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1 ORIGINAL ARTICLE Korean Circ J 2008;38: Print ISSN / On-line ISSN Copyright c 2008 The Korean Society of Cardiology 무증상성인에서관상동맥질환의일차예방전략의비교 서울대학교의과대학내과학교실, 1 분당서울대학교병원심장센터순환기내과, 2 영상의학과 3 조영진 1,2 윤연이 1,2 김지현 1,2 박준빈 1,2 박효은 1,2 이원재 1,2 최의근 1,2 전은주 3 최상일 3 최동주 1,2 장혁재 1,2 Comparison of Primary Prevention Strategies for Coronary Heart Disease in Asymptomatic Individuals: The National Cholesterol Education Program -Adult Treatment Panel III Guideline Versus the Screening for Heart Attack Prevention and Education Guideline Youngjin Cho, MD 1,2, Yeonyee E. Yoon, MD 1,2, Ji-Hyun Kim, MD 1,2, Jun-Bean Park, MD 1,2, Hyo-Eun Park, MD 1,2, Wonjae Lee, MD 1,2, Eue-Keun Choi, MD 1,2, Eun-Ju Chun, MD 3, Sang-Il Choi, MD 3, Dong-Ju Choi, MD 1,2 and Hyuk-Jae Chang, MD 1,2 1 Department of Internal Medicine, Seoul National University, College of Medicine, Seoul, 2 Division of Cardiology and 3 Radiology, The Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Korea ABSTRACT Background and Objectives: The National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) III guideline has been widely accepted for the primary prevention of coronary heart disease (CHD). The coronary artery calcium score (CACS) has recently been recognized as an excellent predictor of CHD events, and a primary prevention strategy based on the CACS [the Screening for Heart Attack Prevention and Education (SHAPE) guideline] has been proposed. The purpose of this study was to explore how the guidelines function for asymptomatic South Korean individuals. Subjects and Methods: We consecutively enrolled 2,079 asymptomatic subjects (age range for men: years, age range for women: years) who underwent CACS and coronary CT angiography (CCTA) as a part of a health check-up. We analyzed the differences of the target population for CHD prevention according to the 2 guidelines and we compared them in terms of the presence of occult CHD. Results: Four-hundred eighteen (20%) individuals were recommended for pharmacotherapy according to the NCEP-ATP III and 371 (18%) were recommended for pharmacotherapy according to the SHAPE guideline (Cohen s κ=0.36). According to the SHAPE guideline, more individuals with significant stenosis noted on the CCTA were categorized into the high or very high risk group (50% vs. 24%, respectively, p<0.001) and recommended for pharmacotherapy (53% vs. 28%, respectively, p<0.001). However, 57 (43%) individuals with significant stenosis on the CCTA were not suitable for pharmacotherapy according to either the NCEP-ATP III or the SHAPE guideline. Conclusion: Comparing the NCEP-ATP III and the SHAPE guidelines, there were considerable differences for primary prevention in the target population. Although SHAPE might provide more accurate stratification in terms of the presence of occult CHD, a more precise risk stratification algorithm needs to be implemented for this population. (Korean Circ J 2008;38: ) KEY WORDS: Coronary artery disease; Primary prevention; Guideline. Received: April 25, 2008 Revision Received: June 16, 2008 Accepted: June 29, 2008 Correspondence: Hyuk-Jae Chang, MD, Division of Cardiology, The Cardiovascular Center, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam , Korea Tel: , Fax: hjchang@snu.ac.kr 483

2 484 Primary Prevention of Coronary Heart Disease 서 론 관상동맥질환으로인한돌연사, 또는심근경색을경험하는환자의상당수는이전에호흡곤란이나흉통과같은증상이없던환자로이들사건으로인한사망률을감소시키기위해서는효과적인치료방침의개발뿐아니라증상이없는관상동맥질환의고위험군환자를선별하는효과적인일차예방전략이반드시필요하다. 1) 현재관상동맥질환의일차예방을위해가장보편적으로사용되는지침으로는관상동맥질환의전통적위험인자들로부터산출된프래밍험위험점수 (Framingham risk score, FRS) 및위험인자수에바탕을둔 National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) 지침이있으나, 2) 이와같은위험도의산출방식은특정인구집단의역학연구에기반한것으로다른인구집단에서관상동맥질환의유무및사건발생을예측하는데명확한한계가있다는것이여러연구를통해지적되어왔다. 3-5) 최근약 10년간전자선컴퓨터단층촬영 (electron-beam CT, EBCT) 등을통해측정한관상동맥석회화점수 (coronary artery calcium score, CACS) 가무증상환자를포함한여러환자군에서관상동맥의동맥경화반의총량과비례하며, 기존의임상적위험인자에비해심장혈관계사건발생을효과적으로예측할수있다는일관성있는연구결과가발표되었다. 6-11) 이러한연구결과에기초해 2006 년유수한의료진으로구성된민간단체인 The Association for Eradication of Heart Attack (AEHA) 는관상동맥질환의위험군분류와예방, 치료방침결정에 CACS 를반영한 Screening for Heart Attack Prevention and Education (SHAPE) 지침을발표하였다. 12) 이에따르면관상동맥질환의임상적위험인자유무와상관없이영상검사를통해동맥경화의증거가있는경우 (CACS >0이거나 common carotid IMT (CIMT)>50 th percentile 또는경동맥죽상판이존재하는경우 ) 고위험군으로분류하고, CACS 가높을수록엄격한저밀도지단백콜레스테롤조절을권장하였다. 반면동맥경화에대한선별검사결과음성 (CACS =0 또는 CIMT<50 th percentile) 인경우임상적위험인자의유무에따라저위험군또는중등도위험군으로분류하고기존의일차예방지침과유사한치료를권장하였다. SHAPE 지침은무증상환자에서동맥경화의지표로서관상동맥석회화를측정하고이를치료에반영함으로써보다정확히위험군을분류하고효과적으로심장혈관계사건발생을예방할가능성이있으나이러한지침에서치료대상군이기존의일차예방지침과비교하여어떻게변화하는지에대한연구는미흡한상태이다. 특히 CACS 가백인종 (Caucasian) 에비해유의하게낮다고알려진동양인 (Asian), 13) 특히한국인을대상으로한연구는전무하다. 본연구에서는무증상환자에서건강검진의일환으로 MDCT (multi-detector computed tomography) 를이용하여 CACS, 관상동맥 CT 혈관조영술 (coronary CT angiograph, CCTA) 을포함한심장 CT검사를시행한사람들을대상으로기존의 NCEP-ATP III 지침에비교하여 SHAPE 지침을따를경우위험군및치료대상환자의분류에어떠한차이를보이는지와 CCTA 를통해확인된관상동맥질환환자를각각의지침이효과적으로선별하는지의여부를확인하고자하였다. 대상및방법 대상 2005 년 12월부터 2008 년 2월까지분당서울대학교병원건강검진센터에서건강검진의일환으로 64-slice MDCT 를이용한심장 CT를시행한무증상환자를후향적으로분석하였다. 흉통또는관상동맥성형술을받은병력이있는환자, 지질강하제를복용중인환자, SHAPE 지침에서위험도분류를위한동맥경화선별검사의대상이되지않는환자 : 1) 남자 <45 세, 여자 <55 세, 2) 75세이상, 3) 초저위험군 ( 총콜레스테롤 <200 mg/dl, 혈압 120/80 mmhg, 당뇨, 흡연, 조기관상동맥질환의가족력및대사증후군의소견이없는환자 ) 을제외하였으며최종적으로 2,079 명의무증상환자가분석에포함되었다. 위험인자평가모든환자에서흉통또는동등한증상이있었는지설문조사를통해확인하였다. 심근경색, 협심증, 고혈압, 뇌경색, 당뇨를포함한과거병력, 흡연, 조기관상동맥질환에대한가족력여부를설문지 (self-reported questionnaire) 를통해조사하였다. 검진시체중, 키, 혈압을측정하였으며, 고혈압은기존병력이있거나측정혈압이 140/90 mmhg 이상인경우로, 당뇨는기존병력이있거나공복혈당이 126 mg/dl 이상으로정의하였다. 총콜레스테롤, 중성지방, 고밀도지단백콜레스테롤 [high density lipoprotein (HDL)-cholesterol], 저밀도지단백콜레스테롤 [low density lipoprotein (LDL)-cholesterol], 공복혈당을 12시간금식상태에서채혈하여측정하였다. 대상환자는 NCEP-ATP III 지침에따라저위험군 ( 위험인자 0~1 개 ), 중동도위험군 ( 위험인자 2개이상, 10년관상동맥질환위험 <10%), 중등고위험군 ( 위험인자 2개이상, 10 년관상동맥질환위험 10~20%), 고위험군 ( 위험인자 2개이상, 10년관상동맥질환위험 >20%) 으로분류하였다. 2) 또한 SHAPE 지침에따라저위험군 (CACS 0, 위험인자없음 ), 중등위험군 (CACS 0, 위험인자있음 ), 중등고위험군 (CACS 1-99), 고위험군 (CACS ), 초고위험군 (CACS 400 이상 ) 으로분류하였다. 12) CT 검사 64-slice MDCT scanner (Brillance 64; Philips Medical

3 Youngjin Cho, et al. 485 systems, Best, The Netherlands) 를이용하였으며, 관상동맥조영을위해사용되는표준 protocol ( mm slice collimation, 420 msec rotation time, 120 kv tube voltage, 800 ma tube current) 에따라영상을획득하였다. 조영제로 Iomeprol (Iomeron 400; Bracco, Milan, Italy) 을초당 4 ml 로총 80 ml 를정주한후같은속도로생리식염수 50 ml를정주하였다. 하행흉부대동맥에관심영역을위치시킨후역치 (150 HU) 에도달하면자동적으로영상을획득하였다 (bolus tracking method). 영상획득시함께기록된심전도에따라 multi-segment algorithm 을이용하여이완중기 (mid-diastolic phase, 75% of R-R interval) 에영상을재구성하였으며, 심장움직임에의한인공물 (motion artifact) 로인해필요한경우추가로영상을재구성하였다. 심장 CT 검사의평균유효선량 (effective dose) 은 14.0±2.2 msv 였다. 자료분석모든심장 CT 영상은임상정보없이동일한연구자에의해분석되었다. 관상동맥협착은상용화된 workstation (Brilliance; Philips Medical Systems, Best, The Netherlands) 을이용하여 1 mm 간격으로영상을재구성하여분석하였다. 유의한협착은 multi-planar reconstruction 영상이나 maximum intensity projection 영상에서내경이 50% 이상좁아졌을때로정의하였다. 동맥경화반은혈관내강및심막주변조직과는명확히구별되며, 혈관내강안, 또는그에인접해있는 1 mm 2 이상의구조물로정의하였다. CACS 는 Agatston 등 14) 에의해발표된방법에따라측정하였다. Table 1. Baseline characteristics of the study population Characterristics N=2,079 Age (years) 55±8 Male (%) 1,596 (77) BMI (kg/m 2) 24.5±2.7 WC (cm) 88±26 SBP (mmhg) 121±15 DBP (mmhg) 76±11 Hypertension (%) 782 (38) Diabetes mellitus (%) 261 (13) Hypercholesterolemia (%) 387 (19) History of stroke (%) 24 (1) F/Hx. of premature CHD (%) 248 (12) Smoking (%) 627 (30) FBS (mg/dl) 97±23 HbA1c (%) 5.9±0.8 Total cholesterol (mg/dl) 211±35 LDL-cholesterol (mg/dl) 118±28 HDL-cholesterol (mg/dl) 54±13 Triglyceride (mg/dl) 141±80 BUN (mg/dl) 14±3 Serum creatinine (mg/dl) 1.1±0.2 CRP (mg/dl) 0.1±0.3 CACS 35±125 Data are expressed as number (%) and mean±sd. BMI: body mass index, WC: waist circumference, SBP: systolic blood pressure, DBP: diastolic blood pressure, F/Hx: family history, CHD: coronary heart disease, FBS: fasting blood sugar, LDL-C: low density lipoproteincholesterol, HDL-C: high density lipoprotein-cholesterol, BUN: blood urea nitrogen, CRP: C-reactive protein, CACS: coronary artery calcium score 통계연속변수는평균 ± 표준편차로, 범주형변수는빈도 (%) 로표기하였다. 연속형변수는독립표본 t-검정, 범주형변수는 χ 2 분석을이용하여통계적유의성을검정하였다. 두지침간의관상동맥질환위험군분류의상관도는 Spearman 상관분석을통해분석하였다. 각지침에따른약물치료대상군선정대상수의차이를비교하기위해대응표본 t-검정을이용했으며, 약물치료대상군선정의상관관계, 일치도를평가하기위해 Cohen 의 κ 검정과 McNemar 검정을시행하였다. 통계프로그램으로 Statistical Package for Social Science (SPSS) 12 (SPSS Inc., Chicago, Illinois) 를사용하였으며 p< 0.05 를유의한것으로간주하였다. 결 과 임상적특성대상군은총 2,079 명으로남자가 1,603 명 (77%) 이었고, 연령분포는 55±8세였다. 고혈압및당뇨의유병률은 782명 (38%) 과 261 명 (13%) 이었으며, 체질량지수는 24.5±2.7 kg/m 2 였다. 총콜레스테롤수치는 211±35 mg/dl 였다 (Table 1). 일차예방지침에따른위험군분류및치료대상의차이 NCEP-ATP III 지침에따라위험군을분류했을때고위험군에해당하는환자는 292 명 (14%) 이었으며, SHAPE 지침에따른분류를할경우이에상응하는초고위험군및고위험군은각각 55명 (3%), 122 명 (6%) 이었다. 두일차예방지침에서 667 명 (32%) 이동일한위험군으로분류되었고, 상관분석계수 Spearman s ρ는 0.34였다 (Table 2). LDL 콜레스테롤농도를고려한약물치료적응여부를각각의지침에따라살펴보았을때, NCEP-ATP III에따를경우 418 명 (20%), SHAPE 에따를경우는 372 명 (17.9%) 이약물치료의대상으로분류되어 SHAPE 에따를경우약물치료가필요한환자의수가유의하게적었다 (p=0.02) (Fig. 1). 두지침모두에서약물치료를추천하는환자는 190 명 (9.1%) 이었다. 두지침의약물치료대상환자의일치도는 Cohen s κ 검정결과 κ=0.36 이었다 (Table 3) 관상동맥질환유무에따른일차예방지침비교심장 CT 검사결과관상동맥동맥경화반이발견된환자는 768 명 (37%) 이었고, 이중 133 명 (6%) 에서 50% 이상의유의한협착이관찰되었다. 관상동맥동맥경화반및유의한협착

4 486 Primary Prevention of Coronary Heart Disease Table 2. Relationship of SHAPE risk stratification with NCEP-ATP III risk stratification NCEP-ATP III* SHAPE risk stratification Low risk Moderate risk Moderately high risk High or very high risk Total (%) Low risk (49) Moderate risk (5) Moderately high risk (32) High risk (14) Total (%) 405 (20) 1069 (51) 428 (21) 177 (9) 2079 (100) Data are expressed as number of individuals (% of total participants). Individuals classified as very high risk (CACS>400) were combined with those categorized as high risk (CACS ) in SHAPE risk stratification. *Individuals were classified as low-risk (0-1 risk factor), moderaterisk ( 2 risk factors but <10% risk of CHD at 10 years), moderately high-risk ( 2 risk factors and 10% to 20% risk of CHD in 10 years), or high-risk ( 2 risk factors and >20% risk of CHD in 10 years). SHAPE: Screening for Heart Attack Prevention and Education, NCEP- ATP: National Cholesterol Education Program-Adult Treatment Panel, CACS: coronary artery calcium score, CHD: coronary heart disease n=2,079 NCEP* SHAPE 222 (10.7%) 159 (7.6%) 31 (1.5%) 39 6 (1.9%) (0.3%) 57 (2.7%) Presence of plaque with significant stenosis n=1,422 (68.4%) 의동반여부에따라 1) 동맥경화반이없는환자, 2) 동맥경화반이있으나유의한관상동맥협착은없는환자, 3) 유의한협착이동반된환자로나누어분석하였을때각각의지침에따른위험군분류는 Fig. 2와같았다. 50% 이상의협착이동반된동맥경화반의유무에대한각지침의 receiver operating characteristics (ROC) 곡선의 area under the curve (AUC) 는 SHAPE 위험군분류 0.84 (95% 신뢰구간 : 0.80~ 0.88), NCEP-ATP III 위험군분류 0.64 (96% 신뢰구간 : 0.59 ~0.68) 로 SHAPE 지침에따른위험군분류가보다높은비율로관상동맥질환자를고위험군으로분류하였다 (Fig. 3). LDL 콜레스테롤수치를고려한약물치료적응여부를살펴보았을때, 각지침에따른약물치료대상군의비율은 Fig. 4 와같았다. McNemar 검정결과관상동맥이정상소견을보인환자에서 NCEP-ATP III 지침에따를경우보다많은환 143 (6.9%) Fig. 1. Venn Diagram illustrating the population qualifying for pharmacotherapy according to NCEP-ATP III or SHAPE guideline. Data are expressed as number (% of total participants). *Individuals qualifying for pharmacotherapy according to NCEP-ATP III guideline, According to SHAPE guideline, Individuals not qualifying for pharmacotherapy according to neither guidelines, Significant stenosis was defined as more than 50% luminal narrowing on MDCT. NCEP-ATP: National Cholesterol Education Program-Adult Treatment Panel, SHAPE: Screening for Heart Attack Prevention and Education. 자가치료대상으로분류되었으며, 관상동맥질환이발견된환자의경우 SHAPE 지침에따랐을때치료대상으로분류되는비율이높았다 (Fig. 4). 그러나관상동맥동맥경화반이존재했던 768 명의환자중 179 명 (23%) 은관상동맥석회화가없이동맥경화반만관찰되었으며 (CACS=0), 이들중 21명에서유의한협착이동반되었다. 이들환자의경우고위험군분류와약물치료대상군의비율은 SHAPE 에따를경우보다낮았다 (Table 4). 또한 50% 이상의관상동맥협착이발견된환자라할지라도두지침모두약물치료대상에서제외된환자는 43% (57/ 133) 였다 (Fig. 1). 고찰 본연구에서는선별검사의일환으로 CACS, CCTA 를포함한심장 CT를촬영한무증상한국인중 SHAPE 지침에서위험도분류를위한동맥경화선별검사가추천되는환자들 (75 세이상의고령, 초저위험군제외 ) 을대상으로관상동맥질환의일차예방에대한임상지침을비교하였다. 두지침에의한위험군분류는서로유의한상관관계를보였으나, 그상관정도가낮았으며두지침에서동일한위험군으로분류된환자수도전체환자의약 1/3에불과하였다. LDL 콜레스테롤수치를기준으로 NCEP-ATP III, SHAPE 지침에따르면각각 418 명 (20%), 372 명 (18%) 이약물치료대상이었으며, SHAPE 지침에따른약물치료대상이유의하게적었다 (p=0.02). 또한두지침모두에서약물치료를추천하는환자는 190 명 (9%) 으로전체약물치료대상의절반에못미쳐약물치료대상군선정에있어서도큰차이를보여주고있다. MDCT 는 CACS 와달리동맥경화반의크기와특성, 협착정도등전반적인관상동맥질환유무및특성에대한정보를제공한다. 15)16) MDCT 에서발견된동맥경화반및그협착의임상적경과와예후에대해서는명확히규명되어있지않으나 MDCT 에서동맥경화반이관찰되지않을경우예후가매

5 Youngjin Cho, et al. 487 Table 3. Proportion of individuals qualifying pharmacotherapy according to each guideline and extent of agreement across the risk categories NCEP-ATP III N Qualifying pharmacotherapy according to Both guidelines (%) NCEP-ATP III (%) SHAPE (%) Low risk (1) 8 (1) 144 (14) 0.09 <0.01 Moderate risk (2) 2 (2) 12 (11) 0.26 <0.01 Moderately high risk (19) 226 (35) 157 (24) 0.52 <0.01 High risk (19) 182 (62) 59 (20) 0.22 <0.01 SHAPE Low risk (0) 5 (1) 0 (0) N/A N/A Moderate risk (5) 242 (23) 86 (8) 0.21 <0.01 Moderately high risk (20) 116 (27) 146 (34) 0.50 <0.01 High or very high risk (31) 55 (31) 139 (79) 0.22 <0.01 Total (9) 418 (20) 371 (18) 0.36 <0.01 Data are expressed as number of individuals (% of individuals categorized into the same risk group). Individuals classified as very high risk (CACS>400) were combined with those categorized as high risk (CACS ) in SHAPE risk stratification. SHAPE: Screening for Heart Attack Prevention and Education, NCEP-ATP: National Cholesterol Education Program-Adult Treatment Panel, CACS: coronary artery calcium score, N/A: not applicable κ p (%) NCEP (%) SHAPE No plaque Plaque without Plaque with significant significant stenosis* stenosis No plaque Plaque without Plaque with significant significant stenosis stenosis A High risk Moderate risk Moderately high risk Low risk High or very high risk Moderate risk Moderately high risk Low risk Fig. 2. Risk stratification for coronary heart disease across the severity of subclinical coronary atherosclerosis detected by MDCT. Individuals were categorized into each risk groups according to NCEP-ATP III guideline (A), and SHAPE guideline (B). *Significant stenosis was defined as more than 50% luminal narrowing on MDCT. MDCT: multi-detector computed tomography, NCEP-ATP: National Chole- Sterol Education Program-Adult Treatment Panel, SHAPE: Screening for Heart Attack Prevention and Education. B 우양호하다는중기추적연구결과들이발표되고있으며, 17)18) 침습적인관상동맥조영술에기반한연구에서 50% 이상의유의한협착이있을경우혈류에악영향을미쳐불량한예후를보였다는사실에비추어보아, 19-21) MDCT 에서관상동맥내경 50% 이상의협착이동반된동맥경화반이관찰될경우역시불량한예후를보일가능성은충분하다고하겠다. 본연구에서 MDCT 소견과잘부합되는위험군분류를보여주는것은 SHAPE 지침이었으며, 이는 50% 이상의협착이동반된동맥경화반의유무에대한두지침의 ROC 분석을통해서도확인할수있다 (Fig. 3). 약물치료대상환자선정에서도유사한경향을보여동맥경화반이없어양호한예후가예상되는환자군에서 SHAPE 지침은 NCEP-ATP III에비해약물치료를권하는비율이절반이하였으며, 유의한협 착이동반된동맥경화반이있어적극적치료가필요할것으로예상되는환자군에서는 NCEP-ATP III에비하여약 2배의환자를약물치료군에포함하였다 (Fig. 4). 이러한결과는 NCEP-ATP III 지침이진행된무증상관상동맥질환환자의상당수를임상적지표들에기반하여과소평가하거나, 또는동맥경화의증거가없는환자들의상당수를고위험군으로분류, 위험도를과대평가한다는기존의연구결과와일치하며, 3)22) CACS 를이용한 SHAPE 지침이보다정확한위험군분류와약물치료대상선정에도움을줄가능성을보여주고있다. 하지만 SHAPE 지침을따르더라도관상동맥의유의한협착이발견된환자의 50% 만이고위험군및초고위험군으로분류되며, 약물치료대상에포함되는환자도 53% 에불과했다. 또한 MDCT 에서동맥경화반이발견된 768명중 179명

6 488 Primary Prevention of Coronary Heart Disease Sensitivity NCEP SHAPE AUC NECP 0.63 SHAPE Specificity Fig. 3. Receiver operating characteristics curves for the presence of the plaque with significant stenosis. Significant stenosis was defined as more than 50% luminal narrowing on MDCT. NCEP-ATP III: NCEP-ATP III risk stratification (AUC, 0.64; 95% confidence interval, ). SHAPE: SHAPE risk stratification (AUC, 0.84; 95% confidence interval, ). AUC: area under the curve, MDCT: multi-detector computed tomography, NCEP-ATP: National Cholesterol Education Program-Adult Treat- Ment Panel, SHAPE: Screening for Heart Attack Prevention and Education. % of individuals qualifying for pharmacotherapy p<0.001 p<0.001 p< No plaque Plaque without Plaque with significant significant stenosis* stenosis NCEP SHAPE Fig. 4. Proportion of individuals qualifying for pharmacotherapy according to NCEP-ATP III or SHAPE guideline across the severity of subclinical coronary atherosclerosis detected by MDCT. *Significant stenosis was defined as more than 50% luminal narrowing on MDCT, p was calculated for McNemar test, Numbers are percentage of individuals qualifying for pharmacotherapy according to each guideline. MDCT: multi-detector computed tomography, NCEP-ATP: National Cholesterol Education Program-Adult Treatment Panel, SHAPE: Screening for Heart Attack Prevention and Education. (23%) 에서는비석회화죽상판만존재했는데 (CACS=0), 이들은모두 SHAPE 지침분류상고위험군에서제외되며, 이중 7명 (4%) 만약물치료대상에포함되었다. 이런비석회화동맥경화반은, 이번연구에서전체관상동맥질환의 23% 를차지하였다. 최근 CACS 0인인구집단에서 MDCT 결과비석회화동맥경화반이발견된경우는 6~9% 로보고되고있는데, 23)24) 본연구에서 CACS 0인환자 1,474 명중비석회화동맥경화반의빈도는 179 명 (12%) 이었다. 기존보고에비해다소높은비석회화동맥경화반의빈도는동양인 (Asian) 의 CACS 가백인종 (Caucasian) 에비하여낮다는점과관련있겠으며, 특히최근한국인의 CACS 분포역시백인에비해낮다고보고되고있는바, 25)26) SHAPE 지침을한국인에게적용시켰을때심혈관계사건의위험도를저평가할가능성을시사하고있다. 또한유의미한관상동맥협착이발견된환자중 43% 나되는환자가두지침모두에서약물치료대상선정에서누락되고있다는점은두일차예방지침모두의문제로지적될수있겠으며, 좀더정확한위험군분류를기반으로한관상동맥질환일차예방지침이요구된다고하겠다. 본연구는자발적으로 MDCT 를촬영한무증상성인들을대상으로하였으나, MDCT 검사는조영제부작용, 과도한방사선노출 27) 에대한우려와비용-대비효과에대한연구가없어현재까지선별검사로추천되지않는다. SHAPE 지침은 CACS 측정을선별검사로권장하고있는데, CACS 측정은조영제를사용하지않을뿐아니라방사선노출과비용측면에서 MDCT 보다유리하다. 그러나무증상성인을대상으로일차적인선별검사로권장하기위해서는 SHAPE 지침의적용으로예상되는비용대비일차예방효과에대한전향적인추가연구가필요하다. 이번연구는횡단면적연구로서 MDCT 를통하여발견된관상동맥질환의이환, 진행여부를각지침이잘반영하고있는가를기준으로유용성을평가하였다. 두지침의유용성에대한엄격한비교는원칙적으로전향적무작위대조군임상시험이필요하며, 이는이번연구의제한점으로생각된다. 하지만, 전향적무작위대조군임상시험은장기간의추적관찰연구에수반될막대한비용이필요하며, 검사를통해병변이발견된환자에서치료를시행하지않고관찰하는것에대한윤리적문제가제기된다는점을고려한다면이번연구와같은횡단면적연구가현실적인대안이라고할수있겠다. 본 Table 4. Risk stratification and proportion of individuals qualifying pharmacotherapy according to each guideline in individuals with exclusively non-calcified plaque as a manifestation of CAD Guideline Occlusive plaque* (n=21) Non-occlusive plaque (n=158) Total (n=179) Classified as NCEP-ATP III (%) 3 (14) 25 (16) 28 (16) high or very high risk group SHAPE (%) 0 (0) 0 (0) 0 (0) Qualifying pharmacotherapy NCEP-ATP III (%) 1 (5) 36 (23) 37 (21) SHAPE (%) 0 (0) 7 (4) 7 (4) Data are expressed as number (%). *Occlusive plaque was defined as more than 50% luminal narrowing on maximum intensity projection images or multi-planar reconstruction images. CAD: coronary arterial disease, NCEP-ATP: National Cholesterol Education Program-Adult Treatment Panel, SHAPE: Screening for Heart Attack Prevention and Education

7 Youngjin Cho, et al. 489 연구의또다른제한점은연구대상환자가 SHAPE 지침에따른동맥경화선별검사의대상으로한정되어있다는점으로심혈관질환의병력을가지고있는환자나 75세이상, SHAPE 지침상초저위험군으로분류되는환자는제외되어있어본연구결과를일반화시킬때주의를요하겠다. 또한모두자발적으로선별검사에참여한사람들이란점에서선택비뚤림 (selection bias) 의가능성이있으며, 관상동맥질환위험인자및병력에대한자기보고식정보취합역시정확성을떨어뜨리는요소로작용했을수있다. 연구대상이모두한국인이라는점역시이연구의결과를일반화하는데문제가될수있다. 결론적으로 SHAPE 지침과 NCEP-ATP III 지침은관상동맥질환의위험군분류와그일차예방을위한약물치료대상의선정에서큰차이가있었으며, CACS 를이용한 SHAPE 지침이기존의 NCEP-ATP III 지침에비하여적은약물치료대상수에도불구하고보다정확한위험군분류를제공해줄가능성을보여주었다. 하지만이번연구의대상이 SHAPE 지침에따른동맥경화선별검사대상군에국한하였다는점에서연구결과를일반화하는데주의가필요하며, 비석회화동맥경화반의존재, 한국인의낮은 CACS 분포는 SHAPE 지침을국내환자에게적용하기앞서보완, 검토가필요한부분이라하겠다. 또한무증상성인을대상으로 CACS 를선별검사로이용하는것은위험성, 비용에대한고찰과함께전향적무작위대조군임상시험을통한검증이필요한부분이며, 어느지침을따르더라도관상동맥질환이발견된환자중상당수가약물치료대상군에서제외되고있어관상동맥질환에대한좀더정확한위험군분류법이필요할것으로보인다. 요약 배경및목적 NCEP-ATP III 지침은관상동맥질환의일차예방에널리쓰이는지침이다. CACS 가관상동맥질환발생예측에있어뛰어난예측인자가된다는보고를바탕으로 CACS 를바탕으로한일차예방전략인 SHAPE 지침이제안되었다. 본연구는무증상관상동맥질환환자들에서각지침들의적절성을살펴보고자한다. 방법건강검진의일환으로 CACS, CCTA 를포함한심장 CT를촬영한무증상한국성인 2,079 명 ( 연령 : 남자 45~75 세, 여자 55~75 세 ) 를대상으로하였다. 각지침에따른관상동맥질환예방대상환자군의차이를무증상관상동맥질환의유무를기준으로분석하였다. 결과 418명 (20%) 이 NCEP-ATP III 지침에따른치료대상군이었고, 371 명 (17.8%) 이 SHAPE 에따라치료대상군으로분류되었다 (Cohen s κ=0.36). SHAPE 지침에따랐을때, CCTA 에서유의한관상동맥질환 ( 50% luminal narrowing) 이발견된환자중더많은환자가고위험군혹은초고위험군으로분류되었으며 (50% vs. 24%, p<0.001), 더많은환자가치료대상군에포함되었다 (53% vs. 28%, p<0.001). 하지만유의한관상동맥질환이발견된사람중 57명 (43%) 은두지침중어느지침에서도약물치료대상에포함되지못했다. 결론 NCEP-ATP III 지침과 SHAPE 지침을비교하였을때, 관상동맥발생위험군분류와치료대상군에상당한차이를보였다. 무증상관상동맥질환의유무에따른분석은 SHAPE 지침이 NCEP-ATP III 지침보다정확한관상동맥질환위험군분류와치료대상선정에도움이될가능성을보였으나, 보다정확한위험군분류법이필요할것으로생각된다. 중심단어 : 관상동맥질환 ; 일차예방 ; 지침. Acknowledgments 본논문은통계분석단계에서서울대학교병원의학연구협력센터의도움을받았기에감사를표합니다. 본논문은 2008 년분당서울대학교병원신진연구비의지원으로수행되었습니다. REFERENCES 1) Myerburg RJ, Interian A Jr, Mitrani RM, Kessler KM, Castellanos A. Frequency of sudden cardiac death and profiles of risk. Am J Cardiol 1997;80:10F-9F. 2) National Cholesterol Education Program (NCEP-ATP III) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Third Report of the National Cholesterol Education Program (NCEP-ATP III) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106: ) Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41: ) Nasir K, Michos ED, Blumenthal RS, Raggi P. Detection of highrisk young adults and women by coronary calcium and National Cholesterol Education Program Panel III guidelines. J Am Coll Cardiol 2005;46: ) Brindle P, Beswick A, Fahey T, Ebrahim S. Accuracy and impact of risk assessment in the primary prevention of cardiovascular disease: a systematic review. Heart 2006;92: ) Wong ND, Hsu JC, Detrano RC, Diamond G, Eisenberg H, Gardin JM. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol 2000;86: ) Raggi P, Cooil B, Callister TQ. Use of electron beam tomography data to develop models for prediction of hard coronary events. Am Heart J 2001;141: ) Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291: ) Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. Arch Intern Med 2004;164:

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