean clinical practice guideline for benign prostate hyperplasia 심각한기저질환등으로수술에적당하지않은경우치료법 간헐적자가도뇨또는도뇨관유치 No clinical or economic studies were identified. NA NA TUNA Almost all the studies in these procedures are not Option 1a/A blinded, and did not report methods for randomization allocation and concealment. These are important study limitations, especially when patient reported or subjective outcomes were considered. There are uncertainties in our confidence of the evidence the quality of ranged from moderate to very low. TUMT Almost all the studies in these procedures are not blinded, Option 1a/A and did not report methods for randomization allocation and concealment. These are important study limitations, especially when patient reported or subjective outcomes were considered. There are uncertainties in our confidence of the evidence the quality of ranged from moderate to very low. 전립선내약물주입 There is high degree of uncertainty with the evidence (low to very low quality further research is very likely to have an important impact on our confidence of the estimate, or may change the estimate). Only one very small RCT with a shortterm follow up was found and it was unclear whether all relevant adverse outcomes had been reported in this study. NA 3/C 추적관찰에필요한검사, 추적관찰의기간 추적관찰기간 No clinical or economic studies were identified. NA 3-4/C 추적관찰에필요한검사 No clinical or economic studies were identified. NA NA 비뇨기과전문의에게의뢰해야하는경우 1 차약물치료로호전되지않는경우 요로감염, 혈뇨, 반복적인요폐색과같은하부요로증상의객관적인이상이나악화소견이동반될때 혈청전립선특이항원검사가비정상이거나직장수지검사에서이상소견이관찰되는경우 NA NA NA NA NA NA NA NA NA NA (not available) 156

158 전립선비대증진료권고안 NCGC Level of evidence 1a 1b II III IV Type of evidence Systematic review with homogeneity (a) of level-1 studies (b) Level-1 studies (b) Level-2 studies (c) Systematic reviews of level-2 studies Level-3 studies (d) Systematic reviews of level-3 studies Consensus, expert committee reports or opinions and/or clinical experience without explicit critical appraisal; or based on physiology, bench research or first principles (a) Homogeneteity indicates there are no or minor variations in the directions and degrees of results between individual studies included in the systematic review (b) Level-1 studies: 1. Use a blind comparison of the test with a reference standard (gold standard) 2. Are conducted in a sample of patients that reflects the population to whom the test would apply (c) Level-2 studies have only one of the following: 1. Narrow population (sample does not reflect the population to whom the test would apply) 2. A poor reference standard (where tests are not independent) 3. The comparison between the test and reference standard is not masked 4. A case-control study design (d) Level-3 studies have two or three of the above features AUA 1. Standard: A guideline statement is a standard if: (1) the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions and (2) there is virtual unanimity about which intervention is preferred. 2. Recommendation: A guideline statement is a recommendation if: (1) the health outcomes of the alternative intervention are sufficiently well known to permit meaningful decisions, and (2) an appreciable but not unanimous majority agrees on which intervention is preferred. 3. Option: A guideline statement is an option if: (1) the health outcomes of the interventions are not sufficiently well known to permit meaningful decisions, or (2) preferences are unknown or equivocal. Options can exist because of insufficient evidence or because patient preferences are divided and may/should influence choices made. EAU Each extracted article was separately analysed, classified, and labelled with a Level of Evidence (LE), according to a classification system modified from the Oxford Centre for Evidence-based Medicine* in 2001 (LE: 1a, highest evidence level) to expert opinion (LE: 4, lowest evidence level). Subsections for the various types of conservative treatments, drugs, and operations are presented in a homogeneous structure listing (1) mechanism of action, (2) available drugs with a table of key pharmacokinetic profiles or operative procedure in case of surgical intervention, (3) efficacy with a table of trials with the highest LE, (4) tolerability and safety, (5) practical considerations, and (6) recommendations, which were drawn from the relevant articles using a Grade of Recommendation (GR) according to a classification system modified from the Oxford Centre for Evidence-based Medicine, ranging from a strong (Grade A) to a weak (Grade C) recommendation. # Madersbacher S, Alivizatos G, Nordling J, et al. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol 2004;46: *Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November [accessed January 2012]. 157

159 Korean clinical practice guideline for benign prostate hyperplasia 5. 델파이합의결과표 권고사항 권고등급 ( 중위수 ) 합의된라운드 동의 (7-9 점 ) 불명확 (4-6 점 ) 동의안함 (1-3 점 ) 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다진단에도움을주는가? 1-1. 국제전립선증상점수 (IPSS) 는치료에대한반응이나추적관찰중증상악화를판단하는데있어중요한요소이다. 따라서치료를시작하고자하는환자들에게치료전 IPSS 를작성하기를권고한다. Strong (9) 1 100% 0% 0% 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을주는가? 2-1. 배뇨일지가병력청취로부터얻어진정보를명확히하고정확한진단에도움이된다. Strong (7) % 17.6% 0% 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을주는가? 3-1 하부요로증상이있는전립선비대증환자에게선택적으로요속검사를시행한다 하부요로증상이있는전립선비대증환자에게선택적으로잔뇨량검사를시행한다 하부요로증상이있는전립선비대증환자에서전문의의평가가필요한경우요속검사와잔뇨량측정을시행한다. Strong (7) Strong (7) Strong (8) 3 80% 6.7% 13.3% % % % 0% 7.7% 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가더정확한평가를할수있는가? 4-1. 정확한전립선의해부학적인평가를위해서는직장수지검사외에전립선초음파가필요하다. Strong (9) 2 100% 0% 0% 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? 세이상의하부요로증상을호소하는전립선비대증환자에서전립선특이항원검사를해야한다. Strong (9) % 5.9% 0% 6. 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? 6-1. 경증의전립선비대증환자는대기요법이적절하다. Strong (7) % 11.8% 0% 6-2. 하부요로증상을가진환자에게약물치료전또는약물치료와동시에생활습관개선에대한교육을시행하여야한다. Strong (9) % 5.9% 0% 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적으로고려되어야하는가? 7-1. 전립선비대증으로인해중등도이상의증상을보이는경우는약물치료가일차적으로권장된다. 그러나, 방광돌이있는경우, Strong (9) 1 100% 0% 0% 158

160 전립선비대증진료권고안 방광기능장애를동반한방광게실이있는경우, 상부요로의확장으로인한신기능부전이동반된경우, 약물치료에도불구하고요폐, 요로감염, 혈뇨가반복되거나배뇨증상, 배뇨후잔뇨량의호전이없는경우에는수술치료가고려되어야한다 α환원효소억제제는중등도이상의하부요로증상을호소하는환자에서직장수지검사또는전립선초음파검사에서전립선크기가크거나혈청전립선특이항원검사에서전립선비대증의진행가능성이보이는경우장기간처방을고려해야하는치료약물이다 항콜린제는중등도이상의하부요로증상을보이는환자중방광자극증상을주로호소하는환자에서고려될수있으며, 방광출구폐색이심하거나배뇨후잔뇨량이많은경우신중한사용이필요하다 알파차단제는중등도이상의하부요로증상을보이는전립선비대증환자에게우선적으로고려되어야하는치료약물이다. Strong (8) Strong (8) Strong (9) % 17.6% 0% % 7.7% 7.7% % 17.6% 0% 8. 전립선비대증환자에서병용요법이알파차단제단독사용보다치료효과를높일수있는가? 8-1. 전립선비대증환자에서알파차단제와 5α환원효소억제제병용요법은알파차단제단독요법보다하부요로증상완화에효과적인치료방법이다 알파차단제와항콜린제병용요법은중등도이상의하부요로증상을가진환자에서알파차단제단독요법의효과가불충분할경우에시행한다. 8-3 알파차단제와항콜린제병용요법은배뇨후잔뇨량이많고방광출구폐색이의심되는남성에서는신중하게시행한다 PDE5 억제제와알파차단제의병용투여는중등도이상의하부요로증상을감소시키는데있어알파차단제단독요법보다효과적이다. Strong (8) Strong (8) Strong (8) Weak (5) % 15.4% 7.7% % 7.7% 7.7% % 0% 7.7% % 76.9% 0% 9. 전립선비대증환자에서급성요폐발생시 TWOC (Trial without catheter) 는수술적치료전에우선적으로고려되어야하는가? 9-1. 급성요폐발생시 TWOC는수술적치료전에고려할수있다 급성요폐를치료하는데있어요도도관유치전후알파차단제사용이도움이된다 요도도관은급성요폐후 2-7일간유치하는것이도움이된다. Strong (7) Strong (9) Strong (8.5) % 5.9% 5.9% % 11.8% 0% 1 100% 0% 0% 159

161 Korean clinical practice guideline for benign prostate hyperplasia 10. 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서우선적으로고려되어야하는가? 경요도전립선절제술은전립선비대증수술에우선적으로고려하여야한다 g 이상의큰전립선비대증환자에서경요도를통한내시경수술은개복전립선수술과함께 1차수술법으로고려할수있다. Strong (9) Strong (8) % 11.8% 0% % 0 7.7% 11. 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경우에는어떠한치료가권장되는가? 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우간헐적자가도뇨또는도뇨관유치를권장한다 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우 TUNA 또는 TUMT 를고려할수있다. 그러나장기적인치료효과 ( 재치료및증상개선정도 ) 는 TURP 에비해좋지않다 전립선비대증환자에서심각한기저질환등으로수술에적당하지않는경우전립선내약물주입이시도되고있으나임상적용은권고하지않는다. Strong (7) Strong (8) Strong (8) % 7.7% 7.7% 2 100% 0% 0% % 15.4% 7.7% 12. 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇이며, 추적관찰의기간은어떻게설정하여야하는가? 전립선비대증치료후추적관찰간격과검사의종류는개별환자의중증도와임상지표를고려하여임상의사의경험이나판단에따른다 전립선비대증의진행을확인하기위해서는국제전립선증상점수, 직장수지검사, 혈청전립선특이항원검사, 요속검사, 잔뇨량측정그리고전립선초음파등을시행한다. Strong (8) Strong (8) % 0% 7.7% 2 100% 0% 0% 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰해야하는경우는무엇인가? 전립선비대증환자에서하부요로증상이 1차약물치료로호전되지않는경우에는비뇨기과의사에게의뢰해야한다 전립선비대증환자에서요로감염, 혈뇨, 반복적인요폐색과같은하부요로증상의객관적인이상이나악화소견이동반될때비뇨기과의사에게의뢰해야한다 전립선비대증환자에서혈청전립선특이항원검사가정상범위를벗어나거나직장수지검사에서이상소견이관찰되는경우전립선암과의감별을위해비뇨기과의사에게의뢰해야한다. Strong (9) Strong (8) Strong (9) 2 100% 0% 0% 2 100% 0% 0% 2 100% 0% 0% 160

162 전립선비대증진료권고안 6. 근거검색식 진료지침검색자료원 검색자료원 검색건수 채택건수 PubMed ( 4 0 Cochrane Library ( 3 0 Embase ( 6 1 National Guideline Clearing House ( CMA Infobase ( 1 1 SIGN ( 6 1 NICE ( 1 1 문헌고찰을위한검색식으로 PubMed에서 (prostate hypertrophy OR Prostatic Hypertrophy OR Prostatic Adenomas) AND (Luts OR Lower Urinary Tract Symptoms) AND ((Guideline[ptyp] OR Practice Guideline[ptyp]) (( 2009/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 4건의문헌을검색하였고, Cochrane Library 에서는 (prostate hypertrophy OR Prostatic Hypertrophy OR Prostatic Adenomas OR Luts OR Lower Urinary Tract Symptoms) AND Guideline 의검색식을사용하여 3건의자료를검색하였으며, EmBase에서 (prostate hypertrophy OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( prostate hypertrophy / exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms / exp OR Luts) AND practice guideline /exp AND [humans]/lim AND [ ]/py AND practice guideline /de AND article /it 을사용하여 6건의문헌을검색하였다. 이가운데주제와관련있는 1건의문헌을리뷰하였다. 또한국가별검색자료원중미국의 National Guideline Clearing House에서 (prostate hypertrophy or Prostate or hypertrophy) AND ( Luts OR Lower Urinary Tract Symptoms ) 의검색식을사용하여 41건의자료를검색하였고, 캐나다의 CMA Infobase 에서는 (prostate and benign) 의검색식을사용하여 1건의자료를검색하였다. 영국의 SIGN 과 NICE 에서는주제별혹은형식별검색을통해각각 6 건과 1건의자료를검색하였다. 161

163 Korean clinical practice guideline for benign prostate hyperplasia KQ 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다진단에도움을주는가? 문헌고찰을위한검색식으로 PubMed 에서 (international prostatic symptom score OR IPSS) AND dignostic evaluation AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 1,372 건의문헌을검색하였고, EmBase 에서 international prostatic symptom score /exp OR IPSS AND dignostic evaluation AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 756 건의문헌을검색하였다. 이가운데주제와관련있는 10건의문헌을리뷰하였다. KQ 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을주는가? 문헌고찰을위한검색식으로 PubMed 에서 voiding diary AND dignostic evaluation AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 854건의문헌을검색하였고, EmBase에서 voiding diary AND dignostic evaluation AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 491 건의문헌을검색하였다. 이가운데주제와관련있는 7건의문헌을리뷰하였다. KQ 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을주는가? 문헌고찰을위한검색식으로 PubMed에서 Uroflowmetry AND Residual urine AND dignostic evaluation AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 543 건의문헌을검색하였고, EmBase 에서 Uroflowmetry AND Residual urine AND dignostic evaluation AND ( prostate hypertrophy /exp OR Prostatic 162

164 전립선비대증진료권고안 Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 307 건의문헌을검색하였다. 이가운데주제와관련있는 6건의문헌을리뷰하였다. KQ 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가더정확한평가를할수있는가? 문헌고찰을위한검색식으로 PubMed에서 (DRE or Digital rectal examination) AND dignostic evaluation AND ultrasonography AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 132건의문헌을검색하였고, EmBase 에서 (DRE or Digital rectal examination) AND ultrasonography AND dignostic evaluation AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/ lim OR [systematic review]/lim) 을사용하여 87건의문헌을검색하였다. 이가운데주제와관련있는 3건의문헌을리뷰하였다. KQ 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? 문헌고찰을위한검색식으로 PubMed에서 (PSA or Prostate specific antigen) AND dignostic evaluation AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 1,864 건의문헌을검색하였고, EmBase 에서 Prostate specific antigen /exp OR PSA AND dignostic evaluation AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 864 건의문헌을검색하였다. 이가운데주제와관련있는 26건의문헌을리뷰하였다. 163

165 Korean clinical practice guideline for benign prostate hyperplasia KQ 6. 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? 문헌고찰을위한검색식으로 PubMed 에서 Life style modification AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 385 건의문헌을검색하였고, EmBase 에서 Life style modification AND dignostic evaluation AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/ lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 212 건의문헌을검색하였다. 이가운데주제와관련있는 9건의문헌을리뷰하였다. KQ 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적으로고려되어야하는가? 문헌고찰을위한검색식으로 PubMed에서 Medical treatment AND Surgical treatment AND overactive bladder AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 1,202 건의문헌을검색하였고, EmBase에서 Medical treatment /exp AND Surgical treatment/exp AND overactive bladder/exp AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 704 건의문헌을검색하였다. 이가운데주제와관련있는 47건의문헌을리뷰하였다. KQ 8. 전립선비대증환자에서병용요법이알파차단제단독사용보다치료효과를높일수있는가? 메타분석을위한체계적문헌검색을위한검색식 α 환원효소억제제병용요법 검색원 MEDLINE 검색결과

166 전립선비대증진료권고안 검색식 검색원 1. tamsulosin[tiab] OR Adrenergic alpha 1 Receptor Antagonists [tiab] OR Adrenergic alpha1-antagonists [tiab] OR Adrenergic alpha1 Antagonists [tiab] OR alpha1-adrenoceptor Blocker [tiab] OR alpha1 Adrenoceptor Blocker [tiab] OR Adrenergic alpha-1 Antagonists [tiab] OR Adrenergic alpha 1 Antagonists [tiab] OR Adrenergic alpha-1 Receptor Blockers [tiab] OR Adrenergic alpha 1 Receptor Blockers [tiab] OR alfuzosin[tiab] OR Doxazosin[tiab] OR Prazosin[tiab] OR silodosin[tiab] OR tamsulosin[tiab] OR Terazosin[tiab] ((( alfuzosin [Supplementary Concept]) OR Doxazosin [Mesh]) OR Prazosin [Mesh]) OR silodosin [Supplementary Concept]) OR Terazosin [Supplementary Concept] ( Adrenergic alpha-1 Receptor Antagonists [Mesh]) OR tamsulosin [Supplementary Concept] naftopidil [Supplementary Concept] OR naftopidil [tiab] /OR alpha Reductase Inhibitors [tiab] OR 5-alpha-Reductase Inhibitors [tiab] OR dutasteride[tiab] OR Finasteride[tiab] (( 5-alpha Reductase Inhibitors [Mesh]) OR dutasteride [Supplementary Concept]) OR Azasteroids [Mesh] OR Prostatic Hyperplasia [tiab] OR Prostatic Hypertrophy [tiab] OR Prostatic Adenomas [tiab] OR Prostatic Adenoma [tiab] Prostatic Hyperplasia [Mesh] OR AND 8 AND (("randomized controlled trial"[publication Type] OR "controlled clinical trial"[publication Type] OR randomized[tiab] OR placebo[tiab] OR "clinical trials as topic"[mesh:noexp] OR randomly[tiab] OR trial[ti])) NOT ((animals[mesh] NOT (humans[mesh] AND animals[mesh]))) AND EMBASE 검색결과 231 검색식 검색원 1. adrenergic alpha 1 receptor antagonists :ab,ti OR adrenergic alpha1-antagonists :ab,ti OR adrenergic alpha1 antagonists :ab,ti OR alpha1-adrenoceptor blocker :ab,ti OR alpha1 adrenoceptor blocker :ab,ti OR adrenergic alpha-1 antagonists :ab,ti OR adrenergic alpha 1 antagonists :ab,ti OR adrenergic alpha-1 receptor blockers :ab,ti OR adrenergic alpha 1 receptor blockers :ab,ti OR alfuzosin:ab,ti OR doxazosin:ab,ti OR prazosin:ab,ti OR silodosin:ab,ti OR tamsulosin:ab,ti OR terazosin:ab,ti alfuzosin /exp OR doxazosin /exp OR prazosin /exp OR silodosin /exp OR terazosin /exp naftopidil /exp OR naftopidil OR 2 OR alpha Reductase Inhibitors :ab,ti OR 5-alpha-Reductase Inhibitors :ab,ti OR dutasteride:ab,ti OR Finasteride:ab,ti azasteroids /exp OR azasteroids OR Prostatic Hyperplasia :ab,ti OR Prostatic Hypertrophy :ab,ti OR Prostatic Adenomas :ab,ti OR Prostatic Adenoma :ab,ti prostatic hyperplasia /exp OR prostatic hyperplasia OR AND 7 AND 'crossover procedure'/exp OR 'crossover procedure' OR 'double blind procedure'/exp OR 'double blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial' OR 'single blind procedure'/exp OR 'single blind procedure' OR random* OR factorial* OR crossover* OR 'cross over' OR 'cross-over' OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign* OR allocat* OR volunteer* AND COCHRANE 검색결과

167 Korean clinical practice guideline for benign prostate hyperplasia 검색식 1. tamsulosin or Adrenergic alpha 1 Receptor Antagonists or Adrenergic alpha1-antagonists or Adrenergic alpha1 Antagonists or alpha1-adrenoceptor Blocker or alpha1 Adrenoceptor Blocker or Adrenergic alpha-1 Antagonists or Adrenergic alpha 1 Antagonists or Adrenergic alpha-1 Receptor Blockers or Adrenergic alpha 1 Receptor Blockers or alfuzosin or Doxazosin or Prazosin or silodosin or tamsulosin or Terazosin:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Doxazosin] explode all trees MeSH descriptor: [Prazosin] explode all trees MeSH descriptor: [Adrenergic alpha-1 Receptor Antagonists] explode all trees naftopidil :ti,ab,kw (Word variations have been searched) #1-5/or "5-alpha Reductase Inhibitors" or "5-alpha-Reductase Inhibitors" or dutasteride or Finasteride:ti,ab,kw (Word variations have been searched) MeSH descriptor: [5-alpha Reductase Inhibitors] explode all trees MeSH descriptor: [Azasteroids] explode all trees #7-9/or "Prostatic Hyperplasia" or "Prostatic Hypertrophy" or "Prostatic Adenomas" or "Prostatic Adenoma":ti,ab,kw (Word variations have been searched) MeSH descriptor: [Prostatic Hyperplasia] explode all trees #11 or # #6 and #10 and # #14/Trials 69 그림 1. 체계적문헌검색분류표 Records identified through database searching Medline (133), EMbase (231), Cochrane (69) Total (n = 433) Records after duplicates (n=146) removed (n = 287) Records screened (n = 287) Records excluded (n =153) Full-text articles assessed for eligibility (n = 134) Full-text articles excluded, with reasons (n =129) Studies included in quantitative synthesis (meta-analysis) (n = 5) 166

168 전립선비대증진료권고안 8-2. 항콜린제병용요법 검색원 MEDLINE 검색결과 137 검색식 검색원 1. "Muscarinic Antagonists [MeSH] OR darifenacin[supplementary Concept] OR fesoterodine[supplementary Concept] OR mirabegron[supplementary Concept] OR oxybutynin[supplementary Concept] OR propiverine[supplementary Concept] OR solifenacin[supplementary Concept] OR tolterodine[supplementary Concept] OR "trospium chloride"[supplementary Concept] "Muscarinic Antagonists [tiab] OR darifenacin[tiab] OR fesoterodine[tiab] OR mirabegron[tiab] OR oxybutynin[tiab] OR propiverine[tiab] OR solifenacin[tiab] OR tolterodine[tiab] OR "trospium chloride"[tiab] OR Impotence[tiab] OR Erectile Dysfunction [tiab] OR Lower Urinary Tract Symptoms [tiab] OR Dysuria [tiab] OR Nocturia [tiab] OR Prostatism [tiab] OR Urinary Incontinence [tiab] OR LUTS[tiab] ("Lower Urinary Tract Symptoms"[Mesh]) OR "Erectile Dysfunction"[Mesh] "Prostatic Hyperplasia"[tiab] OR "Prostatic Hypertrophy"[tiab] OR "Prostatic Adenomas"[tiab] OR "Prostatic Adenoma"[tiab] "Prostatic Hyperplasia"[Mesh] "benign prostatic hyperplasia"[tiab] OR BPH[tiab] /OR AND (("randomized controlled trial"[publication Type] OR "controlled clinical trial"[publication Type] OR randomized[tiab] OR placebo[tiab] OR "clinical trials as topic"[mesh:noexp] OR randomly[tiab] OR trial[ti])) NOT ((animals[mesh] NOT (humans[mesh] AND animals[mesh])) AND EMBASE 검색결과 328 검색식 검색원 muscarinic receptor blocking agent /exp OR darifenacin /exp OR fesoterodine /exp OR mirabegron /exp OR oxybutynin /exp OR propiverine /exp OR solifenacin /exp OR trospium chloride /exp Muscarinic Antagonists :ab,ti OR darifenacin:ab,ti OR fesoterodine:ab,ti OR mirabegron:ab,ti OR oxybutynin:ab,ti OR propiverine:ab,ti OR solifenacin:ab,ti OR tolterodine:ab,ti OR trospium chloride :ab,ti OR lower urinary tract symptoms :ab,ti OR dysuria :ab,ti OR nocturia :ab,ti OR prostatism :ab,ti OR urinary incontinence :ab,ti OR luts:ab,ti 'lower urinary tract symptom'/exp "Prostatic Hyperplasia":ab,ti OR Prostatic Hypertrophy :ab,ti OR Prostatic Adenomas :ab,ti OR Prostatic Adenoma :ab,ti 'prostate hypertrophy'/exp 'benign prostatic hyperplasia':ab,ti OR bph:ab,ti /OR AND 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR random* OR factorial* OR crossover* OR 'cross over' OR 'cross-over' OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign* OR allocat* OR volunteer* AND #12 AND 328 COCHRANE 검색결과

169 Korean clinical practice guideline for benign prostate hyperplasia 검색식 1. MeSH descriptor: [Muscarinic Antagonists] explode all trees "Muscarinic Antagonists" or darifenacin or fesoterodine or mirabegron or oxybutynin or propiverine or solifenacin or tolterodine or "trospium chloride":ti,ab,kw (Word variations have been searched) #1 or # "Lower Urinary Tract Symptoms" or "Dysuria" or "Nocturia" or " Prostatism" or "Urinary Incontinence" or LUTS:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Lower Urinary Tract Symptoms] explode all trees MeSH descriptor: [Erectile Dysfunction] explode all trees "Prostatic Hyperplasia" or "Prostatic Hypertrophy" or "Prostatic Adenomas" or "Prostatic Adenoma":ti,ab,kw (Word variations have been searched) MeSH descriptor: [Prostatic Hyperplasia] explode all trees "benign prostatic hyperplasia" or BPH:ti,ab,kw (Word variations have been searched) /or #3 and # #11/Trials 103 검색원 검색결과 5 KOREAMED 검색식 1. "Muscarinic antagonist" [ALL] OR darifenacin[all] OR fesoterodine[all] OR mirabegron[all] OR oxybutynin[all] OR propiverine[all] OR solifenacin[all] OR tolterodine[all] OR "trospium chloride"[all] Lower Urinary Tract Symptoms [ALL] OR Dysuria [ALL] OR Nocturia [ALL] OR Prostatism [ALL] OR Urinary Incontinence [ALL] OR "Prostatic Hyperplasia"[ALL] OR "Prostatic Adenoma"[ALL] OR BPH[ALL] AND 2 5 그림 2. 체계적문헌검색분류표 Records identified through database searching Medline (137), EMbase (328), Cochrane (103), KoreaMed(5) Total (n = 573) Records after duplicatea (n=143) removed (n = 430) Records screened (n = 430) Records excluded (n = 246) Full-text articles assessed for eligibility (n = 184) Full-text articles excluded, with reasons (n = 171) Studies included in quantitative synthesis (meta-analysis) (n = 13) 168

170 전립선비대증진료권고안 8-3. PDE5 억제제병용요법 검색원 MEDLINE 검색결과 208 검색식 검색원 1. mirodenafil[tiab] OR sildenafil[tiab] OR tadalafil[tiab] OR udenafil[tiab] OR vardenafil[tiab] OR Phosphodiesterase 5 Inhibitors [tiab] OR PDE5 Inhibitors [tiab] OR Phosphodiesterase Type 5 Inhibitors [tiab] OR PDE-5 Inhibitors [tiab] OR PDE 5 Inhibitors [tiab] OR PDE 5 [tiab] OR PDE-5 [tiab] OR PDE5[tiab] ( Phosphodiesterase 5 Inhibitors [Pharmacological Action]) OR Phosphodiesterase 5 Inhibitors [Mesh] OR Impotence[tiab] OR Erectile Dysfunction [tiab] OR Lower Urinary Tract Symptoms [tiab] OR Dysuria [tiab] OR Nocturia [tiab] OR Prostatism [tiab] OR Urinary Incontinence [tiab] OR LUTS[tiab] ( Lower Urinary Tract Symptoms [Mesh]) OR Erectile Dysfunction [Mesh] Prostatic Hyperplasia [tiab] OR Prostatic Hypertrophy [tiab] OR Prostatic Adenomas [tiab] OR Prostatic Adenoma [tiab] "Prostatic Hyperplasia"[Mesh] "benign prostatic hyperplasia"[tiab] OR BPH[tiab] /OR AND (("randomized controlled trial"[publication Type] OR "controlled clinical trial"[publication Type] OR randomized[tiab] OR placebo[tiab] OR "clinical trials as topic"[mesh:noexp] OR randomly[tiab] OR trial[ti])) NOT ((animals[mesh] NOT (humans[mesh] AND animals[mesh]))) AND EMBASE 검색결과 576 검색식 1. mirodenafil:ab,ti OR sildenafil:ab,ti OR tadalafil:ab,ti OR udenafil:ab,ti OR vardenafil:ab,ti OR Phosphodiesterase 5 Inhibitors :ab,ti OR PDE5 Inhibitors :ab,ti OR Phosphodiesterase Type 5 Inhibitors :ab,ti OR PDE-5 Inhibitors :ab,ti 'phosphodiesterase v inhibitor'/exp OR impotence:ab,ti OR 'erectile dysfunction':ab,ti OR 'lower urinary tract symptoms':ab,ti OR 'dysuria':ab,ti OR 'nocturia':ab,ti OR 'prostatism':ab,ti OR 'urinary incontinence':ab,ti OR luts:ab,ti 'lower urinary tract symptom'/exp OR 'erectile dysfunction'/exp "Prostatic Hyperplasia":ab,ti OR Prostatic Hypertrophy :ab,ti OR Prostatic Adenomas :ab,ti OR Prostatic Adenoma :ab,ti 'prostate hypertrophy'/exp 'benign prostatic hyperplasia':ab,ti OR bph:ab,ti /OR AND 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR random* OR factorial* OR crossover* OR 'cross over' OR 'cross-over' OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign* OR allocat* OR volunteer* AND 검색원 COCHRANE 검색결과 69 검색식 1. mirodenafil OR sildenafil OR tadalafil OR udenafil OR vardenafil OR Phosphodiesterase 5 Inhibitors OR PDE5 Inhibitors OR Phosphodiesterase Type 5 Inhibitors OR PDE-5 Inhibitors OR PDE 5 Inhibitors OR PDE 5 OR PDE-5 OR PDE

171 Korean clinical practice guideline for benign prostate hyperplasia 검색식 2. MeSH descriptor: [Phosphodiesterase 5 Inhibitors] explode all trees #1 or # Impotence or Erectile Dysfunction or Lower Urinary Tract Symptoms or Dysuria or Nocturia or Prostatism or Urinary Incontinence or LUTS:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Lower Urinary Tract Symptoms] explode all trees MeSH descriptor: [Erectile Dysfunction] explode all trees "Prostatic Hyperplasia" or "Prostatic Hypertrophy" or "Prostatic Adenomas" or "Prostatic Adenoma":ti,ab,kw (Word variations have been searched) MeSH descriptor: [Prostatic Hyperplasia] explode all trees "benign prostatic hyperplasia" or BPH:ti,ab,kw (Word variations have been searched) /or and 검색원 KOREAMED 검색결과 20 검색식 1. mirodenafil[all] OR sildenafil[all] OR tadalafil[all] OR udenafil[all] OR vardenafil[all] OR Phosphodiesterase Type 5 Inhibitors [ALL] OR PDE5[ALL] Impotence[ALL] OR Erectile Dysfunction [ALL] OR Lower Urinary Tract Symptoms [ALL] OR Dysuria [ALL] OR Nocturia [ALL] OR Prostatism [ALL] OR Urinary Incontinence [ALL] OR "Prostatic Hyperplasia"[ALL] OR "Prostatic Adenoma"[ALL] OR BPH[ALL] AND 2 20 그림 3. 체계적문헌검색분류표 Records identified through database searching Medline (208), EMbase (576), Cochrane (131), KoreaMed (20) Total (n = 935) Records after duplicates (n=146) removed (n = 629) Records screened (n = 629) Records excluded (n = 306) Full-text articles assessed for eligibility (n = 323) Full-text articles excluded, with reasons (n = 312) Studies included in quantitative synthesis (meta-analysis) (n = 10) 170

172 전립선비대증진료권고안 KQ 9. 전립선비대증환자에서급성요폐발생시 TWOC는수술적치료전에우선적으로고려되어야하는가? 문헌고찰을위한검색식으로 PubMed에서 Catheterization AND Surgical treatment AND Acute urinary retention AND TWOC AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 543건의문헌을검색하였고, EmBase 에서 Catheterization AND Surgical treatment AND Acute urinary retention AND TWOC AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/ lim OR [systematic review]/lim) 을사용하여 307 건의문헌을검색하였다. 이가운데주제와관련있는 15건의문헌을리뷰하였다. KQ 10. 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서우선적으로고려되어야하는가? 문헌고찰을위한검색식으로 PubMed 에서 Surgical treatment AND Transurethral surgery AND Open prostatectomy AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 543건의문헌을검색하였고, EmBase에서 Surgical treatment AND Transurethral surgery AND Open prostatectomy ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 307 건의문헌을검색하였다. 이가운데주제와관련있는 12건의문헌을리뷰하였다. KQ 11. 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경우에는어떠한치료가 권장되는가? 문헌고찰을위한검색식으로 PubMed 에서 Surgical treatment AND Conservative management AND 171

173 Korean clinical practice guideline for benign prostate hyperplasia (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 543건의문헌을검색하였고, EmBase 에서 Surgical treatment AND Conservative management AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 307건의문헌을검색하였다. 이가운데주제와관련있는 20건의문헌을리뷰하였다. KQ 12. 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇이며, 추적관찰의기간은어떻게설정하여야하는가? 문헌고찰을위한검색식으로 PubMed에서 PSA AND Prostate specific antigen AND dignostic evaluation AND Observation AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 142건의문헌을검색하였고, EmBase 에서 PSA AND Prostate specific antigen AND dignostic evaluation AND Observation AND AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/ lim OR [systematic review]/lim) 을사용하여 87건의문헌을검색하였다. 이가운데주제와관련있는 8건의문헌을리뷰하였다. KQ 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰해야하는경우는무엇인가? 문헌고찰을위한검색식으로 PubMed에서 urologist AND dignostic evaluation AND (prostate hypertrophy or Prostatic Hypertrophy or Prostatic Adenomas) AND (Luts or Lower Urinary Tract Symptoms) AND (( 1990/01/01 [PDAT] : 2014/6/31 [PDAT]) AND humans [MeSH Terms] AND English[lang]) 를사용하여 1,282 건의문헌을검색하였고, EmBase에서 urologist AND dignostic 172

174 전립선비대증진료권고안 evaluation AND ( prostate hypertrophy /exp OR Prostatic Hypertrophy OR Prostatic Adenomas) AND ( Lower Urinary Tract Symptoms /exp OR Luts) AND [humans]/lim AND [ ]/py AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) 을사용하여 734건의문헌을검색하였다. 이가운데주제와관련있는 14건의문헌을리뷰하였다. 173

175 Korean clinical practice guideline for benign prostate hyperplasia 7. 문헌고찰에인용한참고문헌의근거요약표 근거표 1. 전립선비대증환자를처음진료할때 IPSS 설문지는단순병력청취보다진단에도움을주는가? 1. Barry MJ, Fowler FJ, Jr., O Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148: ; discussion 64. Case-control study 210 BPH patients and 108 control subjects To invent and validate symptom index for BPH The final AUA symptom index includes 7 questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On revalidation, the index was internally consistent (Cronbach's alpha = 0.86) and the score generated had excellent test-retest reliability (r = 0.92). Scores were highly correlated with subjects' global ratings of the magnitude of their urinary problem (r = 0.65 to 0.72) and powerfully discriminated between BPH and control subjects (receiver operating characteristic area 0.85). Finally, the index was sensitive to change, with preoperative scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (p < 0.001). The AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols Level of Study 4 7. O Leary MP, Wei JT, Roehrborn CG, Miner M; BPH Registry and Patient Survey Steering Committee. Correlation of the International Prostate Symptom Score bother question with the Benign Prostatic Hyperplasia Impact Index in a clinical practice setting. BJU Int 2008;101: Large, multicenter, longitudinal observational study 6,439 To evaluate the association between the International Prostate Symptom Score (IPSS) bother question (BQ) and a validated disease-specific quality-of-life questionnaire, the Benign Prostatic Hyperplasia (BPH) Impact Index (BPH-II), using the BPH Registry and Patient Survey database. The mean (sd) score of the IPSS BQ was 2.5 (1.4) and of the BPH-II was 2.8 (2.8). Based on responses to the BPH-II, at least half the men reported that their urinary symptoms were associated with physical discomfort, worry about their health, and bothersomeness. The IPSS BQ score was significantly correlated (P < 0.001) with the BPH-II (r = 0.68) and each of its four questions (physical discomfort, r = 0.52; worry about health, r = 0.53; bothersomeness of trouble with urination, r = 0.67; and time kept from usual activities, r = 0.44). Level of Study 2 근거표 2. 전립선비대증환자를진료할때배뇨일지는단순병력청취보다진단에도움을주는가? 3. Gisolf KW, et al. Analysis and reliability of data from 24-hour frequency-volume charts in men with lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2000;38:

176 전립선비대증진료권고안 Observational study 160 men with BPH To analyse the data from frequency-volume charts and to study the reliability of these charts in men with LUTS due to BPH Another 28 patients who met all other criteria did not complete the frequency-volume charts correctly. Agreement exists between reported voided volumes in the literature and those found by us. We found a significant correlation (p<0.001) between nycturia and score on symptom question 7, and between diuria and score on symptom question 2 of the AUA symptom index. The difference between results obtained from frequency-volume charts completed during 24 h and those obtained from charts completed during three or more 24-hour periods was negligible with respect to the variation of data at al. individual level. Frequency-volume charts are reliable in the investigation of patients with LUTS due to BPH. Reporting on frequency-volume charts during just 24 h is sufficient to gain insight into their voiding habits during normal daily life. Level of Study 3 8. Groutz A, Blaivas JG, Chaikin DC, Resnick NM, Engleman K, Anzalone D, et al. Noninvasive outcome measures of urinary incontinence and lower urinary tract symptoms: a multicenter study of micturition diary and pad tests. J Urol 2000;164(3 Pt 1): Prospective observational study 109 To assess the test-retest reliability of a 24, 48 and 72-hour micturition diary and pad test in patients referred for the evaluation of urinary incontinence and lower urinary tract symptoms The number of pads and total weight gain appeared to be reliable measures of the 24, 48 and 72-hour pad tests. For the 24-hour diary the total number of incontinence episodes was a reliable measure, while the total number of voiding episodes was marginally reliable (mean CCC and , respectively). For the 48-hour diary the number of incontinence episodes and total number of voiding episodes were reliable measures (mean CCC 0.78 and 0.83, respectively), while for the 72-hourdiary each parameter was highly reliable (CCC 0.86 and 0.826, respectively). However, an increased test period was associated with decreased patient compliance. Level of Study 3 근거표 3. 전립선비대증환자에서요속검사및잔뇨량측정은치료법결정에도움을주는가? 1. Oelke M, Hofner K, Jonas U, de la Rosette JJ, Ubbink DT, Wijkstra H. Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume. European Urology 2007;52: Prospective study 160 patients 175

177 Korean clinical practice guideline for benign prostate hyperplasia The aim of this prospective study was to compare the diagnostic accuracy of detrusor wall thickness (DWT), free uroflowmetry, postvoid residual urine, and prostate volume (index tests) with pressureflow studies (reference standard) to detect bladder outlet obstruction (BOO) in men. One hundred sixty men between yr of age (median: 62 yr) were included in the study; 75 patients (46.9%) had BOO according to pressure-flow studies. The results of all investigated index tests differed significantly between obstructed and non-obstructed men. DWT was the most accurate test to determine BOO: the positive predictive value was 94%, specificity 95%, and the area under the curve of ROC analysis There was an agreement of 89% between the results of DWT measurement and pressure-flow studies. Level of Study 3 2. Poulsen AL, Schou J, Puggaard L, Torp-Pedersen S, Nordling J. Prostatic enlargement, symptomatology and pressure/flow evaluation: Interrelations in patients with symptomatic BPH. Scandinavian Journal of Urology and Nephrology Supplementum 1994;157: Prospective study 188 patients Benign prostatic hyperplasia (BPH) is the most common pathologic condition to afflict the aging male. Many patients with symptomatic BPH undergo prostatectomy without rigorous evaluation. Three concepts should be considered before any treatment of a patient with symptomatic BPH; Prostatic enlargement, symptomatology and bladder outflow obstruction. Neither uroflowmetry, symptomatology nor prostate size correlated well with bladder outlet obstruction. The positive predictive value for infravesical obstruction was 88% if a maximum flow rate under 10 ml/s was used. Symptomatology could not be used to differentiate between patients with bladder outlet obstruction and patients without obstruction. The positive predictive value for infravesical obstruction was 76% if a prostate volume over 40 ml was chosen. Level of Study 3 3. Reynard JM, Peters TJ, Lim C, Abrams P. The value of multiple free-flow studies in men with lower urinary tract symptoms. British Journal of Urology 1996;77: Prospective study 165 patients To assess the variability of free-flow studies in men presenting with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) and to determine the sensitivity, specificity and predictive values of consecutive measurements of maximum flow rate for the presence of bladder outlet obstruction (BOO) at several threshold values. The mean Qmax on void 1 was 10.2 ml/s and the mean maximum value for Qmax between voids 1 and 2 was 12.5 ml/s. For voids 1, 2 and 3, the mean maximum Qmax was 13.9 ml/s and for voids 1 to 4 it was 15.2 ml/s. There were no significant changes in PVR among any of these voids. There was a statistically significant, although small, decrease in voided volume between voids 1 to 3 and voids 1 to 4. The specificity and PPV of Qmax for BOO increased with each subsequent void, such that using a threshold value for Qmax of 10 ml/s on the fourth void, the specificity and PPV for BOO were 96% and 93%, respectively. Level of Study 3 176

178 전립선비대증진료권고안 4. Reynard JM, Yang Q, Donovan JL, Peters TJ, Schafer W, De la Rosette JJMC, et al. The ICS-'BPH' Study: Uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. British Journal of Urology 1998;82: Prospective study 1,271 patients To explore the relationship between uroflow variables and lower urinary tract symptoms (LUTS): to define performance statistics (sensitivity, specificity, positive and negative predictive values) for maximum urinary flow rate (Qmax) with respect to bladder outlet obstruction (BOO) at various threshold values; and to investigate the diagnostic value of low-volume voids. The relationship between symptoms and uroflow variables was poor. The mean difference between home-recorded and clinic-recorded voided volumes was -48 ml. Qmax was significantly lower in those with BOO (9.7 ml/s for void 1) than in those with no obstruction (12.6mL/s; P<0.001) and Qmax was negatively correlated with obstruction grade (Spearman's correlation coefficient -0.3, P<0.001), even when controlling for the negative correlation between age and Qmax (Spearman's partial correlation coefficient -0.29, P<0.001). A threshold value of Qmax of 10 ml/s had a specificity of 70%, a positive predictive value (PPV) of 70% and a sensitivity of 47% for BOO. The specificity using a threshold Qmax of 15 ml/s was 38%, the PPV 67% and the sensitivity 82%. Those voiding <150 ml (n=225) had a 72% chance of BOO (overall prevalence of BOO 60%). In those voiding >150 ml the likelihood of BOO was 56%. The addition of a specific threshold of 10 ml/s to these higher volume voiders improved the PPV for BOO to 69%. Level of Study 3 5. D'Silva KA, Dahm P, Wong CL. Does this man with lower urinary tract symptoms have bladder outlet obstruction?: The Rational Clinical Examination: a systematic review. JAMA 2014;312: systematic review To systematically review the evidence on (1) the diagnostic accuracy of office-based tests for bladder outlet obstruction in men with lower urinary tract symptoms; and (2) the accuracy of the bladder scan as a measure of urine volume because management decisions rely on measuring postvoid bladder residual volumes. Among males with lower urinary tract symptoms, the likelihood ratios (LRs) of individual symptoms and questionnaires for diagnosing bladder outlet obstruction from the highest quality studies had 95% CIs that included 1.0, suggesting they are not significantly associated with one another. An International Prostate Symptom Score cutoff of 20 or greater increased the likelihood of bladder outlet obstruction (positive LR, 1.5; 95% CI, ), whereas scores of less than 20 had an LR that included 1.0 in the 95% CI (negative LR, 0.82; 95% CI, ). We found no data on the accuracy of physical examination findings to predict bladder outlet obstruction. Urine volumes measured by a bladder scanner correlated highly with urine volumes measured by bladder catheterization (summary correlation coefficient, 0.93; 95% CI, ). In patients with lower urinary tract symptoms, the symptoms alone are not enough to adequately diagnose bladder outlet obstruction. A bladder scan for urine volume should be performed to assess patients with suspected large postvoid residual volumes. Level of Study 1 177

179 Korean clinical practice guideline for benign prostate hyperplasia 근거표 4. 전립선비대증의해부학적인평가를위해서직장수지검사보다초음파검사가더정확한평가를 할수있는가? 6. Loeb S, Han M, Roehl KA, Antenor JA, Catalona WJ. Accuracy of prostate weight estimation by digital rectal examination versus transrectal ultrasonography. J Urol 2005;173:63-5. Cross-sectional study 2,238 To evaluated the relative accuracy of these weight estimates by comparing them to prostate weight following radical retropubic prostatectomy DRE estimates of prostate weight by multiple examiners correlated poorly with RRP specimen weight (r = ). However, TRUS estimates correlated moderately well (r = ). TRUS provided more accurate estimates of prostate weight for smaller glands, although it generally underestimated gland weight compared to the weight of the surgical specimen.in a large, community based prostate cancer screening study prostate weight estimated by DRE was shown to correlate poorly with actual prostate weight. Compared with DRE, TRUS provides a better estimate of prostate weight. In addition, TRUS measurements were more accurate in smaller prostate glands. Level of Study 3 7. Roehrborn CG, Girman CJ, Rhodes T, Hanson KA, Collins GN, Sech SM, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology 1997;49: Cross-sectional study 397 To correlate prostate size estimates performed by single or multiple examiners through digital rectal examination (DRE) with volume measured by transrectal ultrasound (TRUS) and to propose measures for predicting prostatevolume using DRE estimates in clinical settings DRE estimates and TRUS volumes were significantly correlated (r = 0.4 to 0.9), but prostate size was underestimated by 25% to 55% for men with a prostate volume over 40 ml..according to receiver operating characteristic curves, surface area (SA) showed a 70% and 76% chance of correctly identifying men with prostate volume greater than 30 or 40 ml, respectively; those with larger prostates were best distinguished by SA greater than 7 cm2 (sensitivity greater than 0.74, specificity greater than 0.50). Level of Study 3 8. Roehrborn CG, Sech S, Montoya J, Rhodes T, Girman CJ. Interexaminer reliability and validity of a three-dimensional model to assess prostate volume by digital rectal examination. Urology 2001;57: Cross-sectional study 121 To evaluate the interexaminer reliability and accuracy compared with transrectal ultrasound (TRUS) of a three-dimensional (3D) model and other scales to improve the estimation of prostate volume by digital rectal examination (DRE). 178

180 전립선비대증진료권고안 DRE size estimates and TRUS volume were moderately to highly correlated in men without prostate cancer. A 3D sizing model showed comparable reliability and correlation with TRUS. Although the DRE estimates generally tend to underestimate the TRUS-measured prostate volume, these tools may be useful in identifying men with enlarged prostate glands. Level of Study 3 근거표 5. 전립선비대증환자에서전립선특이항원수치는반드시측정해야하는가? 20. Crawford ED, Wilson SS, McConnell JD, Slawin KM, Lieber MC, Smith JA, et al. Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. J Urol 2006;175: Longitudinal follow up of the placebo arm of an RCT with 4 years follow up - Men with BPH and moderate to severe symptom (AUASS) mean 17 (range of 8-20). - The average age was 62 years. (N=737) Level of Study 2 Analysis of data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression Baseline PSA level was associated with symptom progression. At 4 years, the cumulative probability and incidence rate of overall BPH progression was significantly higher in the baseline high PSA group (p<0.001). Incidence rate of 4 points increase in AUASS was significantly higher in the high PSA group (4.5 vs. 2.8 events/100 person year). The incidence rate of acute urinary retention and invasive therapy was also significantly higher in the group with higher baseline PSA. 21. McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr., Dixon CM, Kusek JW, et al. The longterm effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: RCT double blinded (4 arms) - N: 3047 out of 4391 screened, - Mean age: 62.6 ± 7.3 To know the long-term effect of these drugs, singly or combined, on the risk of clinical progression Prognosis value of PSA, based on placebo arm [Data from Crawford 2006] - Overall BPH progression was defines as the first occurrence of an increase of at least 4 points in the AUASS, AUR, urinary incontinence or renal insufficiency or recurrent UTI - Cumulative probability of BPH progression (4 year follow up) PSA 1.6 ng/ml: 24% PSA<1.6 ng/ml: 13.5% P<0.001 (values read from graph) - Incidence rate of overall BPH progression (events/100 person year) PSA 1.6 ng/ml: 5.9 PSA<1.6 ng/ml: 3.1 P= Incidence rate of 4 points increase in AUASS (events/100 person year) PSA 1.6 ng/ml: 4.5 PSA<1.6 ng/ml: 2.8 P= Incidence rate of AUR (events/100 person year) 179

181 Korean clinical practice guideline for benign prostate hyperplasia PSA 1.6 ng/ml: 1.0 PSA<1.6 ng/ml: 0.3 P= Incidence rate of invasive therapy (events/100 person year) PSA 1.6 ng/ml: 1.8 PSA<1.6 ng/ml: 0.8 P=0.018 Level of Study Roehrborn CG, Boyle P, Bergner D, Gray T, Gittelman M, Shown T, et al. Serum prostatespecific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a fouryear, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54: RCT with follow up of 4 years. - Men with clinical BPH, moderate to severe symptoms - Serum PSA ng/ml with negative biopsy - N: 3,040 (Drop outs: 1,157) - Group 1 Finasteride 5mg/day - Group 2 Placebo Notes: Baseline PSA was divided into 3 tertiles: First ( ) Second ( ) Third ( ) To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. - Baseline PSA predicts deterioration of symptoms in untreated patients. Baseline PSA predicts improvement of symptoms for those patients treated with finasteride relative to placebo Baseline PSA does not predict improvement of symptoms in the finasteride treatment group alone. - Mean Change in Quasi-AUA Symptom Score (± SE) over time (years 1-4) for each PSA tertile in placebo patients (group 2): 1st tertile had a significantly better long-term symptom improvement than those in other tertiles p < There was no significant difference between long term symptom improvement between 2nd and 3rd tertiles p= Mean Change in Quasi-AUA Symptom Score (± SE) over time (years 1-4) for each PSA tertile group 1 vs. group 2: 1st tertile Not sig. 2nd tertile (p=0.004) 3rd tertile (p=0.001) Level of Study Laguna MP, Kiemeney LA, Debruyne FM, de la Rosette JJ. Baseline prostatic specific antigen does not predict the outcome of high energy transurethral microwave thermotherapy. J Urol 2002;167: Cohort - N: Age (mean, range): 66.3 ( ) To assessed the prognostic value of baseline prostate specific antigen (PSA) for outcome after high energy transurethral thermotherapy in patients with lower urinary tract symptoms. Linear regression: Change in QoL vs. pretreatment PSA Spearman r: linear regression coefficient : P value: 0.01 Level of Study Tubaro A, La Vecchia C. The relation of lower urinary tract symptoms with life-style factors and objective measures of benign prostatic enlargement and obstruction: An italian survey. Eur Urol 2004;45:

182 전립선비대증진료권고안 Level of Study 2 Cross sectional, observational - Age: years - N: 866a - Drop outs: 64/866, 802 analysed - Age (mean, range): 64 (50-80) The association between the severity of LUTS and prostate volume, prostate-related variables and general lifestyle factors was investigated in a large number of patients with persistent LUTS suggestive of BPH (LUTS/ BPH). Multiple logistic regressions: IPSS >7 vs. PSA (ng/ml), IPSS<7 is the reference Odds ratio (95%CI) PSA 2: 1.0 PSA>2-4: 1.62 ( ) PSA>4-10: 2.64 ( ) PSA>10: 4.28 ( ) 근거표 6. 전립선비대증환자에서생활습관개선은증상호전에도움이되는가? 1. Isaacs JT. Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. Prostate 1990;3(Suppl):1-7. Review To summarize Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. These comparisons demonstrate that 1) placebo treatment does not affect the natural history of the disease; 2) spontaneous improvement usually occurs within the first 6 months of initial presentation of symptoms, if it is to occur at all; and 3) 3-6 months of follow-up are needed to determine if a patient is going to get worse. Thus, to evaluate accurately the potential benefit of any medical intervention for symptomatic BPH, placebocontrolled clinical trials will be required and should be of at least 6 month's duration. Level of Study 5 2. Flanigan RC, Reda DJ, Wasson JH, et al. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic BPH: a Department of Veterans Affairs cooperative study. J Urol 1998;160:12-6. Control arm of randomized trial 280: TURP 276: Watchful waiting 5 year follow-up To know the outcomes after 5 years of follow-up for men who were randomized to receive TURP or watchful waiting for moderate symptoms of BPH. 181

183 Korean clinical practice guideline for benign prostate hyperplasia Treatment failure rates were 10% for TURP versus 21% for watchful waiting (p = ). The crossover rate at 5 years was 36% and was positively associated with the degree of bother. Level of Study 3 3. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. New Engl J Med 1995;332:75-9. Control arm of randomized trial 280: TURP 276: Watchful waiting 3 year follow-up To know the outcomes after 3 years of follow-up for men who were randomized to receive TURP or watchful waiting for moderate symptoms of BPH. Of the men assigned to the watchful-waiting group, 65 (24 percent) underwent surgery within three years after the assignment. Surgery was associated with improvement in symptoms and in scores for urinary difficulties and interference with activities of daily living (P<0.001 for all comparisons). Level of Study 3 4. Netto NR, de Lima ML, Netto MR, et al. Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urol 1999;53: Study without consistently applied reference standards / Cohort study 479 patients 50 to 81 years old (mean age 63) with lower urinary tract symptoms attributed to BPH. To know the variability of bladder outlet obstruction and mild lower urinary tract symptoms in patients with benign prostatic hyperplasia (BPH) followed up by watchful waiting. Of 50 patients with mild symptoms, 16 (32%) had bladder outlet obstruction. After a period of 9 to 22 months (mean 17) of watchful waiting, these 16 patients were reviewed. Twelve (75%) of the 16 had bladder outlet obstruction reconfirmed by pressure-flow studies, and 3 (18.8%) of 16 had increased symptoms (moderate symptomatic) and underwent treatment. A total of 4 (25%) of 16 patients still had mild voiding disturbances. The remaining 34 patients with no obstruction had annual routine follow-up and had persistent mild symptom scores and normal uroflowmetric results. Level of Study 4 5. Brown CT, Yap T, Cromwell DA, et al. Self-management for men with lower urinary tract symptoms a randomized controlled trial. BMJ 2007;334:25. Control arm of randomized trial men (mean age 63 (SD 10.7) years), referred by general practitioners to urological outpatient departments with uncomplicated lower urinary tract symptoms. - Self management and standard care (n=73) or standard care alone (n=67). 12 months follow-up To evaluate the effectiveness of self management as a first line intervention for men with lower urinary tract symptoms 182

184 전립선비대증진료권고안 Level of Study 3 Level of Study 4 Level of Study 5 At three months, treatment failure had occurred in 7 (10%) of the self management group and in 27 (42%) of the standard care group (difference=32%, 95% confidence interval 18% to 46%). Corresponding differences in the frequency of treatment failure were 42% (27% to 57%) at six months and 48% (32% to 64%) at 12 months. At three months, the mean international prostate symptom score was 10.7 in the self management group and 16.4 in the standard care group (difference=5.7, 3.7 to 7.7). Corresponding differences in score were 6.5 (4.3 to 8.7) at six months and 5.1 (2.7 to 7.6) at 12 months. 6. Ball AJ, Feneley RC, Abrams PH. The natural history of untreated prostatism. Br J Urol 1981;53: Study without consistently applied reference standards / Cohort study 107 patients with symptoms of prostatic obstruction in whom prostatectomy was not clinically indicated. 5 year follow-up To evaluate the natural history of patients with symptoms of prostatic obstruction Ten had subsequently required surgery and 97 remained untreated. In the majority, symptoms did not worsen and only 2 developed acute retention. 7. Kirby RS. The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 2000;56(5 Suppl 1):3-6. Review To summarize our current understanding of the natural history of benign prostatic hyperplasia Age is a strong independent risk factor for the development of AUR. Transurethral resection of the prostate was more effective than watchful waiting in preventing AUR, as shown in the Veteran's Affairs Cooperative Study. Data from the Olmsted County study revealed that urinary flow decreases and prostate size increases with advanced age. 8. Yap TL, Brown C, Cromwell DA, et al. The impact of self-management of lower urinary tract symptoms on frequency-volume chart measures. BJU Int 2009;104: Control arm of randomized trial 140 men with uncomplicated lower urinary tract symptoms. 12 months follow-up To assess the effect of a self-management programme (SMP) on actual voiding behaviour using frequency-volume chart (FVC) data. Of the 140 patients, 104 completed the FVC data at baseline; at 3, 6 and 12 months charts were received from 99, 95 and 70, respectively. Baseline FVC variables were equivalent between the randomized groups. At 3 months the mean voided volume had increased in the SMP group and differed from the control group by a mean (95% confidence interval, CI) of 57 (33-83) ml. The total number of voids and episodes of nocturia were also lower in the SMP group, with a mean (95% CI) decrease of 2.6 (-3.6 to -1.5) and 0.7 (-1.1 to -0.3) episodes, respectively. These changes were maintained at 6 and 12 months. 183

185 Korean clinical practice guideline for benign prostate hyperplasia Level of Study 3 9. Brown CT, van der Meulen J, Mundy AR, et al. Defining the components of self-management programme in men with lower urinary tract symptoms: a consensus approach. Eur Urol 2004;46: multidisciplinary panel rating An eight member multidisciplinary panel rated 94 items To define the components of a self-management programme of lifestyle and behavioural interventions for symptom control in men with uncomplicated LUTS. The panel agreed that 57 of the original 94 items were appropriate to be incorporated in the selfmanagement programme. These interventions were contained within the following categories: patient assessment prior to starting a self-management programme (6), education and reassurance (4), fluid management (6), caffeine (4), alcohol (2), concurrent medication (2), types of toileting (2), bladder re-training (15), miscellaneous (1), and implementation of a self-management programme (15). Level of Study 4 근거표 7. 전립선비대증환자에서일차치료법으로약물치료법이수술적치료보다우선적으로고려되어야 하는가? 1. Djavan B, Chapple C, Milani S, et al. State of the art on the efficacy and tolerability of alpha1- adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 2004;64: Systematic review 33 studies, 22,562 patients To aim in the present report to update the analysis published in 1999 to assess whether these α1-ar antagonists can be distinguished with regard to efficacy and/or tolerability All α1-ar antagonists have comparable efficacy in improving symptoms and Qmax when administered at their full therapeutic dose. α1-ar antagonists that require dose titration and are initiated at subtherapeutic doses (eg, terazosin) have a slower onset of action than α1-ar antagonists that can be initiated at their full therapeutic dose (eg, tamsulosin). The main difference between α1-ar antagonists relates to their tolerability profile, with alfuzosin (especially the XL formulation) and tamsulosin (especially the 0.4 mg o.d. dose) better tolerated than doxazosin (including the GITS formulation) and terazosin. As demonstrated in the direct-comparative studies, tamsulosin tends to interfere less with blood pressure regulation and induces slightly less vasodilatory AEs than alfuzosin. This seems particularly to be the case in the elderly and patients with cardiovascular disease and/or comedication. Abnormal ejaculation has mainly been reported in placebo-controlled trials with tamsulosin. In direct-comparative trials, its incidence with tamsulosin was comparable or slightly greater than that with alfuzosin and greater than that with terazosin. However, it seems that patients with LUTS/BPH are more likely to discontinue α1- AR antagonist therapy because of vasodilatory AEs such as dizziness than abnormal ejaculation and that over-all sexual function is improved with all α1-ar antagonists, including tamsulosin. Vasodilatory AEs may lead to falls, fractures, and institutionalization, in particular in the elderly or very elderly and/or in those with concomitant cardiovascular comorbidity/co-medication. 184

186 전립선비대증진료권고안 Level of Study 1 2. McConnell JD, Roehrborn CG, Bautista O, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Randomized, placebo-controlled trial 3,047 patients To compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia The risk of overall clinical progression-defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection-was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. Level of Study 2 3. Jardin A, Bensadoun H, Delauche-Cavallier MC, et al. Alfuzosin for treatment of benign prostatic hypertrophy. The BPH-ALF Group. Lancet 1991;337: Randomized, placebo-controlled trial 518 patients To assess the long-term efficacy and safety of alfuzosin, a selective alpha 1-adrenergic antagonist Obstructive and irritative symptoms, assessed according to the Boyarsky scale, significantly improved in the alfuzosin group compared with the placebo group (p = ). Fewer patients in the alfuzosin group than in the placebo group dropped out due to lack of efficacy (6.8% vs 14.6%, p = 0.004) and the prevalence of spontaneous acute urine retention was lower in the alfuzosin group (0.4% vs 2.6%, p = 0.04). By 6 months, mean urinary flow rates had increased (p less than 0.05) and residual volume had decreased (p = 0.017) in the alfuzosin group, although the two groups were broadly similar with respect to increase in peak flow rate. The overall incidence of adverse events was similar in the two groups, which led to the withdrawal of 10.8% and 9.0% of patients, respectively. Level of Study 2 4. Buzelin JM, Roth S, Geffriaud-Ricouard C, et al. Efficacy and safety of sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. ALGEBI Study Group. Eur Urol 1997;31: Randomized, placebo-controlled trial 390 patients 185

187 Korean clinical practice guideline for benign prostate hyperplasia To assess the efficacy and safety of a sustained-release (SR) formulation of alfuzosin, a selective alpha(1)-blocker, in patients with symptomatic benign prostatic hyperplasia (BPH) SR-alfuzosin significantly improved urinary symptoms versus placebo assessed using the I-PSS (-31 vs. -18%, p = 0.007) and Boyarsky (-30 vs. -16%, p < 0.001) scores, with a direct correlation between both scores. Maximum flow rate increased significantly with SR-alfuzosin (+2.4 ml/s, i.e. +29%) compared with placebo (+1.1 ml/s, i.e. +14%, p = 0.006). Residual urine was also significantly reduced with SR-alfuzosin. Overall, SR-alfuzosin was as well tolerated as placebo. Nine patients dropped out for adverse events with SR-alfuzosin (4.6%) and 14 (7.1%) with placebo. The incidence of vasodilation-related events (dizziness, postural symptoms, headache) with SR-alfuzosin (3.1%) was similar to that of placebo (3.6%). No first-dose effect was observed compared with placebo. The reduction in supine blood pressure with SR-alfuzosin was minor (< or = 5 mmhg), both in normotensive and hypertensive patients. Level of Study 2 5. van Kerrebroeck P, Jardin A, Laval KU, et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol 2000;37: Randomized, placebo-controlled trial 447 patients To assess the efficacy and safety of a new prolonged release formulation of the uroselective alpha (1)-blocker alfuzosin for a once-daily dosing regimen in patients with lower urinary tract symptoms (LUTS) suggestive of symptomatic benign prostatic hyperplasia (BPH) Both alfuzosin formulations significantly improved urinary symptoms versus placebo assessed using the International Prostate Symptom Score (alfuzosin 10 mg once daily: -6.9; alfuzosin 2.5 mg thrice daily: -6.4; placebo: -4.9, p = 0.005). Peak flow rate increased significantly with alfuzosin 10 mg once daily (+2.3 ml/s, p = 0.03 vs. placebo) and with alfuzosin 2.5 mg thrice daily (+3.2 ml/s, p< vs. placebo) compared to placebo (+1.4 ml/s). Overall both formulations of alfuzosin were well tolerated in comparison with placebo. In addition, vasodilatory adverse events appeared to be less frequent with the once daily than the thrice daily formulation (6.3 vs. 9.4%, respectively). No first-day effect was reported with alfuzosin once daily and the effect on blood pressure did not differ from those observed in placebo, both in normotensive and hypertensive patients. No specific sexual dysfunction including ejaculation disorder was reported in the alfuzosin 10 mg once-daily group. Level of Study 2 6. MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology 2005;66: Systematic review 11 studies, 3,901 patients To evaluate the efficacy and adverse effects of alfuzosin for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH) 186

188 전립선비대증진료권고안 Level of Study 1 Level of Study 2 The search strategy identified 11 trials involving 3,901 men with a mean age of 64 years. Eight trials were placebo-controlled studies, two were alfuzosin versus alternative alpha-blockers, and one was alfuzosin versus finasteride and combination alfuzosin/finasteride therapy. The study durations were short term, 4 to 26 weeks. The mean baseline symptom scores and peak urinary flow rates were indicative of moderate BPH. Alfuzosin (7.5 or 10 mg) improved lower urinary tract symptoms assessed by the International Prostate Symptom Score compared with placebo. The mean absolute change from baseline was -5.4 points for alfuzosin compared with -3.6 points for placebo, a weighted mean difference of 1.8 points (three studies). Alfuzosin increased the peak urinary flow more than did placebo, although the improvement varied across the eight studies. Symptom and flow improvements were generally comparable to that with combination therapy and with other alpha1-blockers. Alfuzosin had good short-term tolerability, and the numbers of study withdrawals were comparable to those with placebo and controls. Efficacy and short-term safety were similar across the various (immediate-release, sustained, and once-daily) formulations. 7. Kirby RS, Andersen M, Gratzke P, et al. A combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int 2001;87: Randomized, placebo-controlled trial 795 patients To report an integrated analysis of two previous studies fully characterizing the clinical utility of the controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin in the treatment of benign prostatic hyperplasia (BPH) Both doxazosin GITS and doxazosin-s significantly improved the symptoms of BPH, as shown by a 45% reduction for each in total IPSS from baseline to final visit, compared with a 34% reduction in patients on placebo. Doxazosin GITS and doxazosin-s produced comparable improvements in Qmax that were significantly greater than with placebo, with a greater improvement sooner after treatment with doxazosin GITS than with doxazosin-s. Nearly half of the patients on doxazosin GITS had symptom relief at the 4-mg starting dose. A similar number of patients in both doxazosin groups were titrated to the maximum dose. Secondary outcomes were consistent with the primary effects. Both doxazosin GITS and doxazosin-s produced significant improvements in sexual function according to IIEF scores among those with dysfunction at baseline. The overall incidence of adverse events was similar among patients treated with doxazosin GITS and placebo, and slightly lower than those on doxazosin-s. There was no apparent difference in the type of adverse events reported for the two formulations of doxazosin, although most adverse events were reported at a lower frequency with doxazosin GITS. 8. Chapple CR, Wyndaele JJ, Nordling J, et al. Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta-analysis of two randomised, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group. Eur Urol 1996;29: Meta-analysis 2 studies, 575 patients 187

189 Korean clinical practice guideline for benign prostate hyperplasia To evaluate the efficacy and safety of modified-release tamsulosin 0.4 mg once daily compared with placebo in patients with benign prostatic enlargement, lower urinary tract symptoms and prostatic obstruction (symptomatic BPH) Maximum urinary flow rate improved to a greater extent in the tamsulosin group (1.6 ml/s, 16%) than the placebo group (0.6 ml/s, 6%) (p = 0.002). Total Boyarsky symptom score also improved to a greater extent in the tamsulosin group (3.3 points, 35.1% reduction) than the placebo group (2.4 points, 25.5% reduction) (p = 0.002). Significantly more tamsulosin patients (66%) than placebo patients (49%) had a > or = 25% decrease in total symptom score at endpoint (p < 0.001). Twelve weeks of treatment with tamsulosin also produced significant improvements in average urinary flow rate (p = 0.005) and voiding or "obstructive" (p = 0.008) and storage or "irritative' (p = 0.017) symptom scores. The incidence of drug-related adverse events was comparable for the tamsulosin and placebo groups (13 and 12% respectively, p = 0.802). The same applies to the incidence of adverse events commonly attributed to alpha 1-adrenoceptor antagonists, such as dizziness, headache, postural hypotension, syncope, asthenia, somnolence and rhinitis. There were no clinically significant changes in blood pressure or pulse rate in tamsulosin patients compared with placebo patients both in hypertensive and normotensive BPH patients. Level of Study 1 9. Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 1998;51: Randomized, placebo-controlled trial 756 patients To evaluate the efficacy and safety of two once-daily doses of tamsulosin, the first selective alpha1a-antagonist studied in clinical trials Statistically significant improvements in all efficacy parameters were observed in tamsulosin-treated compared with placebo-treated patients. Additionally, the 0.4-mg/day dose demonstrated a rapid onset of action (4 to 8 hours) based on Qmax after the first dose of double-blind medication. A review of the safety parameters demonstrated excellent tolerance at 1 week after the initial 0.4- mg/day dose and continued tolerance during the additional 12 weeks of 0.4- and 0.8-mg/day dosing. The incidence of positive orthostatic test results in the tamsulosin groups was comparable to that observed in the placebo group. Adverse events were comparable in the 0.4-mg/day tamsulosin and placebo groups and were somewhat higher in the 0.8-mg/day tamsulosin group. Level of Study Wilt TJ, Mac Donold R, Rutks I. Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2003;(1):CD Systematic review 14 studies, 4,122 patients To assesse the effects of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) compatible with BPH 188

190 전립선비대증진료권고안 Fourteen studies involving 4,122 subjects met inclusion criteria. Study duration ranged from 4-26 weeks, and no placebo-controlled study lasted longer than 13 weeks. The mean age of subjects was 64 years. Baseline symptom scores and urine flow rates demonstrated that men had moderate LUTS. Tamsulosin improved symptoms and peak urine flow relative to placebo. The weighted mean differences (WMD) for mean change from baseline for the Boyarsky symptom score for 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were -1.1 points (95% CI = -1.49, -0.72; 12% improvement) and -1.6 points (95% CI = -2.3, -1.0; 16% improvement), respectively. The WMD for mean change from baseline in peak urine flow were 1.1 ml/sec (95% CI = 0.59, 1.51) and 1.1 ml/sec (95% CI= 0.65, 1.48) for 0.4 mg and 0.8 mg, respectively. Tamsulosin (0.2 mg-0.4 mg) was as effective as other alpha antagonists and the phytotherapeutic agent Permixon in improving symptoms and flow rates though the doses of all alphaantagonists studied may not have been optimal. Discontinuations from treatment for any reason and discontinuations "due to adverse events" were similar in the low dose tamsulosin (0.2 mg) and placebo groups but increased to 16% in trials utilizing a 0.8 mg dose of tamsulosin. Low dose tamsulosin was generally well tolerated although not all the trials reported specific adverse events. The most frequently reported adverse events that were significantly greater than placebo included dizziness, rhinitis and abnormal ejaculation. Adverse effects increased markedly as tamsulosin dosing increased, and were reported in 75% of men receiving the 0.8 mg dose. Men receiving a 0.2 mg dose tamsulosin were less likely to discontinue treatment compared to men receiving terazosin. Level of Study Brawer MK, Adams G, Epstein H. Terazosin in the treatment of benign prostatic hyperplasia. Terazosin Benign Prostatic Hyperplasia Study Group. Arch Fam Med 1993;2: Randomized, placebo-controlled trial 160 patients To evaluate the efficacy and tolerability of terazosin, a long-acting selective alpha 1-receptor antagonist, in patients with benign prostatic hyperplasia Terazosin-treated patients had decreases in Boyarsky obstructive, irritative, and total scores of 3.3 (52%), 1.3 (29%), and 4.6 (42%), respectively, compared with decreases of 0.7 (12%), 0.4 (9%), and 1.1 (11%), respectively, in the placebo group (P <.05). Peak urine flow increased by a mean of 2.6 ml/ s (30%) in terazosin-treated patients and 1.2 ml/s (14%) in placebo-treated patients (P < or =.05). Adverse events that differed significantly in the two groups were dizziness (19% in the terazosin group vs 5% in the placebo group) and urinary tract infection (1% in the terazosin group vs 10% in the placebo group). Level of Study Roehrborn CG, Oesterling JE, Auerbach S, et al. The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator Group. Urology 1996;47: Randomized, placebo-controlled trial 2,084 patients To determine the clinical effectiveness and safety of alpha (1)-blockade therapy versus placebo in the treatment of men with moderate to severe symptoms of prostatism in a community-based population under usual care conditions 189

191 Korean clinical practice guideline for benign prostate hyperplasia AUA-SS (0 to 35 point scale) improved from a baseline mean of 20.1 points by 37.8% during terazosin (n=976) and by 18.4% during placebo (n=973) treatment (P<0.001). Similarly, statistically superior improvements were observed in regard to the AUA-BS, BII, and the QQL score in the terazosin-treated patients. Peak urinary flow rate improved from a baseline of 9.6 ml/s (both regional treatment groups) by 2.2 ml/s in the terazosin group (n=137) and by 0.7 ml/s in the placebo group (n=140) (P< or = 0.05). Treatment failure occurred in 11.2% of terazosin- and 25.4% of placebo-treated patients (P<0.001; Kaplan-Meier adjusted withdrawal rates of 365 days). Withdrawal from study drug treatment due to adverse events occurred in 19.7% of terazosin- and 15.2% of placebo-treated patients (P<0.001). Level of Study Wilt TJ, Howe RW, Rutks I, et al. Terazosin for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002;(4):CD Systematic review 17 studies, 5,151 patients To evaluate the effectiveness and adverse effects of the alpha-blocker, terazosin, for treatment of urinary symptoms associated with BPO 17 studies involving 5,151 subjects met inclusion criteria (placebo-controlled (10); alpha-blockers (7); finasteride alone or in combination with terazosin as well as placebo (1); microwave therapy (TUMT) (1). Study duration ranged from 4-52 weeks. Mean age was 65 years and 82% of men were white. Baseline urologic symptom scale scores and flow rates demonstrated that men had moderate BPO. Efficacy outcomes were rarely reported in a fashion that allowed for data pooling but indicated that terazosin improved symptom scores and flow rates more than placebo or finasteride and similarly to other alpha antagonists. The pooled mean percentage improvements for the Boyarsky symptom score was 37% for terazosin versus 15% for placebo (n=4 studies). The mean percentage improvement for the American Urological Association symptom score (AUA) was 38% compared to 17% and 20% for placebo and finasteride, respectively (n = 2 studies). The pooled mean improvement in the International Prostate Symptom Score (IPSS) (40%) was similar to tamsulosin (43%). Peak urine flow rates improved greater with terazosin (22%), than placebo (11%) and finasteride (15%) but did not differ significantly from the other alpha-blockers. The percentage of men discontinuing terazosin was comparable to men receiving placebo and finasteride but was greater then with other alphaantagonists. Adverse effects were greater than placebo and included dizziness, asthenia, headache and postural hypotension. Level of Study Michel MC, Mehlburger L, Bressel HU, et al. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prost Dis 1998;1: Open-label, observational study (no control group) 19,365 patients To compare treatment efficacy in subgroups of patients with the a1-blocker tamsulosin 190

192 전립선비대증진료권고안 In a comparison of patients aged <61, 61±70 and >70 y thepretreatment IPSS increased with age in both studies (Table 1). However, the treatment-associated reduction of the IPSS was very similar in all three age groups with a mean reduction of _9 points corresponding to _50% (Table 1). The pretreatment Qmax decreased with age in both studies (Table 1). While the tamsulosin-induced absolute increases of Qmax were slightly smaller in the oldest compared to the youngest age group (4.3_0.2 vs 5.1_0.2 ml/s and 4.3_0.1 vs 4.8_0.1 ml/s in studies 1 and 2, respectively; P<0.05), the relative increases of Qmax were similar in all age groups, that is _40% (Table 1). To study treatment effects in relation to disease severity, patients were stratified according to their pretreatment IPSS (0±7, 8±19 and 20±35, Table 2), Qmax (<10, 10± 15 and >15 ml/s, Table 2) and post-voiding residual urine (<100 and _100 ml, Table 2). with the most severe symptoms benefited at least as much from tamsulosin treatment as those with mild or moderate symptoms and, if anything, had even greater improvements (Table 2). Even more importantly 42% and 50% of patients had an IPSS _20 and a Qmax<10 ml/s prior to treatment, but only 5% and 15%, respectively, remained in that category after four weeks of tamsulosin treatment (Figure 1). Among patients with _100 ml residual urine before treatment only 15% remained in that group after four weeks of treatment, while all others dropped to <100 ml residual urine, and 41% of patients had values of <50 ml. Level of Study Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related safety profile and efficacy of a-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract 2008;62: Meta-analysis 30 studies, 1,053 patients To evaluate the safety profile and efficacy of alpha1-adrenergic receptor blockers (A1Bs) currently prescribed for benign prostatic hyperplasia (BPH) Of 2389 potential citations, 25 were usable for evaluation of safety data, 26 for efficacy. A1B use was associated with a statistically significant increase in the odds of developing a vascularrelated event [odds ratio (OR) 2.54; 95% confidence interval (CI): ; p < ]. The odds of developing a vascular-related adverse event were: alfuzosin, OR 1.66, 95% CI: ; terazosin, OR 3.71, 95% CI: ; doxazosin, OR 3.32, 95% CI: and tamsulosin, OR 1.42, 95% CI: A1Bs increased Q(max) by 1.32 ml/min (95% CI: ) compared with placebo. Difference from placebo in American Urological Association symptom index/international Prostate Symptom Score was points (95% CI: to -1.14). Level of Study Barendrecht MM, Koopmans RP, de la Rosette JJ, et al. Treatment for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: the cardiovascular system. BJU Int 2005;95(Suppl.4): Systematic review Not specified in detail review the physiological basis of cardiovascular side-effects of α1-ar antagonists, identify risk factors for these side-effects, and describe their interaction with specific drugs 191

193 Korean clinical practice guideline for benign prostate hyperplasia Level of Study 1 α1-ar antagonists are a reasonably well-tolerated drug class, but cardiovascular side-effects can occur, and these can lead to serious morbidity such as falls and fractures. Although the available data are not conclusive, it appears that patients with cardiovascular comorbidities and those concomitantly using antihypertensives and/or PDE-5 inhibitors might be particularly at risk. The safety of tamsulosin in such risk groups is better documented than that of other α1-ar antagonists, and this should affect drug choice in patients with LUTS/BPH belonging to any of these risk groups. 17. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg 2005;31: Consecutive retrospective study/prospective cohort study 511 patients/741 patients To assess the incidence and possible causative factors of a newly recognized syndrome, the intraoperative floppy iris (IFIS) Three percent (16/511) of the patients in the retrospective study, representing 3.0% (25/706) of the total eyes, were taking tamsulosin (Flomax) for benign prostatic hypertrophy. The overall prevalence of IFIS was 2.0% (10/511 patients). The syndrome was noted intraoperatively in 63.0% (10/16) of the tamsulosin patients but in none of the 11 patients on other systemic alpha-1 blockers. In the prospective study of 900 consecutive cataract surgeries, the prevalence of IFIS was 2.2% (16/741 patients). Ninety-four percent (15/16) of the IFIS patients were taking or had taken systemic tamsulosin. Twenty-six patients (36 eyes) in the 2 studies had IFIS associated with systemic tamsulosin. Sphincterotomies and mechanical pupil stretching were ineffective in maintaining adequate pupil dilation in this surgical population. Level of Study Michel MC, Okutsu H, Noguchi Y, et al. In vivo studies on the effects of a1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits. Naunyn-Schmiedeberg s Arch Pharmacol 2006;372: Animal study In study I we compared the potential of various α1-adrenoceptor antagonists to inhibit the mydriatic effects of phenylephrine in pentobarbital-anaesthetised rabbits. In study II we established effective doses of these drugs for antagonising the effects of phenylephrine on intraurethral pressure (IUP) in order to establish ratios for ocular effects vs. those for the desired effects in the lower urinary tract. In study III we determined the potential of these α1-adrenoceptor antagonists to affect pupil diameter in conscious rabbits. Study I: The mean basal pupil diameter in the vehicle group was 7.15±0.11 mm, and similar basal values were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). The first phenylephrine injection (30 μg/ kg i.v.) transiently (for about 20 s) increased pupil diameter in the vehicle group by 0.96±0.13 mm, and similar dilatations were observed in all groups receiving the α1 adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). Four additional consecutive phenylephrine injections caused roughly similar pupil dilatation. On the other hand, alfuzosin (30 1,000 μg/kg), doxazosin (30 1,000 μg/kg), naftopidil (300 10,000 μg/kg), prazosin ( μg/kg), tamsulosin (1 30 μg/kg) and terazosin (30 1,000 μg/kg) dose-dependently inhibited phenylephrine-induced pupil dilatation without affecting the duration of the mydriatic response in a relevant manner. 192

194 전립선비대증진료권고안 study II: The mean basal IUP in the vehicle group was 21.9±2.8 cmh2o, and similar basal values were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). The first phenylephrine injection (30 μg/kg i.v.) transiently (for about 70 s) increased IUP in the vehicle group by 43.1±5.7 cm H2O, and similar elevations were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a oneway ANOVA, data not shown). Three additional consecutive phenylephrine injections caused roughly similar IUP elevation. On the other hand, alfuzosin ( μg/kg), doxazosin ( μg/kg), naftopidil (300 3,000 μg/kg), prazosin ( μg/kg), tamsulosin (1 10 μg/kg) and terazosin ( μg/kg) dosedependently inhibited phenylephrine-induced IUP elevation without affecting the duration of the response in a relevant manner. A comparison of the ED50 values for inhibition of pupil dilatation and IUP elevation demonstrated that each antagonist required similar doses for inhibition of the two responses. Level of Study 4 Study III: The mean basal pupil diameter in the vehicle group was 6.73±0.27 mm, and similar basal values were observed in all groups receiving the α1-adrenoceptor antagonists (no significant differences among all groups in a one-way ANOVA, data not shown). The pupil size remained relatively stable over the entire 8-h observation period in the vehicle-treated group. All α1- adrenoceptor antagonists tested dose-dependently reduced pupil size with maximum miotic effects after 15 min, except for terazosin where maximum effects were observed after 30 min. Of note, the lowest tested antagonist doses in this study corresponded to or even exceeded the doses that caused almost maximum inhibition of phenylephrineinduced pupil dilatation except for naftopidil ;nevertheless, these doses failed to cause statistically significant miosis except for terazosin, and for most drugs only 30- to 100-fold higher doses (3-fold higher for naftopidil) caused detectable miosis. 19. van Dijk MM, de la Rosette JJ, Michel MC. Effects of a1-adrenoceptor antagonists on male sexual function. Drugs 2006;66: Systematic review Not specified in detail To consider methodological issues in the analysis of adverse effects on sexual function associated with the use of α-blockers, and then summarize the effects of individual α-blockers Numerous studies have reported on possible adverse effects of α-blocker treatment on sexual function. Adverse α-blocker effects on sexual desire, erectile function, ejaculatory function and global sexual function occur in few patients only, and in some cases even improved functions have been reported. In this regard, it should be considered that the overwhelming majority of findings come from BPH patients, that is a condition with major effects on quality of life. When α-blockers improve BPH symptoms, associated improvements of sexual function may reflect a generally improved perception of wellbeing. Therefore, caution needs to be applied when extrapolating findings from BPH to, for example, hypertensive patients, who have not been studied extensively in this regard. There appears to be little difference between α-blockers with regard to effects on sexual function. A notable exception the effect of tamsulosin on ejaculatory function, now proposed to be (relative) anejaculation rather than retrograde ejaculation. While adverse effects of tamsulosin on ejaculatory function have been well documented, the magnitude of differences with other α-blockers is insufficient to be detectable as statistically significant unless very large patient numbers are compared, and the incidence of abnormal ejaculations in OLS is low. Therefore, the possibility of abnormal ejaculation with tamsulosin must be weighed against the unparalleled cardiovascular safety record of this agent when choosing the most appropriate α-blocker for an individual patient. Level of Study 1 193

195 Korean clinical practice guideline for benign prostate hyperplasia 20. Kawabe K, Yoshida M, Homma Y; Silodosin Clinical Study Group. Silodosin, a new a1aadrenoceptorselective antagonist for treating benign prostatic hyperplasia: a results of a phase III randomised, placebo-controlled, double-blind study in Japanese men. BJU Int 2006;98: Randomized, placebo-controlled trial 457 patients To verify the efficacy and safety of the new alpha1a-adrenoceptor-selective antagonist silodosin compared with tamsulosin and placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) In all, 457 patients were randomized (silodosin 176, tamsulosin 192 and placebo 89). The change in the total IPSS from baseline in the silodosin, tamsulosin and placebo groups was -8.3, -6.8 and -5.3, respectively. There was a significant decrease in the IPSS vs placebo in the silodosin group from 1 week. In the early-stage comparison, silodosin showed a significant decrease in IPSS vs tamsulosin at 2 weeks. The change in QoL from baseline was -1.7, -1.4 and -1.1 in the silodosin, tamsulosin and placebo groups, respectively; silodosin showed a significant improvement in the QoL score vs placebo. In the subgroup of patients with severe symptoms (IPSS > or = 20) silodosin also gave a significantly better improvement than placebo (-12.4 vs -8.7). The incidence rates of adverse events and drug-related adverse events were, respectively, 88.6%, 82.3% and 71.6% and 69.7%, 47.4% and 36.4%, respectively. The most common adverse event in the silodosin group was abnormal ejaculation, which occurred more often in the silodosin than in the tamsulosin group (22.3% vs 1.6%). However, only five men (2.9%) discontinued treatment for abnormal ejaculation. Level of Study Garimella PS, Fink HA, Macdonald R, et al. Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. Cochrane Database Syst Rev 2009;(4):CD Systematic review 8 studies, 744 patients To evaluate the efficacy and adverse effects of naftopidil, a selective alpha-1d oral alpha-blocking agent for the treatment of LUTS associated with BPH Eight trials were eligible (N = 744 participants). All trials were conducted in Japan. Study duration ranged from 4 to 17 weeks. The mean age of participants was 68 years; pretreatment mean IPSS = 17.8 and mean peak urine flow (Qmax) = 9.5 ml/s (milliliters/second). No trials compared naftopidil to placebo. In 5 trials (N = 419), naftopidil in doses of 25 to 75 mg/d (milligrams/day) showed a mean IPSS improvement similar to low-dose tamsulosin (0.2 mg/d) (8.4 versus 8.9 points). Compared to a phytotherapy preparation (eviprostat), naftopidil significantly improved total IPSS (-5.9 versus 0.4; P < ). In one trial, the addition of anticholinergic drugs (oxybutynin or propiverine hydrochloride) to naftopidil did not offer any significant improvement for IPSS or Qmax in comparison to treatment with naftopidil alone. Although IPSS did not significantly differ between high- (75 mg/d) and low-dose (25 mg/d) naftopidil, high dose significantly improved Qmax compared to low dose (1.2 ml/s versus 0.2 ml/s). Adverse events reported were few, mild and similar to those seen with 0.2 mg/d tamsulosin. Level of Study 1 194

196 전립선비대증진료권고안 22. Ding H, Du W, Hou ZZ, et al. Silodosin is effective for treatment of LUTS in men with BPH: a systematic review. Asian J Androl 2013;15: Systematic review and Meta-analysis 4 studies, 2,504 patients To review the evidence on the efficacy and safety of silodosin treatments on lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) from randomized controlled trials At the follow-up end points, the pooled results showed that the change from baseline for the silodosin group was significantly higher than the placebo group for the IPSS, QoL score and Q(max) (mean difference (MD)=-2.78, P< ; MD=-0.42, P=0.004; MD=1.17, P< , respectively) and patients felt more satisfied with QoL related to urinary symptoms in the silodosin group than the placebo group. Ejaculation disorder was the most commonly reported adverse effect. The pooled results also showed that the silodosin group was superior to the 0.2 mg tamsulosin group with respect to the IPSS and QoL score (IPSS: MD=-1.14, P=0.02; QoL score: MD=-0.26, P=0.02) and inferior to the 0.2 mg tamsulosin group with respect to Q(max) (MD=-0.85, P=0.01). In contrast, there was no significant difference in the incidence of ejaculation disorder and dizziness between the silodosin and 0.2 mg tamsulosin groups. The current meta-analysis suggested that silodosin is an effective therapy for LUTS in men with BPH and is not inferior to 0.2 mg tamsulosin. Level of Study Rittmaster RS, Norman RW, Thomas LN, et al. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab 1996;81: Randomized, placebo-controlled trial 26 patients To determine the mechanism by which finasteride reduces prostate size The mean epithelial cell width in control prostates (mean +/- SEM, 21 +/- 0.7 microns) decreased with duration of treatment to 19 +/- 1 microns in group 1, 15 +/- 2 microns in group 2, and 8 +/- 0.3 microns in group 3. Mean duct width decreased from 135 +/- 6 microns in the control prostates to 128 +/- 10 microns in group 1, 103 +/- 3 microns in group 2, and 63 +/- 6 microns in group 3. To assess whether prostate cell death was occurring, sections were in situ end labeled for DNA breaks and immunostained for tissue transglutaminase (ttg), a marker of apoptosis (programmed cell death). The percentage of epithelial cells staining for DNA breaks was 0.4 +/- 0.2 in control prostates, 2.8 +/- 0.9 in group 1, 1.7 +/- 0.5 in group 2, and 0.7 +/- 0.3 microns in group 3. Anti-tTG staining of epithelial cells was graded on a scale of 0-4. In control prostates, 3 +/- 1% of the ducts were grade 3 or 4 (> 50% of epithelial cells staining). In finasteride-treated prostates, 2 +/- 2% of the prostates in group 1, 13 +/- 4% of the prostates in group 2, and 0.5 +/- 0.5% of the prostates in group 3 were grade 3-4. These results indicate that a progressive decrease in epithelial cell size and function occurs during the first several months in the prostates of men treated with finasteride. Level of Study Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335: Randomized, placebo-controlled trial 195

197 Korean clinical practice guideline for benign prostate hyperplasia 1,229 patients To compare the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in men with BPH The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. Level of Study Kirby R, Roehrborn CG, Boyle P, et al; Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003;61: Randomized, placebo-controlled trial 1,095 patients To evaluate the efficacy and tolerability of the selective alpha(1)-adrenergic antagonist doxazosin and the 5-alpha-reductase inhibitor finasteride, alone and in combination, for the symptomatic treatment of benign prostatic hyperplasia An intent-to-treat analysis of 1007 men showed doxazosin and doxazosin plus finasteride combination therapy produced statistically significant improvements in total IPSS and Qmax compared with placebo and finasteride alone (P<0.05). Finasteride alone was not significantly different statistically from placebo with respect to total IPSS and Qmax. All treatments were generally well tolerated. Level of Study Andersen JT, Ekman P, Wolf H, et al. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH Study Group. Urology 1995;46: Randomized, placebo-controlled trial 707 patients To study if placebo-induced improvement in men with symptomatic benign prostatic hyperplasia (BPH) is maintained over 2 years, and to study the efficacy and safety from intervention with finasteride 5 mg for 24 months In finasteride-treated patients the total symptom score improved throughout the study, with a significant difference between the two groups at 24 months (P < or = 0.01), whereas in placebotreated patients, there was an initial improvement in the symptom score but no change from baseline at 24 months. The maximum urinary flow rate decreased in the placebo group, but improved in the finasteride group, resulting in a between-group difference of 1.8 ml/s at 24 months (P < or = 0.01). The mean change in prostate volume was +12% in the placebo group versus -19% in the finasteridetreated group (P < 0.01). Finasteride was generally well tolerated throughout the 2-year study period. 196

198 전립선비대증진료권고안 Level of Study 2 Level of Study Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomised controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ 1996;155: Randomized, placebo-controlled trial 613 patients To evaluate the efficacy and safety of 2 years' treatment of moderate benign prostatic hyperplasia (BPH) with finasteride In the efficacy analyses the mean BPH symptom scores decreased 2.1 points (from 15.8 to 13.7) in the finasteride group, as compared with a decrease of 0.7 points (from 16.6 to 15.9) in the placebo group (P < or = 0.01). The maximum urinary flow rate increased by a mean of 1.4 ml/s (from 11.1 to 12.5 ml/ s) in the finasteride group, as compared with an increase of 0.3 ml/s (from 10.9 to 11.2 ml/s) in the placebo group (p < or = 0.01). The mean prostate volume decreased by 21% (from a mean volume of 44.1 cm3 at baseline) in the treatment group; it increased by 8.4% (from a mean volume of 45.8 cm3 at baseline) in the placebo group (p < or = 0.01). In the safety analysis, the proportion of patients who experienced any adverse event was similar in the two groups (81.0% in the treatment group and 81.2% in the placebo group). However, the incidence of adverse events related to sexual dysfunction were significantly higher in the finasteride group than in the placebo group (ejaculation disorder 7.7% v. 1.7% and impotence 15.8% v. 6.3%; p < or = 0.01 for both parameters). 28. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338: Randomized, placebo-controlled trial 3,040 patients To evaluate the extent to which the benefit is sustained and whether finasteride reduces the incidence of related events, including the need for surgery and the development of acute urinary retention During the four-year study period, 152 of the 1,503 men in the placebo group (10 percent) and 69 of the 1,513 men in the finasteride group (5 percent) underwent surgery for benign prostatic hyperplasia (reduction in risk with finasteride, 55 percent; 95 percent confidence interval, 41 to 65 percent). Acute urinary retention developed in 99 men (7 percent) in the placebo group and 42 men (3 percent) in the finasteride group (reduction in risk with finasteride, 57 percent; 95 percent confidence interval, 40 to 69 percent). Among the men who completed the study, the mean decreases in the symptom score were 3.3 in the finasteride group and 1.3 in the placebo group (P<0.001). Treatment with finasteride also significantly improved urinary flow rates and reduced prostate volume (P<0.001). Level of Study Marberger MJ, on behalf of the PROWESS Study Group. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. Urology 1998;51: Randomized, placebo-controlled trial 3,270 patients 197

199 Korean clinical practice guideline for benign prostate hyperplasia To compare the long-term effects of finasteride (5 mg/day) and placebo in patients with moderate symptoms of benign prostatic hyperplasia (BPH) Of the 3,270 men enrolled, 3,168 contributed data to the safety analysis, and 2,902 to the efficacy evaluation. Significantly greater improvement with finasteride compared to placebo was observed at 12 and 24 months for total symptom score (mean -2.9 versus -1.9 at 12 months, P < or =0.001; -3.2 versus -1.5 at 24 months, P < or =0.001), obstructive symptom score (mean -1.9 versus -1.3 at 12 months, P < or =0.001; -2.1 versus -1.1 at 24 months, P < or =0.001), maximal urinary flow rate (mean +1.2 versus +0.6 ml/s at 12 months, P = 0.010; +1.5 versus +0.7 ml/s at 24 months, P = 0.002), and prostate volume (mean versus +5.4% at 12 months, P < or =0.01; versus +8.9% at 24 months, P < or =0.001). Greater improvements in placebo-adjusted total symptom score occurred in men with large prostates than in men with small prostates (mean -2.4 versus -1.1 at 12 months; -3.2 versus -1.3 at 24 months, placebo-adjusted data, P = 0.053). Fifteen of 1,450 men (1.0%) in the finasteride group experienced an acute urinary retention event, compared with 37 of 1452 (2.5%) in the placebo group, and the corresponding figures for surgery were 51 of 1,450 (3.5%) and 86 of 1,452 (5.9%), respectively. The hazard rate for occurrence, computed using the log-rank statistic, decreased by 57% for acute urinary retention and by 40% for surgery accompanied by finasteride therapy compared to placebo. Level of Study McConnell JD, Roehrborn CG, Bautista O, et al; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: Randomized, placebo-controlled trial 3,047 patients Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alphablockers) or 5alpha-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. The risk of overall clinical progression--defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection--was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. Level of Study Roehrborn CG, Boyle P, Nickel JC, et al; ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60: Randomized, placebo-controlled trial 4,325 patients 198

200 전립선비대증진료권고안 Level of Study 2 Level of Study 2 To study the efficacy and safety of dutasteride, a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II At 24 months, serum dihydrotestosterone was reduced from baseline by a mean of 90.2% (median -93.7%; P<0.001), and the total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (P<0.001). The symptom score was improved by as early as 3 months, with pooled significance from 6 months onward (P<0.001) and a reduction of 4.5 points (21.4%) at 24 months (P<0.001). The maximal flow rate improved significantly from 1 month (P<0.01), with an increase of 2.2 ml/s reported at 24 months (P<0.001). Hence, the risk reduction of acute urinary retention was 57% and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48% compared with placebo. The drug was well tolerated. 32. Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2008;179: Randomized, parallel group trial 4,844 patients To investigate whether combination therapy with dutasteride and tamsulosin is more effective than either monotherapy alone for improving symptoms and long-term outcomes in men with moderate to severe lower urinary tract symptoms and prostatic enlargement (30 cc or greater) (Preplanned 2-year analyses) Combination therapy resulted in significantly greater improvements in symptoms vs dutasteride from month 3 and tamsulosin from month 9, and in benign prostatic hyperplasia related health status from months 3 and 12, respectively. There was a significantly greater improvement from baseline in peak urinary flow for combination therapy vs dutasteride and tamsulosin monotherapies from month 6. There was a significant increase in drug related adverse events with combination therapy vs monotherapies, although most did not result in the cessation of therapy. 33. Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombATstudy. Eur Urol 2010;57: Randomized, parallel group trial 4,844 patients To investigate whether combination therapy is more effective than either monotherapy in reducing the relative risk for acute urinary retention (AUR), BPH-related surgery, and BPH clinical progression over 4 yr in men at increased risk of progression Combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery. Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression. Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr. Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies, with the exception of an imbalance in the composite term of cardiac failure among the three study arms. The lack of placebo control is a study limitation. 199

201 Korean clinical practice guideline for benign prostate hyperplasia Level of Study Roehrborn CG, Siami P, Barkin J, et al; CombAT Study Group. The influence of baseline parameters on changes in International Prostate Symptom Score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and enlarged prostate: 2-year data from the CombAT Study. Eur Urol 2009;55: Randomized, parallel group trial 4,844 patients To examine the influence of baseline parameters on changes in International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Q(max)) in men with BPH receiving dutasteride, tamsulosin, or a combination of the two using 2-yr Combination of Avodart and Tamsulosin (CombAT) study data Combination therapy was more effective than either monotherapy after 24 mo in improving IPSS in all baseline subgroups, with benefit onset varying by baseline prostate volume. Combination therapy was also more effective in improving Q(max) versus tamsulosin in all subgroups and versus dutasteride in 10 of 18 subgroups. At 24 mo, dutasteride monotherapy resulted in significantly greater IPSS improvements versus tamsulosin in men with lower age, worse symptoms, worse QoL, less bother, higher BMI, greater Q(max), higher prostate volume, and higher PSA at baseline. Post hoc analyses, the lack of placebo control, and the exclusion of men with unsuccessful medical BPH treatment are study limitations. Level of Study Roehrborn CG. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int 2008;101(Suppl.3): Systematic review 4 studies, 15,929 patients To know effects of alpha-blocker, 5ARI and combination therapy on BPH progression In selected patients, combination of an alpha(1)-blocker and a 5alpha-reductase inhibitor is the most effective form of BPH medical therapy to reduce the risk of clinical progression and relieve LUTS. Monotherapy also significantly reduces the risk of BPH clinical progression, mainly through a reduction of LUTS deterioration for alpha(1)-blockers while 5alpha-reductase inhibitors also reduce the risk of AUR and need for BPH-related surgery. Enlarged prostate and high serum prostate-specific antigen levels have been consistently found to be good clinical predictors of AUR and BPH-related surgery in longitudinal population-based studies and placebo arms of controlled studies. High post-void residual urine (PVR) is also associated with an increased risk of LUTS deterioration and should thus be reconsidered in practice as a predictor of BPH progression. Conversely, baseline LUTS severity and low peak flow rate, initially identified as predictors of unfavourable outcomes in community setting, behave paradoxically in controlled trials, probably as a consequence of strict inclusion criteria and subsequent regression to the mean and glass ceiling effects. Lastly, there is increasing evidence that dynamic variables, such as LUTS and PVR worsening, and lack of symptomatic improvement with alpha(1)-blockers are important predictors of future LUTS/BPH-related events, allowing better identification and management of patients at risk of BPH progression. Level of Study 1 200

202 전립선비대증진료권고안 Level of Study 1 Level of Study Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomised clinical trials. Urology 1996;48: Meta-analysis 6 studies, 2,601 patients Six randomized clinical trials have compared at least 1 year of 5 mg finasteride to placebo in the treatment of clinical benign prostatic hyperplasia (BPH). The findings for the 2601 men in these trials provide an opportunity to investigate the heterogeneity of the effects seen in the individual studies and to identify pretreatment predictors of outcomes as expressed by symptoms or peak urinary flow rates. The effect of finasteride treatment on improvements in total symptom severity, frequency score, and peak urinary flow rate was consistent across all six trials and similar among men with similar prostate volumes at baseline. Symptom severity improved by 1.8 points (95% confidence interval [CI], 0.7 to 2.9) in men with prostate volumes less than 20 cc (n = 72), while the improvement was 2.8 points (95% CI, 2.1 to 3.5) for men with volumes greater than 60 cc (n = 272) on the Quasi-IPSS Scale (range 0 to 30). Similarly, improvements in peak urinary flow rate ranged from 0.89 ml/s (95% CI, to 1.83) for men with prostate volumes less than 20 cc to 1.84 ml/s (95% CI, 1.37 to 2.30) in men with volumes greater than 60 cc. The difference in the magnitude of improvement between finasteride and placebo becomes significant (that is, no overlap in 95% CI) for men with a baseline prostate volume assessed by either transrectal ultrasonography or magnetic resonance imaging of greater than 40 cc, which encompasses approximately 50% of the entire population. Baseline prostate volume is a key predictor of treatment outcomes: approximately 80% of the variation in the treatment effects noted between studies could be attributed to differences in mean prostate volumes at baseline. Variation in entry criteria results in large differences in baseline symptom severity status, prostate volume, and consequently apparent inconsistencies in the overall outcomes of these trials. 37. Roehrborn CG, Boyle P, Bergner D, et al. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urol 1999;54: Non-randomized controlled cohort/follow-up study 3,040 patients To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. Baseline PSA and prostate volume are good predictors of long-term symptomatic and flow rate changes. Baseline PSA levels of 1.4 ng/ml or greater and enlarged prostate glands predict the best long-term response to finasteride compared with placebo. 38. Roehrborn CG, Lukkarinen O, Mark S, et al. Long-term sustained improvement in symptoms of benign protatic hyperplasia with the dual 5a-reductase inhibitor dutasteride: results of 4-year studies. BJU Int 2005;96:

203 Korean clinical practice guideline for benign prostate hyperplasia Randomized, placebo-controlled trial 4,325 patients To report additional analyses of efficacy over the initial 2 years and during a 2-year open-label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5alpha-reductase, was shown to be effective and well tolerated There was a clinically meaningful improvement in AUA-SI in patients on dutasteride in the doubleblind phase, but not in those on placebo. At 48 months, patients on dutasteride in both study phases had greater improvements in AUA-SI score and individual question scores than those on dutasteride in the open-label phase only. The proportion of patients with severe symptoms declined in both study groups, although these changes were more profound in those receiving dutasteride for the 4-year duration of the study. In men with symptomatic benign prostatic hyperplasia, long-term (4- year) treatment with the dual isozyme 5alpha-reductase inhibitor dutasteride resulted in sustained and continued improvements in symptoms and flow rate. For 4 vs 2 years, longer dutasteride therapy resulted in greater symptom improvement. Level of Study Gittelman M, Ramsdell J, Young J, et al. Dutasteride improves objective and subjective disease measures in men with benign prostatic hyperplasia and modest or severe prostateenlargement. J Urol 2006;176: Randomized, placebo-controlled trial 4,325 patients To determine whether the effect of dutasteride for benign prostatic hyperplasia is influenced by baseline prostate volume using data from 3 phase III clinical trials In patients treated with dutasteride throughout the study (dutasteride/dutasteride group) the mean reduction in prostate volume from baseline to month 48 was 30.3% in those with a baseline prostate volume of 30 to less than 40 cc and 26.2% in those with a prostate volume of 40 cc or greater. Mean improvements in peak urinary flow from baseline to month 48 were 2.7 ml per second regardless of baseline prostate volume. Improvements in the American Urological Association symptom index score were 6.3 in men with a prostate volume of 30 to less than 40 cc and 6.5 in those with a prostate volume of 40 cc or greater. No significant relationships between treatment effect and baseline prostate volume were observed for these parameters. In dutasteride/dutasteride treated patients the risk of acute urinary retention was decreased by 60% in those with a prostate volume of 30 to less than 40 cc and 55% in those with a prostate volume of 40 cc or greater vs values in placebo/ dutasteride treated patients (p = and <0.001, respectively). The corresponding values for benign prostatic hyperplasia related surgery were 27% and 48% (p = 0.35 and <0.001, respectively). Level of Study Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5α-reductase inhibitors for the enlarged prostate. Clin Ther 2007;29: Systematic review Not specified in detail To review the natural history of enlarged prostate and the data supporting management of this condition with alpha-blocker and 5ARI therapy, either as monotherapy or combination therapy, for symptomatic relief and a reduction in long-term disease progression 202

204 전립선비대증진료권고안 Clinical trials of alpha-blockers in men with enlarged prostate have reported improvements in total symptom scores of 10% to 20% compared with placebo; however, these agents were not shown to reduce the risk of long-term complications or disease progression. Studies of the 5ARIs have reported significant reductions compared with placebo in the relative risk for AUR and enlarged prostaterelated surgery, slowing of disease progression, and relief of symptoms. In studies of dutasteride, improvements in symptom scores were greater after 4 years of therapy compared with 2 years (-6.4 vs -4.3 points, respectively) and flow rates were better (2.6 vs 2.3 ml/sec). Six-year data for finasteride showed maintenance of the decreased risk for AUR and enlarged prostate-related surgery. Use of combination therapy with an alpha-blocker and a 5ARI may be of benefit in patients who require immediate relief of symptoms, with discontinuation of the alpha-blocker after several months of therapy. 5ARIs were generally well tolerated, with sexual dysfunction the most frequently reported adverse effect, although in only a small proportion of men (1-8%). Level of Study Chung BH, Hong SJ, Cho JS, Seong DH. Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: a multicentre study. BJU Int 2006;97: Non-randomized controlled cohort/follow-up study 5,716 patients To evaluate the relationship between prostate specific antigen (PSA) and prostate volume (PV) in Korean men, as PV is a key predictor of both disease progression and response to medical therapy in patients with benign prostatic hyperplasia (BPH), and PSA has been suggested as a proxy marker to estimate the total PV, mainly in Caucasians. The PSA-PV relationship in Korean men is similar to that in Caucasians, but Korean men have a slightly lower PSA level and a smaller PV than Caucasians. The approximate age-specific criteria for detecting Korean men with a PV of >40 ml were a PSA level of >1.3 ng/ml, >1.7 ng/ml and >2.0 ng/ml for men with BPH in their sixth, seventh and eighth decade, respectively. Level of Study Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 2005;174: Open label, prospective study 43 patients To determine the efficacy and tolerability of tolterodine extended release (ER) in men with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) in whom previous alpha-blocker therapy had failed A total of 39 men (91%) with a mean age of 61 years completed the 6-month trial. Mean 24-hour micturition frequency decreased from 9.8 to 6.3 voids and nocturia decreased from 4.1 to 2.9 episodes nightly. Significant changes in mean American Urological Association symptom scores (-6.1), the peak urinary flow rate (1.9 ml per second) and post-void residual volume (-22 ml) were also observed. Of the men 27 (63%) were potent at baseline and 29 (67%) were potent after 6 months of tolterodine ER treatment. Mean International Index of Erectile Function erectile function domain scores increased (6.9). Four men (9%) discontinued therapy because of intolerable dry mouth. There were no reports of urinary retention. 203

205 Korean clinical practice guideline for benign prostate hyperplasia Level of Study Höfner K, Burkart M, Jacob G, et al. Safety and efficacy of tolertodine extended release in men with overactive bladder symptoms and presumed non-obstructive benign prostatic hyperplasia. World J Urol 2007;25: Prospective, observational non-interventional study 741 patients To generate real-life efficacy and safety data in patients with presumed non-obstructive BPH (Q (max)>or= 15 ml/s) treated with tolterodine ER 4 mg/day for OAB symptoms, alone or added to unsuccessful alpha-blocker treatment of >or=6 weeks duration Mean PVR did not increase (25.4 +/ vs / ml at baseline). AUR requiring catheterization occurred in two patients, acute UTI in four patients. Median IPSS total scores decreased from 17 to 10, IPSS QoL scores from 4 to 2, OAB-q symptom bother scores from 50.0 to 22.5 and OAB-q HRQL scores increased from 59.2 to In men with OAB symptoms and presumed non-obstructive BPH, tolterodine ER provided considerable symptomatic and QoL improvements with a low risk of AUR, acute UTI, or increased PVR. Level of Study Kaplan SA, Roehrborn CG, Chancellor M, et al. Extended-release tolterodine with or without tamsulosin in men with lower urinary tract symptoms and overactive bladder: effects on urinary symptoms assessed by the International Prostate Symptom Score. BJU Int 2008;102: Randomized, placebo-controlled trial 851 patients To evaluate the efficacy of tolterodine extended-release (ER) plus tamsulosin on lower urinary tract symptoms (LUTS) as assessed by changes in the International Prostate Symptom Score (IPSS) in men who met symptom entry criteria for both overactive bladder (OAB) and benign prostatic hyperplasia (BPH) trials receiving tolterodine ER + tamsulosin had significantly greater improvements than those taking placebo on IPSS storage subscale scores and scores for all three individual storage items included on the IPSS (urinary frequency, urgency, and nocturnal micturitions) by 12 weeks. Storage subscale and urgency scores were significantly improved vs placebo at 1 and 6 weeks, whereas frequency scores were significantly improved at 6 weeks. Changes in IPSS storage subscale and individual storage item scores in the tolterodine ER and tamsulosin monotherapy groups were not significantly different from placebo at most time points. IPSS voiding subscale scores and scores for three of four individual voiding items (sensation of incomplete emptying, intermittency, and weak stream) were significantly improved by 12 weeks for patients receiving tamsulosin monotherapy vs placebo. Voiding subscale and intermittency scores were significantly improved vs placebo at 1 week; weak stream scores were significantly improved at 1 and 6 weeks. The IPSS voiding subscale and individual voiding item scores in the tolterodine ER + tamsulosin and tolterodine ER groups were not significantly different from placebo at most time points. Level of Study Kaplan SA, Roehrborn CG, Dmochowski R, et al. Tolterodine extended release improves overactive bladder symptoms in men with overactive bladder and nocturia. Urology 2006;68:

206 전립선비대증진료권고안 Post-hoc analysis of data from randomized, placebo-controlled trial 745 patients To evaluate the efficacy and safety of nighttime dosing with tolterodine extended release (TER) in men with overactive bladder (OAB) and nocturia A total of 745 men (mean age 64 years) were randomized to placebo (n = 374) or TER (n = 371). Of the 745 men, 73% reported no incontinence episodes in a 7-day diary at baseline. At week 12, the weekly values for nighttime severe OAB micturitions and 24-hour and daytime total, OAB, and severe OAB micturitions were significantly reduced in the TER group versus the placebo group. The TERtreated men also reported a significant reduction in the mean urgency rating versus placebo. Adverse events associated with TER were low and comparable to those in the placebo group, with the exception of dry mouth (11% versus 4%). Withdrawals because of adverse events were infrequent (3% TER, 4% placebo). Five men were withdrawn for symptoms suggestive of urinary retention (3 TER, 2 placebo). Level of Study Dmochowski R, Abrams P, Marschall-Kehrel D, et al. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urol 2007;51: Post-hoc analysis of data from randomized, placebo-controlled trial 1,698 patients To evaluate the efficacy and tolerability of tolterodine extended release (ER) in men and women with overactive bladder (OAB) At baseline, 73% (547 of 745) of men and 57% (539 of 953) of women were continent. By week 12, tolterodine ER (n=848) reduced OAB and severe OAB micturitions during 24-h, daytime, and nocturnal intervals in both sexes compared with placebo (n=850). Adverse event rates were low and similar across treatment and gender. Level of Study Abrams P, Kaplan S, De Koning Gans HJ, et al. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006;175: Randomized, placebo-controlled trial 222 patients To evaluate the safety of tolterodine vs placebo in men with OAB and BOO Median treatment differences in Qmax (-0.7 ml per second, 95% CI -1.6 to 0.4) and pdetqmax (-7 cm H2O, 95% CI -3 to 11) were comparable. Tolterodine significantly reduced the BOOI vs placebo (-9 vs 0, p < 0.02). There were significant treatment differences in volume to first detrusor contraction (+59 ml, 95% CI ) and maximum cystometric capacity (+67 ml, 95% CI ), favoring tolterodine over placebo (p < 0.003). Change in PVR was significantly greater among patients treated with tolterodine (+25 ml) than placebo (0 ml, p < 0.004). There were no significant between-group differences in the incidence of adverse events. Urinary retention was reported by 1 patient treated with placebo. Level of Study 2 205

207 Korean clinical practice guideline for benign prostate hyperplasia 48. Kaplan SA, Roehrborn CG, Rovner ES, et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 2006;296: Randomized, placebo-controlled trial 879 patients To evaluate the efficacy and safety of tolterodine extended release (ER), tamsulosin, or both in men who met research criteria for both overactive bladder and benign prostatic hyperplasia A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (P<.001), 146 (71%) receiving tamsulosin (P=.06 vs placebo), or 135 (65%) receiving tolterodine ER (P=.48 vs placebo). receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (-0.88 vs -0.31, P=.005), urgency episodes without incontinence (-3.33 vs -2.54, P=.03), micturitions per 24 hours (-2.54 vs -1.41, P<.001), and micturitions per night (-0.59 vs -0.39, P.02). receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (-8.02 vs placebo, -6.19, P=.003) and QOL item (-1.61 vs -1.17, P=.003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%). Level of Study Disantostefano RL, Biddle AK, Lavelle JP. An evaluation of the economic costs and patient-related consequences of treatments for benign prostatic hyperplasia. BJU Int 2006;97: Decision analysis using published data including systematic reviews Not specified in detail To compare the costs and effectiveness of treatments for benign prostatic hyperplasia (BPH), including watchful waiting, pharmaceuticals (alpha-blockers, 5-alpha-reductase inhibitors, combined therapy), transurethral microwave thermotherapy (TUMT), and transurethral resection of the prostate (TURP) What is the 'best' treatment depends on the value that an individual and society place on costs and consequences. Alpha-blockers are less expensive than the alternatives, and are effective at relieving patient-reported symptoms. Unfortunately, they have little effect on clinical outcomes and have the highest BPH progression rate. Other treatments have lower disease progression and better clinical outcomes, but are more expensive and entail more invasive treatments, and/or more uncertainty. Treatment decisions are made using a variety of information, including the cost and consequences of treatment. The best treatment depends on the patient's preference and the outcome considered most important. alpha-blockers are very effective at treating urinary symptoms but do not improve clinical outcomes, including disease progression, relative to other treatments. TURP remains the 'gold standard' for surgical procedures. The desire to avoid TURP or the 2 weeks of catheterization associated with TUMT might affect a patient's treatment decision when symptoms are severe. Therefore, more information about patient preferences and risk aversion is needed to inform treatment decision-making for BPH. Level of Study 2 206

208 전립선비대증진료권고안 근거표 9. 전립선비대증환자에서급성요폐발생시 TWOC (Trial without catheter) 는수술적치료전에우 선적으로고려되어야하는가? 1. Kurita Y, Masuda H, Terada H, Suzuki K, Fujita K. Transition zone index as a risk factor for acute urinary retention in benign prostatic hyperplasia. Urology 1998;51: Retrospective 331 To examine the efficacy of various parameters obtained by transrectal ultrasonography (TRUS) as predictors of the onset of acute urinary retention in patients with benign prostatic hyperplasia (BPH). There were significant differences in the American Urological Association (AUA) symptom score, total prostate volume, TZ volume, TZ index, and PCAR between patients with and without acute urinary retention, but no significant differences in age and quality of life score. In patients with acute urinary retention, the area under the ROC curve was for the TZ index, for the TZ volume, for the PCAR, for the total prostate volume, and for the AUA symptom score. Level of Study 4 2. Lucas MG, Stephenson TP, Nargund V. Tamsulosin in the management of patients in acute urinary retention from benign prostatic hyperplasia. BJU Int 2005;95: RCT 149 To evaluate the efficacy of tamsulosin compared to placebo for treating catheterized patients with acute urinary retention (AUR) caused by benign prostatic hyperplasia (BPH), by comparing the numbers of patients who voided successfully after removing their catheter. In all, 149 men (mean age 69.4 years) were randomly assigned to receive tamsulosin (75) or placebo (74); eight were not evaluable, so the intent-to-treat population was 141 men. Thirty-four men taking tamsulosin and 18 taking placebo did not require re-catheterization on the day of the trial without catheter (48% and 26% respectively, P = 0.011; odds ratio 2.47, 95% confidence interval, CI, ). Success using free-flow variables was also higher in the men who received tamsulosin, at 37 (52%) vs 24 (34%) on placebo (P = 0.019; odds ratio 2.34, 95% CI ). Withdrawals were high (120 men, 81%), mostly because of a need for re-catheterization (89 men, 60%). Dizziness and somnolence occurred in seven (10%) and four (6%) men who received tamsulosin, and two (3%) who received placebo, but overall the incidence of adverse events was similar in the two groups. One patient died from carcinomatosis. Level of Study 2 3. McNeill SA, Hargreave TB, Roehrborn CG. Alfaur study group. Alfuzosin 10 mg once daily in the management of acute urinary retention: Results of a double-blind placebo-controlled study. Urology 2005;65:83-9. RCT

209 Korean clinical practice guideline for benign prostate hyperplasia To study the impact of alfuzosin 10 mg once daily (OD) on the outcome of a trial without catheter (TWOC) after a first episode of acute urinary retention (AUR) related to benign prostatic hyperplasia (BPH) and the subsequent management of BPH in these patients. Alfuzosin significantly increased the successful TWOC rate (146 of 236, 61.9%) compared with placebo (58 of 121, 47.9%; P = 0.012). In the second phase, 14 (17.1%) of the 82 alfuzosin-treated patients versus 20 (24.1%) of the 83 placebo-treated patients required BPH surgery, 5 (36%) of 14 versus 13 (65%) of 20 within 1 month, and 8 (57%) of 14 versus 17 (85%) of 20 within 3 months of treatment. Emergency surgery because of AUR relapse was the main cause of failure in both groups (11 [78.6%] of 14 in the alfuzosin group and 16 [80.0%] of 20 in the placebo group). Compared with placebo, alfuzosin improved the Kaplan-Meier survival rates by 9.6% (P = 0.04), 11.4% (P = 0.04), and 8.3% (P = 0.20), with surgical risk reductions of 61%, 52%, and 29% at 1, 3, and 6 months of treatment, respectively. High prostate-specific antigen values and the post-twoc residual urine volume significantly increased the risk of AUR relapse and BPH surgery. Alfuzosin 10 mg OD was well tolerated. Level of Study 2 4. The pathophysiology of lower urinary tract symptoms in the ageing male population. Br J Urol 1998;81(Suppl 1): retrospective 3,885 To evaluate the immediate and postoperative complication of transurethral resection of prostate The mortality rate for transurethral prostatectomy was 0.2 per cent in 3,885 patients reviewed retrospectively. The immediate postoperative morbidity rate was 18 per cent. Increased morbidity was found in patients with a resection time of more than 90 minutes, gland size of more than 45 gm., acute urinary retention and patient age greater than 80 years, and in the black population. Of the patients 77 per cent had significant pre-existing medical problems. Operative mortality, significant morbidity and hospital stay were reduced in comparison to studies done 15 and 30 years ago. Level of Study 4 6. Murray K, Massey A, Feneley RC. Acute urinary retention-a urodynamic assessment. Br J Urol 1984;56: Prospective 30 Thirty male patients with acute urinary retention were studied by standard urodynamic techniques on admission to hospital. Ten individuals also underwent cystography and sequential urodynamic testing over 96 h. Twenty-three per cent of patients did not require subsequent prostatectomy. Inability to initiate a voiding contraction during cystometry at the time of admission was associated with a prolonged duration of retention and a greater retained volume. The internal urethral meatus is closed in retention, and release of the retention results in an increase in profile length and maximum urethral closure pressure and a decrease in maximum urethral pressure. Free catheter drainage was associated with a reduction in bladder capacity and the appearance of detrusor instability. Level of Study 3 208

210 전립선비대증진료권고안 7. Pickard R, Emberton M, Neal DE. The management of men with acute urinary retention. National Prostatectomy Audit Group. Br J Urol 1998;81: Prospective study 3,966 To determine the outcome of men with acute urinary retention undergoing prostatectomy and to assess whether discharge with a catheter before subsequent planned re-admission for prostatectomy had an adverse effect on outcome. Compared with those who underwent elective prostatectomy for symptoms alone, men presenting with acute retention had an excess risk of death at 30 days (relative risk [RR], 26.6, 95% confidence interval [CI], ) and at 90 days after operation (RR 4.4, 95% CI ), and an increased risk of perioperative complications. Although men with retention were older, had larger glands and had more comorbidity, these factors did not totally explain the excess risk. The final symptomatic outcome of men with acute retention was no different from that of men presenting for elective treatment. Men with retention who were managed by initial catheterization, sent home and subsequently readmitted for planned operation had similar pretreatment characteristics, post-operative complications and outcomes to those who were kept in hospital throughout, although the men kept in hospital had a total increased length of stay. Level of Study 3 8. Manikandan R, Srirangam SJ, O'Reilly PH, Collins GN. Management of acute urinary retention secondary to benign prostatic hyperplasia in the UK: a national survey. BJU Int 2004;93:84-8. Retrospective 270 To analyse current practice in the management of acute urinary retention (AUR) secondary to benign prostatic hyperplasia (BPH) in the UK, and to assess how much of this is evidence-based We received 270 (66%) replies, of which six were excluded because they were from subspeciality interests (e.g. paediatric urology) or had ambiguous answers; 264 (64%) were therefore available for analysis. Urethral catheterization was the initial management of choice (98%), failing which a suprapubic catheter was inserted. Two-thirds (65.5%) admitted the patient after catheterization. Most consultants initiated alpha-blockers (70.5%), with 64% (118) of these using a TWOC 2 days after starting them. One failed TWOC was an indication for transurethral resection of the prostate for 192 (72.8%), with 136 (49.8%) re-admitting the patient for surgery later. Routine follow-up after a successful TWOC was advocated by 77.3%. Just over half the respondents (52.6%) felt that there was no need for uniform guidelines in the management of AUR secondary to BPH. Level of Study 5 9. Taube M, Gajraj H. Trial without catheter following acute retention of urine. Br J Urol 1989;63: prospective 60 A total of 60 patients with acute urinary retention were studied to establish whether a trial without a catheter was justified and to identify subgroups of patients most likely to benefit from this practice 209

211 Korean clinical practice guideline for benign prostate hyperplasia 17 patients urinated satisfactorily after removal of the catheter. Re-establishment of micturition was not associated with the length of history or severity of symptoms of prostatism, with age or the presence of urinary tract infection. The mean retained volume of urine in patients with a satisfactory result was 786 ml and 1069 ml in the failures. Of the 34 patients with retained volumes of less than 900 ml, 15 were successful in re-establishing micturition compared with 2 of 26 of those with retained volumes greater than 900 ml. The time of catheter removal was not important. The 17 successful patients were reviewed 6 months later. None reported further urinary retention; 6 had required prostatectomy for severe symptoms, 6 had minor symptoms and 5 were symptomless. It was concluded that a trial without a catheter is worthwhile, since 11 of 60 patients had not required surgery, but it should be avoided in patients with a residual volume exceeding 900 ml. Level of Study Kumar V, Marr C, Bhuvangiri A, Irwin P. A prospective study of conservatively managed acute urinary retention: prostate size matters. BJU Int 2000;86: Prospective 40 To evaluate in a prospective study the medium- to long-term outcome of a policy of conservatively managing acute urinary retention (AUR), arising solely by bladder outlet obstruction caused by benign prostatic enlargement (BPE), and to identify the factors favouring a positive outcome of a trial without catheter (TWOC). Of the 40 men with AUR, 22 (55%) voided spontaneously after removing the catheter and continued to do so with mean peak flow rates of 12.2 ml/s and mean PVRs of 69.6 ml over a follow-up of 8-24 months. These patients remained asymptomatic, with a mean IPSS of 5.2 and quality-of-life score of 0.9. These men had a mean prostatic size of 15.9 g and a mean catheterized residual volume of 814 ml, while in those who had an unsuccessful TWOC the mean prostate size was 27.5 g (P = 0.006) and a mean catheterized residual volume of 1062 ml (P = 0.09). Prostate size as assessed by the DRE was the most significant factor in predicting the outcome of a TWOC. Level of Study Ko YH, Kim JW, Kang SG, Jang HA, Kang SH, Park HS, et al. The efficacy of in-and-out catheterization as a way of trial without catheterization strategy for treatment of acute urinary retention induced by benign prostate hyperplasia: variables predicting success outcome. Neurourol Urodyn 2012;31: retrospective 515 To evaluate the efficacy and proper use of in-and-out catheterization as a strategy for trial without catheterization (TWOC) for treatment of acute urinary retention (AUR) TWOC success rate was 25.1% for Group 1 and 30.3% for Group 2. In successful cases, age, retention volume, and prostate sizes were significantly lower than those of failure counterparts in both Groups 1 and 2. Among these, age and retention volume were finally selected for LDA. When comparing successful cases, these two were significantly lower in Group 1 than Group 2. LDA showed an 81.6% hit ratio for cases with successful TWOC. In a prospective trial of 28 patients, using an equation from LDA, five of seven patients in Group 1 (71.4%) and 16 of 21 patients (76.2%) in Group 2 succeeded in their initial TWOC. 210

212 전립선비대증진료권고안 Level of Study Park SH, Kwon TG, Kim DY, Park CH, Seo JH, Lee JH, et al. The factors that influence the clinical outcomes after trial without catheter for acute urinary retention due to benign prostatic hyperplasia: a multicenter trial. Kor J Uro 2006;47: Retrospective 455 Benign prostatic hyperplasia (BPH) is a common problem that's experienced by aging men, and it can lead to serious outcomes, including acute urinary retention (AUR). We studied the factors that influence the clinical outcomes after trial without catheter (TWOC) for AUR due to BPH. From the 292 cases of group I and the 163 cases of group II, the multivariate analysis revealed statistically significant differences in the retention volume (p-0.01), the prostate volume (p-0.01) and the previous use of α-blockers before AUR (p-0.01). The prostate volume, retention volume and previous use of α-blockers before AUR were thought to influence the clinical outcomes of TWOC for the BPH patients with AUR, and these factors should be considered in future treatment planning Level of Study Park KS, Kim SH, Ahn SG, Lee SJ, Ha US, Koh JS, et al. Analysis of the treatment of two types of acute urinary retention. Korean J Urol 2012;53: retrospective This study analyzed the type of acute urinary retention (AUR) and evaluated the treatments used, including trial without catheter (TWOC) Of 299 men with AUR, 160 (54%) had spontaneous AUR and 139 (46%) had precipitated AUR. Compared with group P, patients in group S were more likely to be treated by surgery, either immediately (16.9% vs. 3.6%, p<0.05) or after prolonged catheterization (42.2% vs. 29.1%, p<0.05). The success rate of TWOC was lower in men of older ages ( 70 years) and in those with enlarged prostates ( 50 ml), higher PSA levels ( 3 ng/ml), and a large drained volume at catheterization ( 1,000 ml). Level of Study Kim MJ, Lee JG, Cheon J. The factors that influence the success rate of treatment without using a catheter for the management of acute urinary retention: comparison of in-and-out catheterization and foley indwelling catheterization. Korean J Urol 2008;49: retrospective Acute urinary retention (AUR) is a serious outcome of benign prostatic hyperplasia (BPH). Although Foley indwelling catheterization is a standard treatment for the conservative management of AUR, we studied the success rate of in-and-out catheterization and the factors that favor a positive outcome of a trial treatment without using a catheter (TWOC) 211

213 Korean clinical practice guideline for benign prostate hyperplasia Of the 62 patients who underwent in-and-out catheterization, 30 had no further episodes of AUR during 1-year follow up (group I) and the other patients had repeated episodes (group II). For the clinical parameters, only the retained urine volume was significantly difference between the two groups. The multivariate analysis revealed that the statistically significant influencing factor was urinary retention volume (p<0.01). Level of Study Lee KS, Lim KH, Kim SJ, Choi HJ, Noh DH, Lee HW, et al. Predictors of successful trial without catheter for postoperative urinary retention following non-urological surgery. Int Neurourol J 2011;15: retrospective To investigate the success rate of trial without catheter (TWOC) for postoperative urinary retention (POUR) after non-urological surgery and to determine predictors of successful TWOC. The mean age of the patients was 65.2 (range, 23 to 92) years. There were 45 male and 59 female patients. Intraoperative indwelling catheterization was performed in 69 (66.3%) patients. Mean duration of indwelling catheterization for POUR was 5.0 (range, 3.0 to 7.0) days and 83 (79.8%) patients received medication with an alpha-blocker. A successful TWOC was observed in 70 (67.4%) patients. The mean age of the patients with failure of TWOC was significantly higher than that of the patients with successful TWOC. The percentages of female patients, spinal surgery, and prone position during surgery in patients with unsuccessful TWOC were higher than in those with successful TWOC. In the multivariate logistic regression analysis, age and location of surgery (spine vs. non-spine) were the independent predictors of successful TWOC for POUR. Level of Study 4 근거표 10. 전립선비대증환자에서경요도전립선절제술은개복전립선절제술에비해서우선적으로고려되 어야하는가? 2. Baazeem A, Elhilali MM. Surgical management of benign prostatic hyperplasia: current evidence. Nat Clin Pract Urol 2008;5: Review Benign prostatic hyperplasia (BPH) is one of the most common male urological disorders. The surgical management of BPH is evolving at a rapid rate, with several new procedures available that challenge transurethral resection of the prostate as the standard treatment in the surgical management of small to medium sized glands. The new procedures aim to achieve results comparable to transurethral resection of the prostate while minimizing morbidity and cost. In this Review, we discuss some of the current surgical options for the treatment of BPH that seem popular in the literature. 212

214 전립선비대증진료권고안 Level of Study 5 3. Borboroglu PG, Kane CJ, Ward JF, et al. Immediate and postoperative complications of transurethral prostatectomy in the 1990s. J Urol 1999;162: Retrospective study 520 We compare the morbidity, mortality, hospitalization and urethral catheter time of contemporary transurethral prostatectomy to historical series, and evaluate recent trends in hospitalization and urethral catheter time during the last 8 years A total of 520 patients were identified with an average age of 67 years (range 44 to 89). Significant co-morbidity (2 or more co-morbid disease processes) was identified preoperatively in 30.3% of the patients. The most common indications for transurethral prostatectomy were lower urinary tract symptoms (80.9%) and urinary retention (15.2%). Average preoperative International Prostate Symptom Score was Average weight of resected tissue was 18.8 gm. There was no perioperative patient mortality. Blood transfusion rate was 0.4%. The rate of intraoperative and immediate postoperative complications was 2.5% and 10.8%, respectively. Average hospital stay was 2.4 days, and 1.1 from 1997 through The rate of late postoperative complication was 8.5% and the average postoperative symptom score was 6.4 with an average followup of 42 months (range 6 to 84). Level of Study 4 4. Tubaro A, Carter S, Hind A, et al. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. J Urol 2001;166: prospective 32 We investigate the safety and efficacy of suprapubic transvesical prostatectomy, and the change in bladder wall thickness after surgery. An average of 63 gm. prostate adenoma were enucleated at surgery. An indwelling catheter was required for an average plus or minus standard deviation of 5.4 +/- 2.6 days after treatment. The International Prostate Symptom Score decreased from /- 4.4 to 1.5 +/- 2.7 and the quality of life score decreased from 4.9 +/- 1.0 to 0.2 +/- 0.4 at year 1, respectively. Maximum flow rate improved from 9.1 +/- 5.3 to /- 8.9 ml. per second. Residual urine decreased from 128 +/- 113 to 8 +/- 18 ml. Before surgery 30 patients had obstruction and 2 were in the equivocal zone of the International Continence Society nomogram. At 6 months after prostatectomy 30 patients did not have obstruction, and 2 who were subsequently operated on for bladder neck sclerosis were equivocal and had obstruction, respectively. No patient had significant postoperative bleeding and no heterologous blood transfusions were required. There were 4 men who had urinary tract infection and 1 who had wound infection. A slight decrease in erectile function was observed 6 weeks postoperatively, and no change in patient libido and quality of sex life was reported. The total complication rate was 31.3%. The bladder was unstable in 7 men before and 3 after surgery. A significant decrease in bladder wall thickness was observed from 5.2 +/- 0.7 at baseline to 2.9 +/- 0.9 mm. at year 1 postoperatively. Level of Study 3 213

215 Korean clinical practice guideline for benign prostate hyperplasia 5. Mearini E, Marzi M, Mearini L, et al. Open prostatectomy in benign prostatic hyperplasia: 10-year experience in Italy. Eur Urol 1998;34: review This study reports the experience of 47 Italian urology units together with the urology unit at the University of Perugia concerning open surgery in the management of benign prostatic hyperplasia (BPH). Until years ago, open surgery was the most common approach. In the late 1970s the development of endoscopes and their methodology has led to a gradual reduction in open surgery operations, which decreased rapidly with the introduction of mini-invasive endoscopic techniques. Therefore, open surgery for BPH is declining, though still performed. Skill in traditional surgery is mandatory because, until an alternative is devised, indications for open surgery still exist and cannot be ignored. The survey shows the indications and contraindications, complications and results of a 10- year nationwide experience. Guidelines for open surgery in patients with BPH have been drawn up. Level of Study 5 6. Serretta V, Morgia G, Fondacaro L, et al. Open prostatectomy for benign prostatic enlargement in southern Europe in the late 1990s: a contemporary series of 1800 interventions. Urology 2002;60: retrospective 5,636 Contemporary series of open prostatectomies from Western countries are rare. Frequently, the analysis of the outcome of open prostatectomy refers to old experiences or to series from developing countries. Any comparison with transurethral resection of the prostate can be invalidated by complications of open surgery because of the lack of an adequate healthcare system and technology. Twenty-six units (72.3%) replied. Of 31,558 patients treated for symptomatic benign prostatic hyperplasia, 5636 underwent surgery. Open prostatectomy (n = 1804) accounted for 32% of all surgical treatment. The median prostate volume was 75 cm(3) and the median serum prostatespecific antigen level was 3.7 ng/ml. The postoperative median hospitalization time was 7 days. Concomitant low urinary tract disease was present in 25% of the patients. Severe bleeding occurred in 11.6% of open prostatectomies. Blood transfusions were given in 8.2% of cases. Sepsis was reported in 8.6% of the patients. Reinterventions, within 2 years, mainly due to bladder neck stenosis, were reported in 3.6% of cases. Level of Study 5 7. Giulianelli R, Brunori S, Gentile BC, Vincenti G, Nardoni S, Pisanti F, et al. Comparative randomized study on the efficaciousness of treatment of BOO due to BPH in patients with prostate up to 100 gr by endoscopic gyrus prostate resection versus open prostatectomy. Preliminary data. Arch Ital Urol Androl 2011;83: RCT

216 전립선비대증진료권고안 Aim of this study was to evaluate efficacy and safety of Bipolar TURP (Gyrus electro surgical system) versus standard open prostatectomy in patients with lower urinary tract symptoms (LUTS) due to bladder outlet obstruction (BOO) with markedly enlarged glands refractory to medical therapy. Comparative data on IPSS symptom score, IIEF-5 and Qol, PSA, peak urinary flow rates and postvoid residual urine volume in the 2 groups were similar but showed a significative improvement with respect to baseline value. Postoperative haemoglobin levels, postoperative catheterization, hospital stay and 3-yr overall surgical re-treatment-free rate were significantly better in the Bipolar group. Level of Study 2 8. Kuntz RM, Lehrich K, Ahyai SA. Holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial. European Urology 2008;53: RCT 46 To report 5-year follow-up results of a randomised clinical trial comparing holmium laser enucleation of the prostate (HoLEP) with open prostatectomy (OP). Five years postoperatively, a total of 46 patients (38.3%) were lost to follow-up or had to be excluded from the study. All the remaining 74 patients (42 HoLEP vs. 32 OP patients, p=0.11) had undergone the 5-yr follow-up assessments. Mean AUA-SS was 3.0 in both groups (p=0.98), mean Qmax was 24.4 ml/s in both groups (p=0.97) and PVRU volume was 11 ml in the HoLEP and 5 ml in the OP group (p=0.25). Late complications consisted of urethral strictures and bladder-neck contractures; reoperation rates were 5% in the HoLEP and 6.7% in the OP group (p=1.0). No patient developed benign prostatic hyperplasia recurrence. Level of Study 2 9. Naspro R, Suardi N, Salonia A, Scattoni V, Guazzoni G, Colombo R, et al. Holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24-month follow-up. European Urology 2006;50: RCT 80 Prospectively evaluate perioperative outcomes and 2-yr follow-up after holmium laser enucleation (HoLEP) and standard open prostatectomy (OP) for treating benign prostatic hyperplasia-related obstructed voiding symptoms, with prostates >70 g. Operating room time was significantly shorter for the OP group (72.09+/ min vs / min, p<0.0001); catheter removal (1.5+/-1.07 d and 4.1+/-0.5 d, p<0.001) and hospital stay (2.7+/- 1.1 d vs. 5.4+/-1.05 d, p<0.001) were shorter in the HoLEP group. Blood loss was less and blood transfusions fewer in the HoLEP group (p<0.001). In both groups urodynamic and uroflowmetry findings improved from baseline, were still evident at the 24-mo follow-up, and were comparable between the two groups. Late complications were also comparable. Level of Study 2 215

217 Korean clinical practice guideline for benign prostate hyperplasia 10. Skolarikos A, Papachristou C, Athanasiadis G, Chalikopoulos D, Deliveliotis C, Alivizatos G. Eighteen-month results of a randomized prospective study comparing transurethral photoselective vaporization with transvesical open enucleation for prostatic adenomas greater than 80 cc. Journal of Endourology 2008;22: RCT 125 This is a prospective randomized study showing that for large prostatic adenomas, photoselective vaporization of the prostate requires less blood transfusions, shorter catheterization time and shorter hospital stay compared to open prostatectomy, while achieving similar functional results at the same time Longer length of operation time, shorter length of catheterization and hospital stay were experienced by patients who underwent PVP. Although patients who underwent OP showed a higher transfusion rate, adverse events in general were minor and of similar profile in both groups. All functional parameters improved significantly compared to baseline values in both groups. There was no difference in IPSS between the two groups at 3, 6, 12, and 18 months postoperatively. who underwent OP scored better in the IPSS-Quality of life score at 18 months postoperatively. At 18 months there were no significant differences between the two groups in the Qmax, post void residual urine volume and in the International Index for Erectile function-5 questionnaire. At three months prostate volume was significantly lower in the OP group and remained as such throughout follow-up. Level of Study Chen H, Tang P, Ou R, Deng X, Xie K. Holmium laser enucleation versus open prostatectomy for large volume benign prostatic hyperplasia: a meta-analysis of the therapeutic effect and safety. Nan Fang Yi Ke Da Xue Xue Bao 2012;32: Metanalysis To compare holmium laser enucleation (HoLEP) versus open prostatectomy (OP) for large volume benign prostatic hyperplasia. Three RCTs were included in the analysis. No significant differences were found in IPSS or Qmax between HoLEP and OP (P>0.05). Compared with OP, HoLEP was associated with significantly less blood loss, a shorter catheterization time and a shorter hospital stay, but a longer operating time. HoLEP and OP were similar in terms of urethral stricture, stress incontinence, transfusion requirement and the rate of reintervention. Level of Study Lee SW, Choi JB, Lee KS, Kim TH, Son H, Jung TY, et al. Transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement: a quality and meta-analysis. Int Neurourol J. 2013;17: meta-analysis 216

218 전립선비대증진료권고안 Thanks to advancements in surgical techniques and instruments, many surgical modalities have been developed to replace transurethral resection of the prostate (TURP). However, TURP remains the gold standard for the surgical treatment of benign prostatic hyperplasia (BPH). We conducted a meta-analysis on the efficacy and safety of minimally invasive surgical therapies for BPH compared with TURP. Only 2 articles (5.56%) were assessed as having a low risk of bias by use of the Cochrane collaboration risk of bias tool. On the other hand, by use of the Jadad scale, there were 26 high-quality articles (72.22%). Furthermore, 28 articles (77.78%) were assessed as high-quality articles by use of the van Tulder scale. Holmium laser enucleation of the prostate (HoLEP) showed the highest reduction of the International Prostate Symptom Score compared with TURP (P<0.0001). Bipolar TURP, bipolar transurethral vaporization of the prostate, HoLEP, and open prostatectomy showed superior outcome in postvoid residual urine volume and maximum flow rate. The intraoperative complications of the minimally invasive surgeries had no statistically significant inferior outcomes compared with TURP. Also, there were no statistically significant differences in any of the modalities compared with TURP. Level of Study 1 근거표 11. 전립선비대증환자에서심각한기저질환등으로수술이적당하지않은경우에는어떠한치료가 권장되는가? Level of Study 2 1. Ghalayini IF, Al-Ghazo MA, Pickard RS. A prospective randomized trial comparing transurethral prostatic resection and clean intermittent self-catheterization in men with chronic urinary retention. BJU Int 2005;96:93-7. RCT 41 patients To determine whether a preliminary period of clean intermittent self catheterization (CISC) before transurethral resection of the prostate (TURP) improves bladder contractility and surgical outcome in men with chronic urinary retention (CUR), and whether pressure-flow studies (PFS) before TURP predict the outcome. Of the 41 patients, 17 (mean age 67 years, range 52 84) were randomized to immediate TURP and 24 (mean age 69 years, range 55 85) to CISC. There was a significant improvement in IPSS and quality of life at 6 months in both groups (P<0.001). In the CISC group there was a significant improvement in voiding and end-filling pressures, indicating recovery of bladder function (P<0.001 for each). Of the 41 men, nine (22%) with voiding pressures of 45 cmh2o had no significant improvement in symptoms or urodynamic variables. Detrusor overactivity was found in 17 (41%) patients, of whom six had upper tract dilatation which 2. Logan K, Shaw C, Webber I, Samuel S, Broome L. experiences of learning clean intermittent self-catheterization: A qualitative study. J Adv Nurs 2008;62: Qualitative study 15 patients 217

219 Korean clinical practice guideline for benign prostate hyperplasia To explore the experiences of learning to carry out clean intermittent self-catheterization and user views of service provision. Themes identified were psychological issues, physical problems and service interaction. The communication skills of nurses helped facilitate the learning experience. In conjunction with nurses' skills, a friendly relaxed approach alleviated embarrassment and anxiety, thus facilitating information exchange and retention of information. Level of Study 3 3. Saint S, Lipsky BA, Baker PD, McDonald LL, Ossenkop K. Urinary catheters: What type do men and their nurses prefer? J Am Geriatr Soc 1999;47: Qualitative study-interviews 104 patients, 99 nursing staff members Urinary catheters are used frequently, but the relative risks and benefits of different types of devices are not clear. We sought to determine the beliefs of both older male patients and nursing staff about the relative merits and problems of condom and indwelling catheters. were mostly older and predominantly hospitalized on the medical service. Compared with those using an indwelling catheter, patients using a condom catheter were more likely to believe that their catheter was comfortable (86 vs 58%, P =.04) and less likely to believe it was painful (14 vs 48%, P =.008) or to restrict their activity (24 vs 61%, P =.002). The nursing staff had a mean of 13 years nursing experience, and the majority worked in the nursing home unit. Most of the nursing staff respondents believed that condom catheters were less painful and restrictive for patients and were easier to apply, but they also believed that they fell off and leaked more often and required more nursing time. Level of Study 3 4. Shaw C, Logan K, Webber I, Broome L, Samuel S. Effect of clean intermittent self-catheterization on quality of life: A qualitative study. J Adv Nurs 2008;61: Quallitative study 15 patients to describe the experience of people carrying out clean intermittent self-catheterization and the impact on their quality of life The core category consisted of two subcategories of positive and negative impacts. Positive impacts were related to improvement in lower urinary tract symptoms, whereas the negative impacts resulted from the practical difficulties encountered, and the psychological and cultural context of worry and stigma. The factors influencing variations in quality of life impacts were sex, lifestyle, frequency and duration of carrying out self-catheterization, technical difficulties, type of catheter, comorbidities and individual predispositions. Level of Study 3 5. Jakobsson L. Indwelling catheter treatment and health-related quality of life in men with prostate cancer in comparison with men with benign prostatic hyperplasia. Scand J Caring Sci 2002;16:

220 전립선비대증진료권고안 Cohort study 108 patients The aim of this study was to investigate what was felt of uneasiness when having an indwelling urinary catheter installed and while wearing it, and the problems related to catheter handling in men with prostate cancer in comparison with men with BPH. The aim was also to investigate the association between health-related quality of life (HRQOL) and SOC in the two groups Men with catheter experience (prostate cancer n = 71, BPH n = 37) were selected from a larger questionnaire study. Assessment was made with study-specific questions together with the QLQ C-30 assessing HRQOL and the SOC questionnaire measuring sense of coherence. Data reduction method was applied to study specific variables to determine problem patterns. Correlation between HRQOL and SOC was determined. Results showed similar problem patterns in men with prostate cancer and BPH: discomfort in wearing catheter (e.g. uneasiness 48.2%), practical and psychosocial difficulties in handling and wearing catheter (e.g. attaching catheter 32.4%) and discomfort at installation (e.g. pain 29.7%). There was lack of knowledge about wearing and practical handling of the catheter. Having a cancer diagnosis did not add to uneasiness or practical problems. Life quality was correlated to SOC (p <or= 0.001). Level of Study 3 6. D Ancona FC, van der Bij AK, Francisca EA, Kho H, Debruyne FM, Kiemeney LA, et al. Results of high-energy transurethral microwave thermotherapy in patients categorized according to the ameerican society of anesthesiologists operative risk classification. Urology 1999;53: Cohort study 246 patients To evaluate the relation between the American Society of Anesthesiologists (ASA) classification and response to transurethral microwave thermotherapy (TUMT) in patients with lower urinary tract symptoms and benign prostatic hyperplasia (BPH). There was a significant improvement in objective and subjective parameters at 12, 26, and 52 weeks of follow-up in both ASA 1 and 2 patients and ASA 3 and 4 patients. There was no difference in objective and subjective improvement between both groups at each point of follow-up. Objective and subjective improvement in ASA 3 and 4 patients with cardiovascular disease and ASA 3 and 4 patients with noncardiovascular disease was the same, although patients with cardiovascular disease received less energy during TUMT. Using logistic regression analysis, ASA classification was not predictive of response after high-energy TUMT. Level of Study 3 7. de la Rosette JJ, Laguna MP, Gravas S, de Wildt MJ. Transurethral microwave thermotherapy: The gold standard for minimally invasive therapies for patients with benign prostatic hyperplasia? J Endourol 2003;17: Meta-analysis 4 studies 219

221 Korean clinical practice guideline for benign prostate hyperplasia Describes the status of TUMT in the treatment of lower urinary tract symptoms related to BPH, focusing on variations in the outcomes with different devices, the durability of treatment outcomes, morbidity, selection criteria, and cost. The relation of TUMT to medical management and TURP also is addressed. The literature supports TUMT as the only viable treatment among the minimally invasive options for BPH that have appeared during the past decade. The clinical trials report durable and significant symptomatic and objective improvement with minimum morbidity. In sum, TUMT is anesthesia free, safe and effective. Also, economic considerations favor this truly outpatient-based procedure. Level of Study 1 8. Hill B, Belville W, Bruskewitz R, Issa M, Perez-Marrero R, Roehrborn C, et al. Transuethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective, randomized, multicenter clinical trial. J Urol 2004;171: RCT 121 patients the 5-year efficacy and safety of transurethral needle ablation of the prostate (TUNA) compared to transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Improvement from baseline for TUNA and TURP retained statistical significance at each interval for International Prostate Symptom Score, quality of life and peak flow rate. Post-void residual volume was statistically significant at all time points for TURP and at year 5 for TUNA. The TURP group reported 41% retrograde ejaculation, while the TUNA group reported none. The incident of erectile dysfunction, incontinence and stricture formation was also greater in TURP than in TUNA cases with significantly fewer adverse events for TUNA than for TURP. Level of Study 2 9. Mattiasson A, Wagrell L, Schelin S, Nordling J, Richthoff J, Magnusson B, et al. Five- year followup of feedback microwave thermotherapy versus TURP for clinical BPH: A prospective randomized multicenter study. Urology 2007;69:91-6. RCT 154 patients To compare the efficacy and safety of transurethral microwave thermotherapy (TUMT) with ProstaLund Feedback Treatment, using the CoreTherm device, with transurethral resection of the prostate (TURP) 5 years after treatment. Of the 154 patients, 66% completed the 60 months of follow-up. Statistically significant improvements in the TUMT and TURP groups were observed for IPSS, QOL, and Qmax at 60 months. The average values for the TUMT group were an IPSS of 7.4, QOL score of 1.1, and Qmax of 11.4 ml/s. The values for the TURP group were IPSS of 6.0, QOL score of 1.1, and Qmax of 13.6 ml/s. No statistically significant differences were found in any of these variables between the two treatment groups. In the TUMT group, 10% needed additional treatment versus 4.3% in the TURP group. 220

222 전립선비대증진료권고안 Level of Study Bouza C, Lopez T, Magro A, Navalpotro L, Amate JM. Systemic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia. BMC Urol 2006;6:14. Systemic review and meta-analysis 35 studies To ascertain the efficacy and safety of TUNA in the treatment of BPH. 35 studies (9 comparative, 26 non-comparative) were included. Although evidence was limited by methodological issues, the analysis of relevant outcomes indicates that while TUNA significantly improves BPH parameters with respect to baseline, it does not reach the same level of efficacy as TURP in respect to all subjective and objective variables. Further, its efficacy declines in the longterm with a rate of secondary-treatment significantly higher than of TURP [OR: 7.44 (2.47, 22.43)]. Conversely, TUNA seems to be a relatively safe technique and shows a lower rate of complications than TURP [OR:0.14 (0.05, 0.14)] with differences being particularly noteworthy in terms of postoperative bleeding and sexual disorders. Likewise, TUNA has fewer anesthetic requirements and generates a shorter hospital stay than TURP [WMD: -1.9 days (-2.75, -1.05)]. Scarce data and lack of replication of comparisons hinder the assessment of TUNA vs. other local therapies. No comparisons with medical treatment were found. Level of Study Hoffman RM, Monga M, Elliott SP, Macdonald R, Langsjoen J, Tacklind J, et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012:CD Systemic review 15 studies, 1,585 patients To assess the therapeutic efficacy and safety of microwave thermotherapy techniques for treating men with symptomatic benign prostatic obstruction. In this update, we identified no new randomized comparisons of TUMT that provided evaluable effectiveness data. Fifteen studies involving 1,585 patients met the inclusion criteria, including six comparisons of microwave thermotherapy with TURP, eight comparisons with sham thermotherapy procedures, and one comparison with an alpha-blocker. Study durations ranged from 3 to 60 months. The mean age of participants was 66.8 years and the baseline symptom scores and urinary flow rates, which did not differ across treatment groups, demonstrated moderately severe lower urinary tract symptoms. The pooled mean urinary symptom scores decreased by 65% with TUMT and by 77% with TURP. The weighted mean difference (WMD) with 95% confidence interval (CI) for the International Prostate Symptom Score (IPSS) was (95% CI to -0.03), favoring TURP. The pooled mean peak urinary flow increased by 70% with TUMT and by 119% with TURP. The WMD for peak urinary flow was 5.08 ml/s (95% CI 3.88 to 6.28 ml/ s), favoring TURP. Compared to TURP, TUMT was associated with decreased risks for retrograde ejaculation, treatment for strictures, hematuria, blood transfusions, and the transurethral resection syndrome, but increased risks for dysuria, urinary retention, and retreatment for BPH symptoms. Microwave thermotherapy improved IPSS symptom scores (WMD -5.15, 95% aci to -6.04) and peak urinary flow (WMD 2.01 ml/s, 95% CI 0.85 to 3.16) compared with sham procedures. 221

223 Korean clinical practice guideline for benign prostate hyperplasia Level of Study 1 Microwave thermotherapy also improved IPSS symptom scores (WMD -4.20, 95% CI to -5.25) and peak urinary flow (WMD 2.30 ml/s, 95% CI 1.47 to 3.13) in the one comparison with alphablockers. No studies evaluated the effects of symptom duration, patient characteristics, prostatespecific antigen levels, or prostate volume on treatment response. 12. Li Y, Zhao Q, Dong L. Efficacy and safety of ultrasound-guided transrectal ethanol injection for the treatment of benign prostatic hyperplasia in patients with high-risk comorbidities: A long-term study at a single tertiary care institution. Urology 2014;83: Prospective cohort study 70 patients To evaluate the efficacy and safety of ultrasound-guided transrectal ethanol injection for the treatment of benign prostatic hyperplasia (BPH) in patients with high-risk comorbidities. After 24 months of treatment, prostate volume, international prostate symptom score, quality of life score, and postvoid residual of patients were significantly reduced when compared with the pretreatment values (55.9 ± 16.7 vs 46.8 ± 8.1 ml, 29.3 ± 6.7 vs 9.8 ± 2.4 points, 5.3 ± 1.7 vs 1.9 ± 0.7 points, and ± 71.5 vs 25.9 ± 12.0 ml, respectively, P <.05). Qmax significantly increased to 15.3 ± 3.2 ml/s than the pretreatment Qmax of 4.7 ± 3.1 ml/s (P =.001). Four of 36 patients who received a high dose of ethanol developed liquefaction necrosis and urinary tract injury (2 patients each). However, the subsequent 34 patients received a reduced dose of ethanol and had no complications. Level of Study Kuo H-C. Prostate botulinum A toxin injection-an alternative treatment for benign prostatic obstruction in poor surgical candidates. Urology 2005;65: Prospective cohort study 10 patients To evaluate, in a prospective study, the effectiveness of prostate injection of botulinum A toxin in patients who were poor surgical candidates. with benign prostatic hyperplasia (BPH) are usually successfully treated with medical treatment or transurethral resection. However, some patients with chronic urinary retention or a large postvoid residual urine volume due to BPH are poor surgical candidates or are patients in whom medical treatment has failed. All patients had an improvement in spontaneous voiding after treatment. Of them, 8 had an excellent result (80%) and 2 had an improved result. Both voiding pressure and postvoid residual volume were significantly decreased after treatment. The total prostate volume was significantly reduced, and the maximal flow rate was significantly increased after treatment. The maximal effects of botulinum A toxin appeared at about 1 week and were maintained at 3 and 6 months after treatment. At 6 to 12 months (mean 9) of follow-up, no patient had had recurrence of urinary retention and the voiding condition in all patients remained at the post-treatment status. No adverse effect was noted. Level of Study 3 222

224 전립선비대증진료권고안 14. Silva J, Silva C, Saraiva L, Silva A, Pinto R, Dinis P, et al. Intraprostatic botulinum toxin type a injection in patients unfit for surgery presenting with refractory urinary retention and benign prostatic enlargement. Effect on prostate volume and micturition resumption. Eur Urol 2008;53: Prospective cohort study 21 patients To evaluate the effect of intraprostatic injection of botulinum toxin A (BoNTA) on prostate volume and refractory urinary retention in patients with benign prostatic enlargement. had a mean age of 80 _ 2 yr. Injections were done without anaesthetic support as an outpatient procedure. No significant local effects occurred. Baseline prostate volume of 70 _ 10 ml decreased to 57 _ 10 ml (p < ) at 1mo and to 47 _7 ml (p =0.03 against 1 mo) at 3 mo. At 1 mo, 16 patients (76%) could resume voiding with a mean Qmax of 9.0 _ 1.2 ml/s. At 3 mo, 17 patients (81%) voided with a meanqmax of 10.3 _ 1.4 ml/s. Residual urine was 80 _ 19 ml and 92 _ 24 ml at the two time points, respectively. Mean serum total PSA decreased from 6.0 _ 1.1 ng/ml at baseline to 5.0 _ 0.9 ng/ml at 3 mo (p = 0.04). Level of Study Marchal C, Perez JE, Herrera B, Machuca FJ, Redondo M. The use of botulinum toxin in benign prostatic hyperplasia. Neurourol Urodyn 2012;31: Meta-analysis 24 studies To summarize the action mechanisms of BoNT/A on experimental animals and to analyze its effectiveness according to published clinical studies We located 24 papers on the treatment of HBP with BoNT/A. The doses applied ranged from 100 (OnabotA) to 600 U (OnabotA and AbobotA). The IPSS score presented a mean post-treatment reduction, for all series, of 10.8 þ 2.66 points. Other significant results included the overall mean reduction in QoL score of 2.1 _ 0.62 points, and the pre and post-treatment differences in prostate volume (22.43 _ 20.2 cm 3 ), post-voiding residue (76.77 þ cm 3 ) and PSA (1.15 þ 0.93 ng/ml). However, only two clinical trials were on sufficient quality to be selected for meta-analysis, and it was observed that the difference of the means, pre- and post-treatment of maximum flow, prostate volume, IPSS and PSA were not statistically significant (P ¼ 0.18). Neither was there any statistically significant difference between pre- and post-treatment post-voiding residue(p ¼ 0.65). In conclusion, BoNT/A alleviates lower urinary tract symptoms due to HBP, but different studies present considerable variations regarding the dose administered, inclusion criteria and follow-up time, as well as poorly defined retreatment, losses to follow up and, above all, a high degree of variability in the communication of results (with large standard deviations). Level of Study Andersson KE. Intraprostatic injections for lower urinary tract symptoms treatment. Curr Opin Urol 2014;24:1-7. Systemic review 2 RCT Patient :

225 Korean clinical practice guideline for benign prostate hyperplasia The purpose of this study is to review and discuss recently published ( ) experimental and clinical studies of intraprostatic injection therapy as an alternative treatment of lower urinary tract symptoms (LUTS). Recent focus has been on intraprostatic injection of botulinum toxin both with regard to mechanism of action and efficacy. In contrast to the promising findings in several previous studies, a recent large, randomized, placebo-controlled trial found no differences between onabotulinumtoxin A treatment and placebo. There is little new information on the use of anhydrous ethanol and agents such as NX and PRX302, which previously have been reported to have promising effects. Level of Study Denmeade SR, Egerdie B, Steinhoff G, Merchant R, Abi-Habib R, Pommerville P. Phase 1 and 2 studies demonstarate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2011;59: Studies without consistently applied reference standards Phase 1: 15 patients, Phase 2: 18 patients To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH. Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had 30% improvement compared to baseline in IPSS out to day 360. also experienced improvement in QoL and reduction in prostate volume out to day 360. receiving 1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size. Level of Study Pisco JM, Rio Tinto H, Campos Pinheiro L, Bilhim T, Duarte M, Fernandes L, et al. Embolisation of prostatic arteries as treatment of moderate to severe lower urinary symptoms (LUTS) secondary to benign hyperplasia: Results of short- and mid-term follow-up. Eur Radiol 2013;23: Cohort study 255 patients To evaluate the short- and medium-term results of prostatic arterial embolisation (PAE) for benign prostatic hyperplasia (BPH). PAE was technically successful in 250 patients (97.9 %). Mean follow-up, in 238 patients, was 10 months (range 1-36). Cumulative rates of clinical success were 81.9 %, 80.7 %, 77.9 %, 75.2 %, 72.0 %, 72.0 %, 72.0 % and 72.0 % at 1, 3, 6, 12, 18, 24, 30 and 36 months, respectively. There was one major complication. Level of Study Masood S, Djaladat H, Kouriefs C, Keen M, Palmer JH. The 12-year outcome analysis of an endourethral wallstent for treating benign prostatic hyperplasia. BJU Int 2004;94: Cohort study 62 patients 224

226 전립선비대증진료권고안 To evaluate the long-term results of using the Urolume(TM) endourethral prosthesis (American Medical Systems, Minnetonka, MN, USA) for managing benign prostatic hyperplasia (BPH), an alternative minimally invasive option. Twenty-two and 11 patients completed the 5- and 12-year follow-up, respectively. Twenty-one (34%) patients died with the stent in situ from causes unrelated to BPH and Urolume insertion. Twenty-nine (47%) stents were removed; 18 in the first 2 years, seven at 3-5 years and four at 9-10 years. Early stent explantation was primarily a result of poor case selection, or stent malposition/migration. Four stents were removed because the patient was dissatisfied. Late stent explantation was for symptom progression. At 5 years, the symptom score and PFR were 6.82 an 11.7 ml/s, respectively, compared with 20.4 and 9 ml/s at basleine (P < 0.05); at 12 years, the symptom score, PFR and PVR were 10.82, 11.5 ml/s and 80 ml, respectively. The mean quality of life score was 2 and no patient opted for any further treatment. Level of Study Armitage JN, Cathcart PJ, Rashidian A, De Nigris E, Emberton M, van der Meulen JH. Epithelializing stent for benign prostatic hyperplasia: A systematic review of the literature. J Urol 2007;177: Systemic review 20 studies, 990 patients To review the literature on the effectiveness, durability and safety of the UroLume stent for men with benign prostatic hyperplasia. A total of 20 case series evaluated the UroLume stent in a total of 990 patients with benign prostatic hyperplasia. Of the patients 84% who were catheter dependent voided spontaneously after stent insertion. Ten studies assessed symptoms before stent insertion and at some point within 1 year after stent insertion. All reported decreases in symptom scores, including Madsen-Iversen by 7.9 to 14.3 points and International Prostate Symptom Score by 10 to 12.4 points. Peak urine flow rates increased by 4.2 to 13.1 ml per second. A total of 104 stents (16%) failed in 606 patients who were evaluable at 1 year and migration was the commonest cause of failure (38 stents or 37%). Most patients initially experienced perineal pain or irritative voiding symptoms following stent placement. Level of Study 1 근거표 12. 전립선비대증으로진단받은환자의추적관찰에필요한진단적검사는무엇이며, 추적관찰의 기간은어떻게설정하여야하는가? 1. Chung BH. Medical management for benign prostatic hyperplasia. Korean J Urol 2007;48: Review To summarize our current management for benign prostatic hyperplasia 225

227 Korean clinical practice guideline for benign prostate hyperplasia Level of Study 5 2. Joung JY, Park JK, Park CH, Lee JG, Chung BH, Hong SJ, et al. The role of alpha 1 (A) adrenoceptor antagonist tamsulosin for the treatment of patients with benign prostatic hyperplasia:the effect on lower urinary tract symptoms and nocturia. Korean J Urol 2006;47:1-6. Case-control study 268 patients with BPH treated with tamsulosin at a dose of 0.2 mg/day. effectiveness of administering alpha 1 (A)-adrenoceptor antagonist tamsulosin for the patients with benign prostatic hyperplasia The change of nocturnal frequency was 2.2 at baseline to 1.4 after 12 weeks of treatment. Level of Study 4 3. Jeong DH, Park YI. Clinical experience of symptomatic management of BPH with terazosin, doxazosin or combination of terazosin and finasteride. Korean J Urol 1998;39: Single blind case-control study 60 patients were divided 3 groups (terazosin group, doxazosin group, terazosin with finasteride group. To compare the efficacy of terazosin, doxazosin and terazosin (alpha-1 adrenoreceptor antagonist) with finasteride (5-alpha reductase inhibitor) in the treatment of patient with benign prostatic hyperplasia At baseline, 1-PSS, QOL index and Qmax were 18.8+/-4.3, 3.7+/-1.0, 8.6+/-1.7 in terazosin group, 19.3+/-3.9, 3.6+/-1.0, 7.8+/-1.8 in doxazosin group, 20.1+/-4.4, 3.8+/-1.0, 72 +/-1.6 in combination group, respectively. After 12 weeks trial, 1-PSS, QOL index and Qmax were 12.0+/-2.8, 1.9+/-0.9, 11.4+/-2.8 respectively in terazosin group, 11.3+/-3.0, 1.7+/- 0.7, 10.6+/-2.6 in doxazosin group, 10.9+/- 4.0, 1.8+/-0.9, 9.8+/-1.0 in combination group, respectively. Level of Study 4 4. Chung BH, Chung HJ, Hong SJ. Long-term efficacy and safety of terazosin in the symptomatic treatment of benign prostatic hyperplasia. Korean J Androl 1999;17: Case-control study 228 male patients aged 50 years or older who had clinical evidence of BPH To evaluate the long-term efficacy and safety of terazosin, a selective alpha-1 blocker, in the treatment of benign prostatic hyperplasia The mean IPSS was reduced by 35% or greater. In the hypertensive patients, the mean systolic BP was reduced by 11.9% (-18 mmhg) and the mean diastolic BP by 16.8% (-17 mmhg), whereas in normotensive patients, the reductions were 4.0% (-5 mmhg) and 1.2% (-1 mmhg), respectively. There were no significant differences in the IPSS improvement in these two groups. Level of Study 4 5. Cho SH, Lee SK. The experience with combination of finasteride and tamsulosin on benign prostatic hyperplasia. Korean J Urol 2003;44:

228 전립선비대증진료권고안 Case-control study 210 men with symptomatic benign prostatic hyperplasia who were treated with a combination of finasteride and tamsulosin for 12 months. To evaluate the sustained efficacy and the safety of finasteride and tamsulosin in combination in the treatment of benign prostatic hyperplasia Finasteride plus tamsulosin combination therapy produced statistically significant improvements in the urinary obstructive symptoms score and led to overall reduction from baseline of 9.8% in prostatic volume and 55% in serum PSA at the end of a 12-month trial. In men with prostatic volume greater than 30ml (n=28), a decrease in prostatic volume was higher than that less than 30ml (n=31) (13.1% vs. 6.9% from baseline respectively, p=0.0001, p=0.02). Level of Study 4 6. Noh JH, Oh BR, Park YI. The efficacy of combination therapy of 5alpha-reductase inhibitor and of -adrenergic blocker in benign prostate hyperplasia. Korean J Urol 1998;39: Case-control study 85 patients with BPH divided into three groups: Group 1 (doxazosin 3 mg/day), Group 2 (finasteride 5 mg) and Group 3 (combination of both drugs). 6 months followup. To evaluate the efficacy of the combination of 5 alpha -reductase inhibitor (finasteride) and alpha1- adrenergic blocker (doxazosin) In Group 1 and 3, IPSS were more decreased than In Group 2 immediately (p < 0.001). In Group 1 and 3, maximal flow rate was more increased than in group 2 immediately (p < 0.001) Level of Study 4 7. Yu HS, Kim WT, Ham WS, Choi YD. Transurethral resection of prostate in benign prostatic hyperplasia patients with large prostate volume. Korean J Urol 2008;49: Case-control study 211 patients treated with TURP in BPH with large prostate. Each group was divided by prostate volume (group 1; , group 2; , group 3; , group 4; , group 5; >100 cc of prostate volume) To investigate the safety and efficacy of transurethral resection of the prostate in benign prostatic hyperplasia more than 60 cc Prostate volume, adenoma volume, resection time, Resection volume, irrigation volume of each groups were different significantly. But, resection volume/resection time and irrigation volume/ resection time were not different significantly Level of Study 4 8. Kim HG, Lee BK, Paick SH, Lho YS. Efficacy of bipolar transurethral resection of the prostate: comparison with standard monopolar transurethral resection of the prostate. Korean J Urol 2006;47:

229 Korean clinical practice guideline for benign prostate hyperplasia Case-control study 25 patients with symptomatic benign prostatic hyperplasia (BPH) who underwent TURP compared with standard monopolar TURP. to assess the efficacy of bipolar transurethral resection of the prostate (TURP) compared with standard monopolar TURP The mean weight of resection was 29.7 g for the bipolar TURP and 22.5 g for the monopolar TURP. The operative time was shorter (82.5 vs 98.1 minutes, respectively), the estimated blood loss was less (252 vs 268 cc, respectively) and the mean post-operative hospital stay was shorter (5.3 vs 5.7 days, respectively) in the bipolar TURP group. However, these differences were not statistically significant. The acute complications were significant hyponatremia in one patient and clot retention in one patient after monopolar TURP, but no complications occurred after bipolar TURP. The maximal flow rate increased from 6.4 to 14.7 ml/sec in the bipolar TURP group, and it increased from 6.7 to 15.2 ml/sec in the monopolar TURP group Level of Study 4 근거표 13. 전립선비대증으로진단받은환자들중에반드시비뇨기과전문의에게의뢰해야하는경우는 무엇인가? 1. Abrams P, Chapple C, Khoury S, et al. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2009;181: Expert opinion The 6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases met from June 24-28, 2005 in Paris, France to review new developments in benign prostatic disease. The Consultation endorsed the appropriate use of the current terminology lower urinary tract symptoms/benign prostatic hyperplasia/benign prostate enlargement and benign prostatic obstruction, and recommended that terms such as "clinical benign prostatic hyperplasia" or "the benign prostatic hyperplasia patient" be abandoned, and asked the authorities to endorse the new nomenclature. The diagnostic evaluation describes recommended and optional tests, and in general places the focus on the impact (bother) of lower urinary tract symptoms on the individual patient when determining investigation and treatment. The importance of symptom assessment, impact on quality of life, physical examination and urinalysis is emphasized. The frequency volume chart is recommended when nocturia is a bothersome symptom to exclude nocturnal polyuria. The recommendations are summarized in 2 algorithms, 1 for basic management and 1 for specialized management of persistent bothersome lower urinary tract symptoms. Level of Study 5 2. Kaplan SA. Update on the American Urological Association guidelines for the treatment of benign prostatic hyperplasia. Rev Urol 2006;8(Suppl.4):S

230 전립선비대증진료권고안 Expert opinion The updated 2003 American Urological Association (AUA) Guidelines for the treatment of benign prostatic hyperplasia (BPH) are the culmination of an exhaustive effort predicated on scientifically accepted methods of reviewing the medical literature. In this second publication of the guidelines, a multidisciplinary panel reviewed a new meta-analysis of outcome data from the BPH literature from before and after 1994 The major differences between the 2 guidelines are the changes in our understanding of the biology of the prostate and the introduction of new therapies. The vast majority of randomized controlled trials, particularly with respect to minimally invasive therapies and progression of BPH, were performed after the release of the 1994 guidelines. Also, the most recent AUA panel carefully reviewed unpublished data to make the guidelines as timely as possible. Studies that were subsequently published included those on the value of combination medical therapy for BPH. The panel agreed on updated recommendations for the treatment of moderate-to-severe lower urinary tract symptoms associated with BPH, and diagnostic algorithms were revised. The durability and utility of the present guidelines should exceed that of its predecessor. Level of Study 5 3. Grosse H. Frequency, localization and associated disorders in urinary calculi: analysis of 1671 autopsies in urolithiasis. Z Urol Nephrol 1990; 83: Cross sectional study 27,133 In the area of Rügen-Stralsund a maximum value of urolithiasis and cholelithiasis was found. In 27,133 autopsies the frequency of urolithiasis was 6%. Obesity, hypertension and diabetes mellitus may increase the tendency of cholelithiasis patients to develop additional urolithiasis Ureteral and urinary bladder calculi are more frequently among male patients. In cases with benign prostatic hyperplasia the incidence of urolithiasis was not higher than in female patients. In the autopsy material multiple calculi and bilateral cases occur more frequently. Hypertension and increased heart weight did occur more frequently in patients suffering from oxalate lithiasis. Some of the calculi may develop in the terminal age of life Level of Study 3 4. Wasson JH, Reda DJ, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995;332:75 9. RCT 556 Transurethral resection of the prostate is the most common surgical treatment for benign prostatic hyperplasia. We conducted a multicenter randomized trial to compare this surgery with watchful waiting in men with moderate symptoms of benign prostatic hyperplasia. 229

231 Korean clinical practice guideline for benign prostate hyperplasia Of the men randomly assigned to the surgery group, 249 underwent surgery within two weeks after the assignment. Surgery was not associated with impotence or urinary incontinence. The average follow-up period was 2.8 years. In an intention-to-treat analysis, there were 23 treatment failures in the surgery group, as compared with 47 in the watchful-waiting group (relative risk, 0.48; 95 percent confidence interval, 0.30 to 0.77). Of the men assigned to the watchful-waiting group, 65 (24 percent) underwent surgery within three years after the assignment. Surgery was associated with improvement in symptoms and in scores for urinary difficulties and interference with activities of daily living (P < for all comparisons). The outcomes of surgery were best for the men who were most bothered by urinary symptoms at base line. Level of Study 2 5. Holtgrewe HL, Mebust WK, et al. Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 1989;141: Expert opinion In a national survey of all American urologists transurethral prostatectomy accounted for 38 per cent of the major surgical procedures performed by the respondents. They regarded the operation as complex and they believe achievement of proficiency requires that more be performed during residency training than any other urological operation. Furthermore, they assigned transurethral prostatectomy a significantly higher relative value than have medical economists doing research in the field of physician reimbursement. The effect of recent legislated congressional reductions in the allowable Medicare fees for transurethral prostatectomy is discussed along with the impact of these reductions on urological patient care and the American urologist. Practice patterns and geographic variations in the costs of transurethral prostatectomy also are considered. Level of Study 5 6. McConnell JD, Roehrborn C, et al. The long-term effects of doxazosin, finasteride and the combination on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349: RCT 2,872 We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short- Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS- QoL, International Prostate Symptom Score-QoL) during 4 years. Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS- QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group. 230

232 전립선비대증진료권고안 Level of Study 2 7. Levin RM, Longhurst PA, et al. Effect of bladder outlet obstruction on the morphology, physiology, and pharmacology of the bladder. Prostate [Suppl] 1990;3:9 26. Observational study Bladder outlet obstruction secondary to benign prostatic hyperplasia induces numerous changes in bladder morphology, physiology, and pharmacology. These changes have been studied experimentally in various animal models, and while each species has advantages and disadvantages, it is unclear which is the most like man. It has been shown that tissue hypertrophy leading to an increase in tissue mass develops rapidly after bladder outlet obstruction. It has been shown that tissue hypertrophy leading to an increase in tissue mass develops rapidly after bladder outlet obstruction. Ischemia induced by the obstruction results in acute muscle dysfunction. The degree of functional impairment is directly related to the degree of tissue hypertrophy. However, the bladder contractile apparatus appears to have a surprising regenerative ability, such that recovery of bladder function becomes obvious 14 days after obstruction. Urodynamic changes include an increase in urinary frequency and voiding pressure and a decrease in voided volume. Clinically, involuntary bladder contractions are often present. Determination of which of these specific aspects of outlet obstruction the investigator is interested in studying will dictate the selection of the most appropriate animal model. Level of Study 5 8. McConnell JD, Barry MJ, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guideline no. 8. Rockville, MD: U.S. Department of Health and Human Services, Agency for Health Care Policy and Research, Public Health Service; 1994; Expert opinion This Quick Guide for Clinicians contains highlights from the Clinical Practice Guideline of Benign Prostatic Hyperplasia: Diagnosis and Treatment. The Benign Prostatic Hyperplasia Guideline Panel, a private-sector panel of health care providers, developed the guideline after comprehensively analyzing the research literature. As a result, this guideline comprises the most current scientific knowledge of the development, diagnosis, and treatment of benign prostatic hyperplasia (BPH). The guideline makes specific recommendations to identify both the most effective methods for diagnosing BPH and the most appropriate treatments for BPH based on patient preference and clinical need. BPH affects quality of life and is very rarely a life-threatening disease. Motivation to seek active treatment will, for most patients, depend on how much their symptoms bother them. Many patients choose a regimen of "watchful waiting." The guideline details the relative benefits and harms associated with all diagnostic and treatment approaches. Treatment options discussed include watchful waiting, alpha blocker and finasteride medications, balloon dilation, and the surgical options of transurethral incision, transurethral resection, and open prostatectomy. Level of Study 5 231

233 Korean clinical practice guideline for benign prostate hyperplasia 10. DiPaola RS, Kumar P, et al. State-of-the-art prostate cancer treatment and research. A report from the Cancer Institute of New Jersey. N J Med 2001;98: Expert opinion Prostate cancer is a devastating disease that will be diagnosed in approximately 200,000 men in New methods for screening, prevention, and treatment are being developed Novel agents for the treatment of resistant prostate cancer are being developed in clinical trials. This review summarizes the recent efforts in diet, screening, novel systemic therapies, and alternative medicine for prostate cancer. Level of Study Madersbacher S, Alivizatos G, Nordling J, et al. EAU 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines). Eur Urol 2004;46: Expert opinion To provide the first update of the EAU guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). During initial assessment the following tests are recommended: medical history, physical examination including digital-rectal examination, International Prostate Symptom Score, urinalysis, serum creatinine and prostate specific antigen measurement, uroflowmetry and post-void residual volume. All other tests are optional or not recommended. Aim of treatment is to improve LUTS and quality of life and to prevent severe BPE-related complications. Development of a 5alpha-reductase type I and II inhibitor and the data of the MTOPS trial providing scientific evidence for a combination therapy were the most significant innovations since the first version. Finally a more detailed knowledge on the natural history with identification of several risk factors for progression is the basis for a riskprofile orientated (preventive) therapy. Level of Study Roehrborn CG, Malice M, Cook TJ, Girman CJ. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58: Meta analysis 5,355 To comprehensively evaluate clinical predictors of spontaneous acute urinary retention (AUR) across pooled data of placebo-treated patients from clinical trials conducted in men with lower urinary tract symptoms and clinically diagnosed benign prostatic hyperplasia. 232

234 전립선비대증진료권고안 The different methods of analysis identified consistent potential predictors of episodes of AUR. When prostate volume was included in the analyses, it was selected as the initial variable discriminating men with and without subsequent AUR. Omitting prostate volume because of its availability in only a subset of men, a logistic model including serum prostate-specific antigen (PSA), urinating more than every 2 hours, symptom problem index, maximum urinary flow rate, and hesitancy of urination had good predictive properties (area under the receiver-operating characteristic curve [AUC] = / ), as did a model with PSA (AUC = / ). A classification and regression decision tree with the same variables predicted AUR (AUC = 0.74, sensitivity = 72%, specificity = 67%) as well as did a tree with PSA alone (AUC = 0.70, sensitivity = 75%, specificity = 64%). Level of Study M. Oelke (chairman), A. Bachmann, A. Descazeaud, M. Emberton, S. Gravas, M.C. Michel, et al. Guidelines on the Management of Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO). EAU2012. Expert opinion To present a summary of the 2013 version of the European Association of Urology guidelines on the treatment and follow-up of male lower urinary tract symptoms (LUTS). Men with mild symptoms are suitable for watchful waiting. All men with bothersome LUTS should be offered lifestyle advice prior to or concurrent with any treatment. Men with bothersome moderateto-severe LUTS quickly benefit from α1-blockers. Men with enlarged prostates, especially those >40 ml, profit from 5α-reductase inhibitors (5-ARIs) that slowly reduce LUTS and the probability of urinary retention or the need for surgery. Antimuscarinics might be considered for patients who have predominant bladder storage symptoms. The phosphodiesterase type 5 inhibitor tadalafil can quickly reduce LUTS to a similar extent as α1-blockers, and it also improves erectile dysfunction. Desmopressin can be used in men with nocturia due to nocturnal polyuria. Treatment with an α1- blocker and 5-ARI (in men with enlarged prostates) or antimuscarinics (with persistent storage symptoms) combines the positive effects of either drug class to achieve greater efficacy. Prostate surgery is indicated in men with absolute indications or drug treatment-resistant LUTS due to benign prostatic obstruction. Transurethral resection of the prostate (TURP) is the current standard operation for men with prostates ml, whereas open surgery or transurethral holmium laser enucleation is appropriate for men with prostates >80 ml. Alternatives for monopolar TURP include bipolar TURP and transurethral incision of the prostate (for glands <30 ml) and laser treatments. Transurethral microwave therapy and transurethral needle ablation are effective minimally invasive treatments with higher retreatment rates compared with TURP. Prostate stents are an alternative to catheterisation for men unfit for surgery. Ethanol or botulinum toxin injections into the prostate are still experimental. Level of Study Aziz DC, Barathur RB. Prostate-specific antigen and prostate volume: a meta-analysis of prostate cancer screening criteria. J Clin Lab Anal 1993;7:

235 Korean clinical practice guideline for benign prostate hyperplasia Meta analysis To establish the value of serum prostate-specific antigen (PSA) and prostate-specific antigen per unit volume of prostate gland (PSAD) in detecting prostate carcinoma (CaP) in a hypothetical screening algorithm, a meta-analysis of the sensitivities, specificities, predictive values and likelihood ratios were combined from the published data. Hypothetical cohorts of 1,000 men between the ages of 60 and 70 years were screened using three different screening decision algorithms. Using a serum PSA cutoff of 3.0 ng/ml for referral for transrectal biopsy, 59 of 80 (74%) CaP would be detected and 21 (26%) would be missed. 209 transrectal biopsies would be performed, and 150 (72%) of them would be negative for CaP. Using a serum PSA cutoff of 4.0 ng/ml, 52 of 80 (65%) CaP would be detected and 28 (35%) would be missed. 146 transrectal biopsies would be performed, and 94 (64%) of them would be unnecessary. Using a cutoff of 2.0 ng/ml for serum PSA and 0.1 ng/ml/cc for PSAD, 55 of 80 (69%) of the cancers would be detected and 25 (31%) would be missed. Only 84 transrectal biopsies would be performed, and 29 (35%) of them would be negative for cancer. Level of Study 1 234

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237 전립선비대증진료권고안 Korean clinical practice guideline for benign prostate hyperplasia 인 발 쇄 2015 년 6 월 15 일 행 2015 년 6 월 22 일 지은곳대한비뇨기과학회 서울특별시용산구서빙고로지하 83 ( 용산동 5 가 ) 용산파크타워오피스텔 103 동 1102 호 TEL: FAX: [email protected] 펴낸곳에이플러스기획서울시중구퇴계로 30 길 24 ( 예장동, 삼익파크빌 ) B211-3 호 TEL: FAX: [email protected] 출판등록 ISBN [ 비매품 ] 이도서의국립중앙도서관출판예정도서목록 (CIP) 은서지정보유통지원시스템홈페이지 ( 와국가자료공동목록시스템 ( 에서이용하실수있습니다. (CIP 제어번호 : CIP ) 이책의판권은대한비뇨기과학회에있습니다. 파본은교환해드립니다. 이책내용의전부또는일부를사용하시려면반드시대한비뇨기과학회의서면동의를받으셔야합니다.

238 대한비뇨기과학회 I 대한가정의학회 I 대한배뇨장애요실금학회 I 근거창출임상연구국가사업단 비매품 ISBN