Original ORIGINAL Article ARTICLE Korean Circulation J 2006;36:600-604( 단축X) ISSN 1738-5520 c 2006, The Korean Society of Circulation 동일인에삽입된 Sirolimius-Eluting(Cypher ) Stent 와 Paclitaxel-Eluting(Taxus ) Stent 의단기조영술성적비교 동아대학교의과대학내과학교실, 1 심혈관연구소 2 박민아 1 유정남 1 임태형 1 유현승 1 윤현아 1 구정모 1 이수이 1 백정환 1 김경호 1 한진 1 박태호 1 차광수 1 김무현 1 김영대 1,2 Comparisons of the Short-Term Angiographic Outcomes of Cypher and Taxus Stents Implanted in the Same Patient Min-A Park, MD 1, Jung Nam Ryu, MD 1, Tae Hyung Lim, MD 1, Hyun Seung Yoo, MD 1, Hyun Ah Yoon, MD 1, Jeong Mo Koo, MD 1, Sue Ee Lee, MD 1, Jeung Hoan Paik, MD 1, Kyung Ho Kim, MD 1, Jin Han, MD 1, Tae Ho Park, MD 1, Kwang Soo Cha, MD 1, Moo Hyun Kim, MD 1 and Young Dae Kim, MD 1,2 1 Department of Internal Medicine and 2 Cardiovascular Research Institute, Dong-A University College of Medicine, Busan, Korea ABSTRACT Background and Objectives:Drug-eluting stents (DES) have been shown to substantially reduce both angiographic and clinical restenosis. Cypher (sirolimus-eluting stent, Cordis, Johnson and Johnson, Florida, USA) and Taxus (paclitaxel-eluting stent, Boston Scientific, Boston, USA) are the two most widely used DESs, and they both have distinct pharmacological properties and release kinetics. It has been not studied whether these two DESs show different angiographic outcomes when they are simultaneously implanted in the same patient. Subjects and Methods:We retrospectively analyzed the angiographic findings of the short-term follow-up in 34 patients (average age: 63 year old, 9 women) in whom both Cypher and Taxus stents were implanted at the same time for the treatment of obstructive coronary lesion. Results:There was no significant difference in the basal angiographic characteristics of the lesions that had two stents deployed in terms of the AHA/ACC classification, reference diameter, the percent diameter stenosis and minimal luminal diameter. The post-procedure results were similar between the two stents. At 6 months follow-up, the Cypher stent displayed significantly less in-stent lumen loss compared with the Taxus stent (0.16±0.04 mm vs 0.27±0.04 mm; respectively, p=0.040) and a smaller percent diameter stenosis (15.9±1.3% vs 19.9±2.2%, respectively, p=0.049). Conclusion:The Cypher stent showed significantly less luminal loss during short term follow-up compared with the Taxus stent when implanted in the same patient. This result suggests that in a given individual patient, the Cypher stent induces less neointimal proliferation than does the Taxus stent. (Korean Circulation J 2006;36:600-604) KEY WORDS:Sirolimus;Paclitaxel;Coronary restenosis. 서 약물용출스텐트 (Drug-eluting stent; DES) 는관상동맥 론 병변부위에항증식효과가있는약제 (antiproliferative agents) 를국소적으로도입함으로써일반금속스텐트 (bare metal stent; BMS) 사용시가장큰단점으로알려진재협착 논문접수일 :2006 년 6 월 30 일심사완료일 :2006 년 7 월 31 일교신저자 : 김영대, 602-715 부산광역시서구동대신동 3 가 1 동아대학교의과대학내과학교실전화 :(051) 240-5040 전송 :(051) 242-5852 E-mail:kimyd@mail.donga.ac.kr 600
Min-A Park, et al:ses and PES in the Same Patient 601 발생을효과적으로감소시켰다. 1)2) 현재임상에서가장널리사용되고있는상용제폼인 Cypher 와 Taxus 스텐트는각각 polymer 에약물을함유시켜일정기간 sirolmus 와 paclitaxel 이라는항증식약제가유리되도록고안된것으로서 BMS 에비해서조영술에서의재협착율과임상에서의병변재시술율 (target lesion revascularization; TLR) 을현저하게줄이는것으로나타났으며단기간안전성면에서는두스텐트모두양호한것으로나타났다. 3-6) 그러나, Cypher 와 Taxus 가 BMS 에대비하여전체적으로유사한효과를보고하고있지만각각의 stent 는용출약물의성상과스텐트구조, polymer 배치, 약물용출의역동면에서상이한특징을지니고있다. 7)8) 따라서각종관상동맥환자들을대상으로한중재시술에서이두가지스텐트의효능을비교한임상연구가최근수년에걸쳐발표되었다. 9) 종합적으로이들연구에서 Cyper 스텐트는 Taxus 에비해서스텐트부위내강의후기소실 (luminal late loss) 이상대적으로작게나타났으며 9-13) 연구에따라서이같은결과가전체재협착율이나병변재시술율의감소와같은임상적인차이로이어질수있는것으로보고되었다. 10)11) 그러나이들연구는두스텐트가각각다른환자들에삽입된경우를대상으로한것으로서동일한환자에삽입된 Cypher 와 Taxus 의효과를비교한연구는보고된바가없다. 동일인에서의양스텐트의비교는각개인의생물학적인변이를배제하여스텐트차이점을보다객관적으로관찰할수있는기회를제공한다. 그러므로본연구는관상동맥협착치료를위해서동일인에서두스텐트가동시에삽입된경우를대상으로단기간의조영술추적소견을측정하여이들간의차이를분석하고자하였다. 대상및방법 대상 2004 년 4월 7일부터 2005 년 1월 14일까지급성심근경색증, 불안정형협심증, 혹은안정형협심증으로입원하여관상동맥중재술을받았던환자로서복수의협착병변치료를위해 Cypher 와 Taxus 스텐트가동시에삽입된경우를대상으로하였다. 이들중단기조영술분석을위해시술후 6 개월이후에추적조영술이시행된 34명의환자를선정하였다. 대상환자모두는시술전하루 aspirin 100 mg 와 clopidogrel 75 mg의유지량을복용하거나그렇지않은경우급성으로 aspirin 325 mg과 clopidogrel 300 mg을단기에복용하였으며시술이후는유지량으로하루 aspirin 100 mg 과 clopidogrel 75 mg을추적조영술시행까지계속복용하였다. 시술전의 heparin 혹은 glycoprotein IIb/IIIa 차단제사용과그밖의심장약물투여는담당의의판단에의해결정되었다. 경피적관상동맥중재술은표준방식에따라시행되었으며시술후잔여협착이 20% 이하이면서입원기간중주 요심혈관합병 ( 사망, 심근경색발생, 관상동맥중재술의재시술, 응급관상동맥우회술, 스텐트혈전발생 ) 이발생하지않은경우를성공적인시술로간주하였다. 스텐트의선정은시술자의판단에의해서결정되었다. 추적관상동맥조영술은스텐트시술 6개월후부터 9개월이전시기에시행하였다. 방법각환자에서관상동맥위험인자를비롯한각종임상특성을조사하였으며스텐트가삽입된관상동맥병변의조영술상특성을구별하기위해서 American Heart Association/ American College of Cardiology(AHA/ACC) 분류법을 14) 이용하였다. 관상동맥조영상은디지털방식으로기록되었다. 관상동맥병변의정량적측정 (quantitative coronary angiogram; QCA) 은시술결과를알지못하는제3의분석자가실시하였으며, Phillips(Netherland) 사의 Allular 디지털정량분석프로그램에장착된자동경계탐지방식 (automated edge detection system) 에의거하여측정하였다. 정량적관상동맥병변측정의항목은기준혈관내경 (reference diameter; RD), 최소혈관내경 (minimal luminal diameter; MLD), 병변길이 (lesion length), 내경협착백분율 (percent diameter stenosis; % DS: (RD-MLD)/RD 100), 및후기내경소실 (late lumen loss; LL: MLD after stenting-mld at follow-up) 을포함하였다. 이분법적인재협착 (binary restenosis) 은추적시삽입된스텐트내혹은근위부와원위부 5 mm까지의내경협착백분율이 50% 이상인것으로정의하였다. 통계분석연속형변수는모두평균 ± 표준편차로표시하였다. 스텐트종류에따른조영술소견의연속형변수의비교는 Student s t test 를, 범주형변수의비교는 chi-square test 를이용하였다. 통계치는 p값이 0.05 미만인경우를유의한것으로판정하였다. 결과 대상환자의특징 (Table 1) 대상환자는 34 명으로서남자 25명여자 9명이었으며평균연령은 63세이었다. 임상진단은급성심근경색증 11명, 불안정형협심증 23명, 안정형협심증 1명이었으며동반된위험인자는고혈압 23명 (65.7%), 당뇨병 20명 (57.1%), 고콜레스테롤혈증 13명 (37.1%), 흡연 16명 (45.7%) 이었다. 기저관상동맥병변의특성 (Table 2) 기저관상동맥조영술에서 Cypher 스텐트가삽입된혈관은좌전하행지가 19, 좌회선동맥 10, 우관상동맥 5곳이었으며 Taxus 스텐트가삽입된혈관은각각 8, 9, 17곳으로서
602 Korean Circulation J 2006;36:600-604 Cypher 는주로좌전하행지에 Taxus 는주로우관상동맥에주로삽입되었다 ( χ 2 =10.71, p<0.005). 그러나병변의 AHA/ ACC 분류유형은 Cypher 스텐트와 Taxus 스텐트삽입혈관의분포가유사하였으며 ( χ 2 =1.66, p=0.647), B2/C 유형 즉난이도가높은병변의비율은각각 76.4%, 67.6% 로서양군모두 2/3 이상을차지하였다. 또한시술전혈관의기준내경 (RD), 병변의최소혈관내경 (MLD), 병변길이, 내경협착백분 (% DS) 은모두양군간유의한차이가없었다. Table 1. Clinical characteristics of the subjects Characteristics Total (n=34) Age (years) 63 (43-75) Sex (Male/Female) 25/9 Clinical diagnosis Acute myocardial infarction 11 Unstable angina 22 Stable angina 01 Risk factor Hypertension 22 (65.7%) Diabetes mellitus 19 (57.1%) Hypercholesterolemia 12 (37.1%) Smoking 05 (45.7%) Echocardiographic ejection fraction 55±12% 시술직후및추적관상동맥조영술소견 (Table 3) 스텐트삽입시술후시행한관상동맥조영술에서병변의내경은시술전에비해양군모두성공적으로늘어났으며 Cypher 스텐트와 Taxus 스텐트사이에병변부위의최소혈관내경 (2.40±0.06 mm vs 2.40±0.07 mm, p=0.956) 과내경협착백분율은 (9.6±1.0% vs 8.4±1.2%, p=0.567) 양군간통계적으로유의한차이가없었다. 추적관상동맥조영술은스텐트시술후평균 201 일후시행되었다. 추적관상동맥조영술에서측정한병변의최소내경은 Cyper 스텐트와 Taxus 스텐트에서각각 2.23±0.06 mm 와 2.12±0.07 mm 로서통계적으로유의한차이는없었다 (p=0.21). 그러나후기내경소실은 Cyper 스텐트가 Taxus 에비해서유의하게작게나타났으며 (0.17±0.03 mm vs 0.27±0.04 mm; Table 2. Basal angiographic characteristics of lesions Characteristic SES (Cypher) PES (Taxus) Statistic value p Involved vessel χ 2 =10.7 0.004 LAD 19 18 LCX 10 19 RCA 15 17 Complexity of lesion χ 2 =1.66 0.647 A 13 12 B1 15 19 B2 18 17 C 18 16 QCA value of lesion Reference vessel diameter (mm) 2.62±0.63 2.67±0.31 t=-0.85 0.404 Lesion length (mm) 17.21 ±4.84 17.18 ±6.01 t=0.02 0.982 MLD (mm) 0.57±0.32 0.54±0.39 t=0.33 0.714 Diameter stenosis (%) 77.1±12.2 78.9±12.2 t=-0.19 0.560 Size and length of stent Stent size (mm) 2.79±0.23 2.80±0.32 t=-0.22 0.831 Stent length (mm) 21.97 ±4.23 20.24±5.21 t=1.66 0.107 SES: sirolimus-eluting stent, PES: paclitaxel-eluting stent, LAD: left anterior descending artery, LCX: left circumflex artery, RCA: right coronary artery, QCA: quantitative coronary angiography, MLD: minimal luminal diameter Table 3. Angiographic results, immediate post-procedure and 6 months follow up Immediate post-procedure Variable SES (Cypher) PES (Taxus) t value p Diameter stenosis (%) 9.6±5.6 8.4±7.2 0.54 0.567 MLD (mm) 2.39±0.34 2.40±0.39 0.06 0.954 Follow-up Diameter stenosis (%) 15.9±7.37 19.9±12.7-2.04 0.049 MLD (mm) 2.23±0.36 2.12±0.42 1.27 0.213 Late loss (mm) 0.16±0.17 0.27±0.22-2.14 0.040 SES: sirolimus-eluting stent, PES: paclitaxel-eluting stent, MLD: minimal luminal diameter
Min-A Park, et al:ses and PES in the Same Patient 603 p=0.040), 내경협착백분율도 Cypher 스텐트에서보다작은것으로나타났다 (15.9±1.3% vs 19.9±2.2%, p=0.049). 이분법적인재협착은 Cypher 스텐트군에서는관찰되지않았고, Taxus 군에서는 1명이발견되었다. 고 약물용출스텐트의임상도입은기존의금속스텐트의문제점으로남아있던내막증식에의한재협착을효과적으로감소시킴으로써경피적관상동맥중재술분야에서중요한진전을이룩하였다. 1)2)15) 약물용출스텐트에주로사용되는약제는 sirolimus 와 paclitaxel 로서혈관내평활근세포의증식을억제함으로써내막증식을최소화하는공통적인특징을가지고있으며이들약제를용출하는스텐트는일반금속스텐트에비해현저히개선된재협착율을나타내었다. 3-6)16) 그러나 sirolimus 와 paclitaxel 을도포한스텐트인 Cypher 와 Taxus 는여러가지면에서서로다른특성을가지고있다. 7)8) 근간이되는스텐트는각각기존의상용제품 (BX VELO- CITY, NIR III 혹은 EXPRESS 2) 으로서디자인과유연성이다르며, 7) 약물을저장하는 polymer 의성분과유형도상이하여약물이방출되는시간적인역동학 (kinetics) 도다르다. 17) 또한도포약제의약물학적성상은두제품차이를규정하는중요한요소로서, sirolimus 는세포주기 (cell cycle) 의초기인 G1 시기를차단하지만 18) paclitaxel 은유사분열 (M phase) 시기를차단함으로써세포의증식을억제한다. 19) 이결과 sirolimus 는세포억지작용 (cytostatic) 을보이는반면 20) paclitaxel 은세포독성 (cytotoxic) 작용을나타낸다. 21) 그리고 paclitaxel 과는달리 sirolimus 는 interleukin-6 과같은시토카인을감소시켜서항염증작용을발휘하는특징을가지고있다. 22) 국소독성 (local toxicity) 면에서 paclitaxel 은 sirolimus 보다치료가능영역 (therapeutic window) 가작으며상대적으로작은양에서혈관조직의괴사를초래할수있다. 23) 이러한특성의상이점은스텐트가실제환자에사용될때의각종성적차이로나타날수있다. 각각의약물스텐트의특성이궁극적으로그차이를드러내는것은시술후나타나는혈관의신생내막증식으로서이는혈관조영술에서후기내강소실 (late lumen loss) 로가장잘반영된다. 24) 이를관찰한다수의임상연구는분석에서 Cypher 스텐트가 Taxus 스텐트에비해서후기내강소실이작음을보고하고있다. 9-14) Sirolimus 용출스텐트를일반금속스텐트와비교한연구들을종합한분석에서 Cypher 스텐트의후기소실은 0.18 mm이었으며 25) 이는 TAXUS IV 연구에서 26) 나타난 Taxus 스텐트의 0.39 mm에비해유의하게작은수치이다. 이같은차이는긴병변이나 27)28) 복잡병변, 29) 그리고작은혈관의병변에서도 30) 관찰되었다. 후기내강소실의감소는연구에따라서는재시술율의감소와같은임상적인차이로나타나기도하였으나 9-11) 최근의 REALITY 연구에서는 13) 임상적 찰 인차이로귀결되지는않았다. 그러나이제까지의비교연구에서는각스텐트가서로다른사람에삽입되었으며이러한방식은무작위선정을한다고하더라도사람마다다른생물학적조건을완전하게통제할수는없다. 동일인에서삽입된약물용출스텐트의비교는개인간의생물학적변이를배제하여제품의차이를보다객관적으로관찰할기회를제공한다. 본연구에서양제품을동일인의관상동맥혈관에같이사용하였을경우에도 Cypher 스텐트는 Taxus 스텐트에비해단기추적시의내경소실이유의하게작은것으로나타났다. Cypher 스텐트의후기내경소실은평균 0.17 mm로서 SIRIUS 연구의결과와일치하며. Taxus 스텐트의경우내경소실은 0.27 mm로서 TAXUS Ⅳ 연구의 28) 0.35 mm 보다는작으나 SIRTAX 연구의 10) 0.25 mm에상응하였다. 또한내경협착백분율역시 Cypher 스텐트가 15.9% 로서 Taxus 스텐트의 19.9% 보다유의하게작게나타나앞서발표된 SIRTAX 10) 나 REALITY 13) 와동등한결과를보였다. 본연구의대상이적은수였음에도단기간의추적조영술분석에서유의한차이가나타난것은동일인의혈관에서각스텐트의약물효과가신생내막증식을억제함에있어서실질적인효능차이가있음을시사한다. 본연구의제한점은후향적인연구로서병변에따른스텐트선정이시술당시에시술자의선택에의해서이루어짐으로해서스텐트가삽입된혈관부위가양군에서균일하지않았다는점이다. 그결과 Cypher 스텐트는전체 34곳중 19 군데가좌전하행지에삽입되었으며 Taxus 스텐트는 17군데가우관상동맥에삽입되어양군간분포에유의한차이가있었다. 비록대상병변의 AHA 분류유형, 병변길이, 기준혈관내경면에서양군간에차이는없어병변특성은유사하였지만, 혈관분포나위치에따른변이는편의 (bias) 의소지를제공할수있다. 또한대상수가적어서조영술상에나타난차이가임상결과로연계되는지의여부를분석할수도없었다. 향후보다광범위한수를대상으로한전향적인연구가이러한문제를해결할수있을것으로사료된다. 요약 배경및목적 : 약물용출스텐트의사용은일반금속스텐트의단점인재협착율문제를효과적으로감소시켰다. 가장널리쓰이는약물용출스텐트인 sirolimius-eluting(cypher ) stent 와 paclitaxel-eluting(taxus ) stent 는여러임상연구를통하여조영술상의성적에차이가있음이보고되었으나동일인에서두스텐트가동시에삽입된경우에이를비교한연구는없었다. 방법 : 복수의관상동맥협착병변을치료하기위해서 Cypher 와 Taxus 스텐트를동시에삽입하였던 34명의환자 ( 남 25명,
604 Korean Circulation J 2006;36:600-604 여 9명, 평균나이 63세 ) 를대상으로하였다. 시술전후와 6개월이후에시행된추적기간에시행된정량적관상동맥조영술을통하여시술병변을후향적으로분석하였다. 결과 : Cypher 와 Taxus 스텐트는각각좌전하행지와우관상동맥에절반이상이삽입되었으나병변의특성은 AHA/ACC 분류, 병변길이, 기준혈관내경면에서양군에서유사하였으며시술직후의혈관최소내경도차이가없었다. 6개월이후에시행된추적조영술에서 Cypher 스텐트는 Taxus 스텐트에비해후기내경소실이유의하게작았으며 (0.16±0.029 mm vs 0.27±0.039 mm; p=0.040), 내경협착백분율도유의하게작았다 (15.9±1.26% vs 19.9±2.18%, p=0.049). 결론 : 본연구의결과동일인의관상동맥병변에삽입된경우에 Cypher 스텐트는 Taxus 스텐트에비해서후기내경소실이유의하게작았으며, 이는병변의신생내막증식억제에서 Cypher 스텐트가 Taxus 에비해보다효과적임을시사한다. 중심단어 :Sirolimus;Paclitaxel; 재협착. REFERENCES 1) Hill RA, Dundar Y, Bakhai A, Dickson R, Walley T. Drug-eluting stents: an early systematic review to inform policy. Eur Heart J 2004;25:902-19. 2) Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomized clinical trials of drug-eluting stents. Lancet 2004;364:583-91. 3) Morice MC, Serruys PW, Sousa JE, et al. 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