Original ORIGINAL Article ARTICLE Korean Circulation J 2006;36:121-125 ISSN 1738-5520 c 2006, The Korean Society of Circulation 스텐트내재협착에시행한 Sirolimus 약물방출스텐트삽입의임상적결과 : 관상동맥조영술에의한정량적연구 건양대학교의과대학심장내과학교실 유기현 배장호 김기영 현대우 Clinical Outcomes of Using Sirolimus-Eluting Stents for Treating In-Stent Restenosis: A Quantitative Coronary Angiography Study Ki-Hyun Ryu, MD, Jang-Ho Bae, MD, Ki-Young Kim, MD and Dae-Woo Hyun, MD Division of Cardiology, Heart Center, College of Medicine, Konyang University, Daejeon, Korea ABSTRACT Background and Objectives:There is little clinical data on the results of using Sirolimus-Eluting Stent (SES) for treating In-Stent Restenosis (ISR). We performed this study to evaluate the clinical outcomes for implanting SES for treating ISR in a real world hospital environment. Subjects and Methods:A total of 30 patients with 32 ISRs (males: 73.3%, mean age: 60.2) (focal lesions: 21.9%, diffuse intra-stent lesions: 34.4%, proliferative lesions: 21.9%, total occlusions: 21.9%) were treated with SES after balloon predilation was performed. We evaluated the clinical results and the performed coronary angiography after 6 months. Results:All the procedures were successful. The mean SES diameter and length were 3.0±0.3 mm and 27.1±5.5 mm, respectively, and the mean acute gain was 2.42±0.38 mm. No in-hospital major adverse cardiac events (MACE) were observed. Twenty five patients with 27 lesions (84.4%) underwent coronary angiography at their 6 month follow-up. The late loss and loss index were 0.41±0.56 mm and 0.18±0.22, respectively. The binary restenosis rate was 7.4% (2/27 lesions). The rate of target lesion revascularization was 3.7% (1/27 lesion). The incidence of MACE at 6 months was 3.3% (1/30 patient). Conclusion:Treating ISR with SES is a safe and effective procedure for reducing ISR without the occurrence of acute or sub-acute thrombosis. (Korean Circulation J 2006;36:121-125) KEY WORDS:Coronary artery disease;coronary restenosis;stents. 서 관상동맥스텐트삽입술은경피적관상동맥성형술 (percutaneous transluminal coronary angioplasty, PTCA) 의 80% 이상에서시행되고있으며이는단순한풍선확장술에비해임상적인면이나관상동맥조영술상으로재협착을현저히줄 논문접수일 :2005 년 17 월 22 일수정논문접수일 :2005 년 9 월 20 일심사완료일 :2005 년 12 월 13 일교신저자 : 배장호, 302-718 대전광역시서구가수원동 685 건양대학교의과대학심장내과학교실전화 :(042) 600-6400 전송 :(042) 600-6399 E-mail:jhbae@kyuh.co.kr 론 여주고있다. 1) 관상동맥에스텐트삽입후발생하는재협착은스텐트내재협착이대부분을차지하며그발생빈도는약 20~40% 정도로보고되고있다. 2) 최근약물방출스텐트의등장이후스텐트내재협착의비율을 10% 미만으로낮추고있으나완전히없애지는못하고있다. 3-5) 스텐트내재협착에대한치료로는풍선성형술, cutting balloon 성형술, 죽상반회전절제술 (rotational atherectomy) 및방향절제술 (directional coronary atherectomy), 관상동맥내국소방사선조사요법, 단순스텐트나약물방출스텐트재삽입등의다양한방법이사용된다. 그동안의무작위적임상연구에의하면스텐트내재협착의치료는관상동맥내국소방사선조사요법 (brachytherapy) 이효과적인것으로알려져왔으나치료에있어서상당한장비및방사물리학적지원이필요하고우려할 121
122 Korean Circulation J 2006;36:121-125 정도의부작용이관찰됨으로써실제임상적치료에있어한계를가지고있었다. 6) 그에비해최근의연구들은스텐트내재협착에대한치료로써 Sirolimus, Paclitaxel 등의약물방출스텐트의삽입을그러한국소방사선요법의단점을극복하면서스텐트내재협착에대한치료효과를향상시킬수있는치료법으로제시하고있다. 본연구는스텐트내재협착의치료에있어 Sirolimus 약물방출스텐트 (Sirolimus Eluting Stent, SES) 의유용성과안정성에대해정량적관상동맥조영술및임상적결과를통해평가하였다. 대상및방법 결과 임상적특성 (Table 1) 총 30명의환자를대상으로하였고, 평균연령은 60.2± 9.4 세였으며, 성별은남자가 22 명 (73.3%) 이었다. 위험인자로고혈압을가지고있는환자가 24 명 (80.0%), 당뇨 12 명 (40.0%), 흡연력 12명 (40.0%), 이상지질혈증 23명 (76.7%) 이었다. 이전일반스텐트삽입시급성심근경색으로진단을받았던환자는 19명 (63.3%) 이었다. 스텐트내재협착당시의진단으로안정형협심증은 22 명 (73.3%), 불안정형협심증은 4명 (13.3%), 급성심근경색증은 4명 (13.3%) 이었다. 본연구의대상은일반금속스텐트를이용한관상동맥성형술이후 QCA(quantitative coronary angiography) 상 50% 이상의스텐트내재협착이발생한환자중 70% 이상의재협착이관찰되어재개통을시행하여성공적인결과를얻은환자를대상으로하였다. 재개통시의성공적인결과는시술직후 Thrombolysis In Myocardial Infarction(TIMI 7) ) grade 3 flow 의회복과잔여협착이 30% 미만인것으로하였다. 스텐트내재협착은과거스텐트를삽입한부위에급성혹은아급성의혈전증이없이 50% 이상의내경감소가정량적관상동맥조영술에의해관찰된것으로정의하였다. 정량적관상동맥조영술은 CAAS-I(Cardiovascular Angiography Analysis System; Pie Medical Imaging, Netherlands) 를이용하여수행되었고, 국소마취후우측대퇴동맥을 Seldinger 씨방법으로천자하거나, 요골동맥을통하여동맥 sheath 를삽입하였다. 관상동맥조영술을실시하여 70% 이상의스텐트내재협착이관찰되는경우 Sirolimus 약물방출스텐트 (Cypher, Cordis, Miami, USA) 를삽입하였다. 목표병변에대한관상동맥성형술은성형술전아스피린, clopidogrel 을경구투여하고헤파린을정맥주사하는등표준적인방법을사용하였다. 이후 6개월추적관상동맥조영술을시행하였다. 시술전과시술후, 6개월추적검사에서최소혈관직경 (minimal luminal diameter, MLD) 과기준혈관직경 (reference diameter, RD), 협착정도를측정하였으며직경의기록은관상동맥조영시혈관직경이가장좁아보이는방향을기준으로하여기록하였다. 관상동맥조영술상성공적인결과는 6개월추적검사에서스텐트내재협착이 50% 미만인것으로정의하였다. 임상적으로성공적인결과는관상동맥조영술상성공적인결과와함께주요심장사건 (Major Adverse Cardiac Event) 이없는것으로정의하였고, 주요심장사건이라함은사망, 급성심근경색증, 목표병변재개통 (TLR; Target Lesion Revascularization) 을시행한경우로정의하였다. 검사실소견대상환자들의공복시혈당은 176±121 mg/dl, 총콜레스테롤 148±31 mg/dl, 중성지방 165±80 mg/dl, 고밀도지질단백 38.8±9.1 mg/dl, 저밀도지질단백 84.6±24.2 mg/ dl, 호모시스테인 9.8±3.6(mol/L, Hs-CRP 0.22±0.30 mg/dl 였다. 초음파를이용하여측정한좌심실구혈률은평균 62.5±11.9% 였다. 연구대상의특성 (Table 2) 총병변의수는 32 개였고 50% 이상의협착이보이는병변혈관의숫자에따라단일혈관질환 20예 (66.7%), 두혈관질환 6예 (20.0%), 세혈관질환 4예 (13.3%) 이었다. 목표병변의위치는좌주간부 1예 (3.1%), 좌전하행동맥 17예 (53.1%), 좌회선동맥 7예 (21.9%), 우관상동맥 7예 (21.9%) 였다. Mehran 분류 8) 에의한재협착병변은 Ⅰ형 (focal) 7예 (21.9%), Ⅱ형 (diffuse) 11예 (34.4%), Ⅲ형 (proliferative) 7예 (21.9%), Ⅳ 형 (total occlusion) 7예 (21.9%) 였다. 병변의길이는평균 23.9±12.7 mm였고, 목표병변내에 1개의스텐트를삽입한경우가 26예 (81.3%), 2개의스텐트를삽입한경우가 6예 (18.8%) 이었다. Table 1. Baseline clinical characteristics Variable Number (%) Patients 30 Age (years) 60.2±9.4 Male 22 (73.3) Risk factors Hypertension 24 (80.0) Diabetes 12 (40.0) Smoking 12 (40.0) Dyslipidemia 23 (76.7) Diagnosis Stable angina 22 (73.3) Unstable angina 04 (13.3) Acute myocardial infarction 04 (13.3) Previous myocardial infarction 19 (63.3)
Ki-Hyun Ryu, et al:usefulness of Sirolimus-Eluting Stent for In-Stent Restenosis 123 Table 2. Lesion characteristics Variable No (%) No of target lesion 32 No of coronary vessel 50% stenosed 1 20 (66.7) 2 06 (20.0) 3 04 (13.3) Treated vessel Left main 01 (03.1) Left anterior descending 17 (53.1) Left circumflex 07 (21.9) Right coronary artery 07 (21.9) In-stent restenosis type Focal 07 (21.9) Diffuse intra-stent 11 (34.4) Proliferative 07 (21.9) Total occlusion 07 (21.9) Lesion length (mm) 23.9±12.7 Previous implanted stent Diameter (mm) 03.1±0.40 Length (mm) 24.9±7.50 Implanted SES Diameter (mm) 03.0±0.30 Length (mm) 27.1±5.50 Maximal inflation pressure (atm) 15.5±1.70 Binary in-stent restenosis of SES (%) 7.4 No: number, SES: sirolimus eluting stent 관상동맥조영술상결과 재협착에대한스텐트삽입시총병변 32 부위에서기준혈관내경이 2.90±0.40 mm, 최소혈관내경이 0.32±0.25 mm, 이전에사용한일반스텐트삽입시의스텐트내경과길이는각각 3.1±0.4 mm, 24.9±7.5 mm 였고, 병변길이는 23.9± 12.7 mm 였다. 스텐트내재협착의치료로사용한 Sirolimus 약물방출스텐트직경과길이는각각 3.0±0.3 mm, 27.1± 5.5 mm 였고, 최대팽창압은 15.5±1.7 기압이었고, 스텐트중복은 4예 (12.5%) 에서시행되었다. 스텐트삽입후임상적으로모든환자를추적관찰하였고 6개월후시행한관상동맥조영술을통한추적관찰은 30 명의환자중 25명에서시행되었고, 32개의예중 27예 (84.4%) 에서시행되었다. 기준혈관직경은시술직후 2.97±0.33 mm, 6개월추적검사에서는 2.99±0.34 mm이었고, 최소혈관직경은시술전 0.32±0.25 mm 시술직후 2.74±0.30 mm 이였고초기획득 (acute gain) 은 2.42±0.38 mm였다. 6개월추적검사시 2.32±0.66 mm였다. 6개월추적관상동맥조영술후측정한최소혈관직경과관상동맥중재시술후의최소혈관직경의차이를나타내는후기손실 (late loss) 은 0.41± 0.56 mm, 중재술전후의최소혈관직경의차이 (acute gain) 와 late loss 사이비율인 loss index 의값은 0.18±0.22 이었다 (Table 3). 6개월추적관상동맥조영술상 2예 (7.4%) 에서 Table 3. Quantitative coronary angiographic analysis Parameters Preprocedure Postprocudure Follow-up RD (mm) 02.90±0.400 2.97±0.33 02.99±0.340 MLD (mm) 00.32±0.250 2.74±0.30 02.32±0.660 DS (%) 88.72±8.990 7.42±7.92 22.70±19.38 Lesion length (mm) 023.9±12.73 Late loss (mm) 00.41±0.560 Loss index 00.18±0.220 RD: reference diameter, MLD: minimal luminal diameter, DS: diameter stenosis 재협착이발생되었고, 그중 1예에서는관상동맥조영술상스텐트내근위부가장자리에 89% 의협착소견을보여 cutting balloon 을이용하여재개통이시행되었으며, 다른 1예에서는 55% 의스텐트내협착소견을보여약물요법시행후추적관찰중이다. 임상적결과모든환자에서성공적으로 SES 를시술하였으며병원내임상경과는양호하였고시술과관련된주요심장사건과혈관합병증은없었다. 6개월간임상적인경과관찰중주요심장사건은사망이나심근경색증은발생하지않았고. 1예 (3.3%) 에서추적관상동맥조영술후목표병변재개통을시행하였다. 고 본연구는그동안여러연구에서언급되어진바와같이 Sirolimus 약물방출스텐트가스텐트내재협착방지에긍정적인작용을한다는이론에근거하여스텐트내재협착병변에대한치료에있어서도그유용성과안정성이있음을임상연구에서직접확인하였다는데그의의가있다. 몇몇무작위연구에의하여스텐트내재협착병변에대한치료로서국소방사선조사요법이다시발생하는재협착을억제하고, 주요심장사건을줄이는데효과적인것으로알려져있었지만, 9)10) 후기혈전증, 11) 치유지연, 12) black hole 현상, 13) geographic miss 14) 등의부작용이관찰되었다. Saia 등 15) 은 43 명의관상동맥내국소방사선조사요법 (Vascular Brachytherapy; VBT) 시행군과 44명의 Sirolimus 약물방출스텐트삽입술시행군을 9개월동안임상적으로추적하였고결과적으로주요심장사건없이생존할확률은두군에서큰차이가없었으며 (79.1% VBT vs. 81.5% SES), Sirolimus 약물방출스텐트가기술적인면에서간단하여효용성이더높은것으로기술하였다. Sirolimus 또는 Rapamycin 은천연 macrocyclic lactone 으로면역억제제이며이는세포내수용체단백질 (FK506 결합단백 12) 과그복합체에결합하여세포분화의중요한역할을하는 mammalian target of rapamycin (mtor) 16) 이라고불리는효소를억제함으로써세포분화를후기 G1 기에멈추게하고횡문근의증식을억제하게된다. 17)18) 찰
124 Korean Circulation J 2006;36:121-125 Degertekin 등 19) 은 Sirolimus 약물방출스텐트가재협착을예방함에있어 de novo 병변 (n=45) 과스텐트내재협착병변 (n=41) 에동일한효과를나타냄을관상동맥내초음파추적검사를통해관찰하였다. 다른약물방출스텐트로는 paclitaxel-eluting stents (TAXUS NIRx TM, Boston Scientific Corporation), QuaDS- QP2 stent(quanum Medical Corporation), everolimus(guidant Corporation), ABT-578(Abbott Vascular and Medtronic), and biolimus(terumo and Biosensors) 와같은것들이있다. Paclitaxel 은난소암이나유방암에사용되는항암약물로혈관횡문근의증식이나이동을억제하는것으로알려져있다. 20)21) TAXUS Ⅲ연구에서는 28 명의스텐트내재협착환자를대상으로 paclitaxel 약물방출스텐트를삽입하여 6개월후시행한관상동맥조영술추적관찰에서 16% 의재협착병변을관찰할수있었으며, 6개월에서 12개월사이에목표병변재개통은 21.4% 에서시행되었고, 주요심장사건은 29% 에서발생하였다. 22) 그러나 paclitaxel 유도체인 7-hexanoyltaxol(QP2)-eluting polymer stent system(quads) 의경우재협착에대한시술후 6개월에관상동맥조영술상 13.3% 의재협착률을보였으나 12개월추적관찰시에는 61.5% 로증가하는양상을보여재협착에대한시술로적합하지않음을보여줬다. 23) 과거의연구를보면 Rotterdam FIM(First In Man) 연구에서는 16명의중증의재발성스텐트내재협착환자를대상으로 1개이상의 18-mm SES 를삽입하여 4개월후관상동맥조영술을통해추적관찰하였는데, 추적중 1예에서급사하였으며, 나머지 15명의인원중 3예 (20%) 에서재협착이재발하였다. 24) Sao Paulo FIM 연구에서는 25명의스텐트내재협착환자를대상으로 1개이상의 18-mm SES 삽입하였고 12개월후관상동맥조영술을통한추적관찰결과 1예 (4%) 에서스텐트내재협착이발생하였다. 25) 본연구에서는 30 명의환자를대상으로하여 1개이상의 SES( 길이 27.1±5.5 mm) 를삽입하였으며, 6개월후관상동맥조영술추적검사를시행한 27 예중 2예 (7.4%) 에서재협착이발생하였고, 1예에서목표병변재개통을시행하였다. 본연구는그동안의연구에비하여비교적적지않은환자를대상으로약물방출스텐트중 SES 에대해서만연구가행해졌으며, 비교적높은추적관상동맥조영술 (84.4%) 을시행한것이특징이다. 이연구의제한점은목표병변재협착에혈관내초음파검사가시행되지못하였고, 스텐트내재협착 (2예 ) 이적어재협착에영향을주는임상양상과관상동맥조영술소견, 그리고스텐트삽입술에관한인자들 26)27) 에대한분석을시행하지않았다. Sirolimus 약물방출스텐트는일반적인경피적관상동맥성형술을시행할수있는시술인력이나장비만있으면쉽게시행할수있는장점을가지고있다. 그러나이러한 SES 삽입후발생하는스텐트내재협착의발생은현재 de-novo 병변의경우 2 년, 28)29) 스텐트내재협착병변의경우 1 년 30) 의추적관찰에대한연구들이있는상태이고, 기타다른약물방출스텐트의경우에있어서도그이후에발생할수있는후기재협착에대한연구는아직없는상태이므로위에서기술한 7-hexanoyltaxol(QP2)-eluting polymer stent system 처럼장기적인추적관찰기간동안부정적인결과를보일가능성을배제하지는못하는상태이다. 요 배경및목적 : 본연구는 Sirolimus 약물방출스텐트가스텐트내에발생하는재협착을억제한다는것에기초하여스텐트내재협착병변에대한치료에있어서도그유용성과안정성이있는지를확인하고자하였다. 방법 : 과거스텐트내재협착이발생한총 30 명의환자, 총 32 개의병변을대상으로하였고병변의특성에따라적절한길이와직경의 Sirolimus 약물방출스텐트를삽입하였다. 이후지속적인임상적추적관찰을하였고, 6개월이후의관상동맥조영술추적검사를통하여기준혈관직경, 최소혈관직경, late loss, loss index 등을측정하였다. 결과 : 총 27 개의예에서 6개월추적관상동맥조영술상 late loss 는평균 0.41±0.56 mm, loss index 는평균 0.18±0.22 이었고, 재협착 2예 (7.4%) 중 1예에대해서표적병변재개통이시행되었다. 임상적추적관찰결과주요심장사건은없었다. 결론 : 본연구에서보듯이 Sirolimus 약물방출스텐트는스텐트내재협착의치료에있어유용성과안정성이있다고볼수있다. 약 중심단어 : 관상동맥질환 ; 재협착 ; 스텐트. REFERENCES 1) Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994;331: 496-501. 2) Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol 2002;39:183-93. 3) Seung KB. Drug eluting stent and percutaneous coronary intervention. Korean Circ J 2003;33:857-60. 4) Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-23. 5) Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221-31. 6) Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis
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