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THE CYPHER STENT CLINICAL TRIALSThe Summary of a Clinical RevolutionSirolimus-eluting Stent

THE CYPHER STENT CLINICAL TRIALSThe Summary of a Clinical Revolution

Cordis would like to extend their gratitude to all investigatorsinvolved in the CYPHER Sirolimus-eluting Stent clinical trialprogramme for their remarkable achievements to date.This book is presented to you to acknowledge those achievements,which have enabled a breakthrough in interventional cardiology.By helping to bring the first drug-eluting stent to market, you havecreated the opportunity to dramatically improve patient outcomes,and reduce the need for repeat interventions. The implications ofthis will no doubt be highly valued for years to come, and mark akey turning point in the history of interventional cardiology.

IntroductionDrug-eluting Stents:A New Era in Interventional CardiologyNot since the groundbreaking early days of balloonangioplasty in the late 1970s has there been a moreexciting time to be involved in interventional cardiology.The potential of drug-eluting stents is immense and bringscardiologists another important step closer to the idealin patient care.Until recently, arterial restenosis has been the Achilles’heel of interventional cardiology. The introduction ofcoronary stents in the early 1990s was seen as abreakthrough in interventional medicine. These deviceseffectively abolished early elastic recoil and late constrictiveremodelling, two of the primary mechanisms of restenosisfollowing angioplasty, and provided significantimprovements in angiographic and clinical outcomes.However, restenosis continued to be the major limitationof stent implantation due to neointimal hyperplasia. Thiscomplex biological process, in response to vessel injuryincurred during stent deployment, causes in-stentrestenosis in as many as 30% of patients who receive abare metal stent.Various approaches have been proposed for the treatmentof in-stent restenosis including repeat balloon angioplasty,directional and rotational atherectomy, cutting balloonand brachytherapy. But none of these have provided anoptimal solution. Prevention is better than cure, and soattention turned to pharmacological agents that mightprevent neointimal hyperplasia following delivery via thestent. A drug-eluting stent was seen as an attractiveoption because it provides an efficient method to addressrecoil, remodelling and neointimal hyperplasia in onedevice. Local drug delivery maximises the effect whenand where it is needed, with minimal potential for systemictoxicity.Sirolimus: a Novel Approach to the Treatment ofNeointimal HyperplasiaThe Cordis programme to identify drugs with the potentialto prevent restenosis when mounted on a stent screenedseveral hundred compounds. Sirolimus was selectedbecause it is ideally suited to block the key steps in theprocess of neointimal hyperplasia, while not affecting cellviability or natural healing.Vascular injury following stent implantation triggers acomplex wound healing process. The release of growthfactors and cytokines from endothelial cells, platelets andinflammatory leukocytes initiates the proliferation of smoothmuscle cells (SMCs).In preventing neointimal hyperplasia, sirolimus exhibits adual mechanism of action. Not only does it act directlyon SMCs to stop them from proliferating, but it alsoexhibits anti-inflammatory effects by blocking T-cellactivation and proliferation in the vessel wall. Thissubsequently reduces tissue injury and further amplificationof SMC proliferation.Sirolimus blocks the proliferation of both SMCs andT-cells through its action on a key signal transductionenzyme called TOR (target of rapamycin). This stopsgrowth factor signals and safely arrests the cell cycle inthe early G1 phase. This cytostatic effect allows SMCsto remain viable and return to a resting state or G0.Through this action on TOR, sirolimus selectively targetsSMCs and inflammatory cells, leaving the natural healingprocess of re-endothelialisation to progress unhindered,as demonstrated in animal models.In pre-clinical animal trials, sirolimus-eluting stentsdemonstrated a broad therapeutic window. Biologicalactivity was exhibited with doses ranging from18-1200 µg/stent without displaying toxicity to the vesselwall. In the clinical setting, a broad therapeutic profilemay mean that long, overlapping or adjoining stents canbe deployed without the risk of toxicity.CYPHER Sirolimus-eluting Stent: The First Anti-Proliferative InterventionThe development of a sirolimus-eluting stent involved theapplication of sirolimus in a proprietary biocompatiblepolymer to the Bx Stent platform. The closed cell designof the Bx Stent offers optimal drug delivery by providinguniform coverage of the vessel wall for even drugdistribution. The polymer coating was developed to releasethe majority of the sirolimus dose over the first 30 daysafter implantation – the critical time for the inhibition ofneointimal hyperplasia. Furthermore, tests confirmed thatthe polymer is non-thrombogenic, does not induceinflammation of the vessel wall, and maintains its integrityeven when overexpanded. The resulting CYPHERSirolimus-eluting Stent was the first anti-proliferativeintervention specifically designed to prevent in-stentrestenosis due to neointimal hyperplasia.The CYPHER Stent was the first drug-eluting stent toreceive CE mark and FDA approval, being the first tocomplete a first-in-man pilot study, and subsequentrandomised, controlled clinical trials. The CYPHERStent clinical trial programme has been instrumental inheralding a new era in interventional cardiology, not leastfor bringing the first drug-eluting stent to market. Scientificrigour applied to an exhaustive study programme hasprovided meaningful and dependable results. Essentially,physicians can expect to achieve the same excellentresults in practice as demonstrated in the following clinicaltrials.3

ContentsChapter 1: Summary of Pivotal Clinical Trials1.1 Studies in De Novo Coronary Artery Lesions1.1.1 First-In-Man Pilot Study1.1.2 RAVEL1.1.3 SIRIUS1.1.4 E-SIRIUS1.1.5 C-SIRIUS1.2 Studies in In-Stent Restenosis1.2.1 In-Stent Restenosis Registry56681114161919Chapter 2: High-Risk Subgroups2.1 Diabetes2.1.1 Diabetic Subgroup Analysis from RAVEL2.1.2 Diabetic Subgroup Analysis from SIRIUS2.2 Small Vessels2.2.1 Vessel Size Sub-Analysis from RAVEL2.2.2 Vessel Size Sub-Analysis from SIRIUS2.2.3 Small Vessel Bifurcation Feasibility Study2.3 Long Lesions/Overlapping Stents2.3.1 Long Lesion and Overlapping Stent Analysesfrom SIRIUS2.4 LAD Lesions2.4.1 LAD Subgroup Analysis from SIRIUS212222222323242528283030Chapter 3: Long-Term Follow-Up3.1 Studies in De Novo Coronary Artery Lesions3.1.1 First-In-Man Pilot Study3.1.2 RAVEL3.1.3 SIRIUS3.2 Studies in In-Stent Restenosis3.2.1 In-Stent Restenosis Registry31323233343535Ongoing Clinical Trials37Implications384

Chapter 1Summary of Pivotal Clinical Trials

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution1.1 Studies in De Novo Coronary Artery Lesions1.1.1 First-In-Man (FIM) Pilot StudyThe Pioneering First Clinical Experience of the CYPHER Sirolimus-eluting StentInvestigators:J Sousa, P Serruys, AC Abizaid, M Costa, AS Abizaid, F Feres, I Pinto, A Seixas, R Staico, L Mattos, A Sousa, R Falotico,J Jaeger, J Popma, L Tanajura, K Kozuma, G van Langenhove, B Rensing, J Vos, P Smits, D Foley, M van den Brand,W van der Giessen, P de Feijter.Aims of the study:(1) Assess the feasibility and safety of implanting two different formulations of the CYPHER Stent in de novo atherosclerotic humancoronary arteries(2) Assess the impact of the stents on neointimal proliferationStudy design• Open-label safety study of the CYPHER Stent (140µg sirolimus/cm 2 )• De novo lesions 28 days)G3 - Slow release (elution >28 days)SitesInst. Dante Pazzanese, São Paulo, BrazilInst. Dante Pazzanese, São Paulo, BrazilThoraxcenter, Rotterdam, The NetherlandsPatientsn=15n=15n=15All patients received:• One 18mm CYPHER Stent• Aspirin (325mg) indefinitely• Clopidogrel (75mg) for 60 daysEndpoints:• MACE at 30 days, 6 months and out to 5 years• QCA and IVUS F/U at 4-6, 12-18, 24 and 48 months• Clinical F/U at 4-6, 12-18, and 24 monthsData analysis by independent core laboratories:• QCA: Brigham and Women’s Hospital, Boston, USA• IVUS: Cardialysis BV, Rotterdam, The NetherlandsPatient demographics (n=45)Mean age (years)Male genderUnstable anginaPrior MIPrior PCIDiabetesHyperlipidemiaHypertensionCurrent smoker58.364%29%44%4.7%13.3%60%56%56%Baseline angiographyRVD (mm)In-Stent MLD Post (mm)Lesion Length (mm)G12.942.8313.1G22.982.9412.9G32.852.909.316

Initial QCA results (4-6 months): In-Stent Late LossCYPHER Stent0.8FR= fast-releaseSR= slow-releaseIn-Stent Late Loss (mm)0.60.40.20-0.24 monthsG1 (FR)(n=15)-0.10.094 monthsG2 (SR)(n=15)0.256 monthsG3 (SR)(n=15)In-Stent and In-Lesion Restenosis:• 0% in all groupsInitial IVUS results (4-6 months)G1 (n=14) 4 monthsG2 (n=13) 4 monthsG3 (n=13) 6 monthsNIH volume (mm 3 )0.30.45.7% obstruction volume0.30.31.8NIH = neointimal hyperplasia• No edge effect was observed in the segments proximal or distal to the stentsInitial clinical results (6 months, n=45)Death*MI**TLR (clinically-driven)TVRThrombosisMACE (clinically-driven)1 (2.2%)1 (2.2%)01 (2.2%)02 (4.4%)* One patient died 1 day after successful stent implantation because of intra-cerebral bleeding.** One patient suffered a subacute occlusion 2h after the procedure. Additional stenting of a distal dissection was performed.Subsequent clinical follow-up was uneventful.ConclusionsThe implantation of the CYPHER Stent is feasible and safe and elicits minimal neointimal proliferation.Additional placebo-controlled trials are required to confirm these promising results.7

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution1.1.2 RAVELThe First Randomised, Controlled, Double-Blind Study of the CYPHER Sirolimus-eluting StentInvestigators:MC Morice, P Serruys, J Sousa, J Fajadet, E Ban Hayashi, M Perin, A Colombo, G Schuler, P Barragan, G Guagliumi,F Molnar, W Wijns, D Blanchard, H Eltchaninoff, J Guermonprez, G Holubarson, A Bartorelli, G Laarman, C ConstantiniAim of the study (primary objective):To assess the safety and effectiveness of the CYPHER Stent in reducing angiographic in-stent late loss (at 6-month follow-up) inde novo native coronary artery lesions as compared to the uncoated stent (control)Study design• Multi-centre, prospective, double-blind, two-arm, randomised, controlled study of the CYPHER Stent (140µg sirolimus/cm 2 )• Involved 238 patients from 19 centres (Europe, Central and South America)• De novo lesions

QCA results (6 months): Late Loss0.80.70.6p

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical RevolutionInitial clinical results (hierarchical ranking of MACE to 210 days)CYPHER Stent (%) n=120Control (%) n=118p-valueDeath0.01.7MI Q-wave1.70.0MI Non Q-wave0.82.5CD TLR*0.8**13.6p

1.1.3 SIRIUSThe First Study of the CYPHER Sirolimus-eluting Stent in a High-Risk “Real World” Patient PopulationInvestigators:J Moses, M Leon, J Popma, R Kuntz, P Fitzgerald, C O’Shaughnessy, P Caputo, D Kereiakes, D Williams, C Brown, P Teirstein,T Fischell, SC Wong, M Midei, J Douglas, C Lambert, M Mooney, M Buchbinder, S Yakubov, W Bachinsky, D Baim, T Bass,W O’Neill, S DeMaio, E Fry, J Carrozza, J Zidar, G Mishkel, L Satler, R Wilensky, B Cohen, A Raizner, J Midwall, M Clark, S Ellis,P Coleman, J Lasala, C Simonton, D Holmes, E Perin, S Sorenson, F Kiernan, C Davidson, T Vellinga, P Coleman, H Madyhoon,N Laufer, D McCormick, D Roberts, M Cleman, S Raible, I Palacios, M Bates, J Lopez, A Yeung, C Chapman, F LeyaAim of the study (primary objective):To assess the safety and effectiveness of the CYPHER Stent in reducing target vessel failure in de novo native coronary arterylesions compared with the uncoated stent (control)Study design• Multi-centre, prospective, double-blind, two-arm, randomised, controlled study of the CYPHER Stent (140µg sirolimus/cm 2 )• Involved 1058 patients from 53 centres (USA)• De novo lesions 15-30mm• Vessel size 2.5-3.5mmAll patients received:• One or more multiple or overlapping 8mm/18mm CYPHER Stents• Aspirin (325mg) indefinitely• Clopidogrel (75mg) or ticlopidine (250mg b.d.) for 3 monthsEndpoints:• Primary endpoint: TVF (cardiac death, MI or TVR) at 9 months• QCA F/U substudy at 8 months (first 850 patients)• IVUS F/U substudy at 8 months (selected sites, n=250)• Clinical F/U at 30 days, 6, 9 and 12 months, then yearly out to 5 years• Economic factors – index hospitalisation costs, length of stay, and repeat hospitalisations (up to 12 months)Data analysis by independent core laboratories:• QCA: Brigham and Women’s Hospital, Boston, USA• IVUS: Stanford Medical Center, Palo Alto, USAPatient demographicsMean age (years)Male genderUnstable anginaPrevious MIPrevious PCI/CABGDiabetesHyperlipidemiaHypertensionCurrent smokerCYPHER Stent (%) n=5336273442826/1025736818Control (%) n=5256270443323/1028756822RVD (mm)In-Stent MLD Post (mm)Lesion Length (mm)Type C LesionsMultivessel DiseaseBaseline angiographyCYPHER Stent (n=533)2.792.6714.426%41%Control (n=525)2.812.6814.421%42%11

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical RevolutionStented Length (mm)Overlapping StentsProcedural characteristicsCYPHER Stent (n=533)21.528%Control (n=525)21.227%QCA results (8 months): Late Lossp

Event-Free Survival from MACEPatients without Event (%)10090807060p

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution1.1.4 E-SIRIUSA Study of the CYPHER Sirolimus-eluting Stent in the Most Challenging Patient and Lesion Types to dateInvestigators:J Schofer, G Breithardt, W Wijns, A Gershlick, E Garcia, E Schampaert, D Glogar, V Legrand, I Taeymans, F van den Branden,M Zelizko, H Kelbaek, L Thuesen, J Fajadet, JM Fauvel, G Finet, T Wichter, P Hanrath, R Simon, R Strasser, A Zeiher,P Crean, R Beyar, C Lotan, A Colombo, G Guagliumi, L Inglese, S Petronio, B Reimers, P Rubino, H Suryapranata,A van Boven, R Seabra-Gomes, C Macaya, F Eberli, S Windecker, S Redwood, M Rothman.Aim of the study (primary objective):To assess the safety and effectiveness of the CYPHER Stent in maintaining MLD at 8 months in de novo native coronary arterylesions compared with the uncoated stent (control)Study design• Multi-centre, prospective, double-blind, two-arm, randomised, controlled study of the CYPHER Stent (140µg sirolimus/cm 2 )• Involved 352 patients from 35 centres (Europe)• De novo lesions 15-32mm• Vessel size 2.5-3.0mmAll patients received:• One or two 8mm/18mm CYPHER Stents• Combined antiplatelet therapy for 2 monthsEndpoints:• Primary endpoint: In-stent MLD at 8 months• QCA F/U at 8 months• IVUS F/U substudy (6 sites, n=60)• MACE at 30 days, 6, 9 and 12 months, then 2 to 5 years• Clinical F/U at 30 days, 6, 9 and 12 months, then yearly out to 5 years• Direct stenting vs. predilatation• Cost effectivenessData analysis by independent core laboratories:• QCA: Brigham and Women’s Hospital, Boston, USA• IVUS: Cardialysis BV, Rotterdam, The NetherlandsPatient demographicsMean age (years)Male genderUnstable anginaPrevious MIPrevious PCI/CABGDiabetesHyperlipidemiaHypertensionCurrent smokerCYPHER Stent (%) n=1756270474119/619776336Control (%) n=1786371514322/627716430RVD (mm)In-Stent MLD Post (mm)Lesion Length (mm)Type C LesionsMultivessel DiseaseBaseline angiographyCYPHER Stent (n=175)2.62.4314.924%36%Control (n=177)2.52.3815.124%35%14

Stented Length (mm)Overlapping StentsDirect StentingProcedural characteristicsCYPHER Stent (n=175)23.034%26%Control( n=177)22.331%26%QCA results (8 months): Late LossLate Loss (mm)1.21.00.80.60.4p

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical RevolutionEvent-Free Survival from MACEPatients without Event (%)100908070605091.9%77.2%p

Mean age (years)Male genderPrevious MIPrevious PCI/CABGDiabetesHyperlipidemiaHypertensionCurrent smokerPatient demographicsCYPHER Stent (%) n=506070488/624855736Control (%) n=506168428/224864938RVD (mm)In-Stent MLD Post (mm)Lesion Length (mm)Type C LesionsBaseline angiographyCYPHER Stent (n=50)2.652.5314.530%Control (n=50)2.622.5012.616%Procedural characteristicsStented Length (mm)CYPHER Stent (n=21)Control (n=21)25.3 22.1QCA results (8 months): Late Loss1.210.8p

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical RevolutionCYPHER Stent (%) Control (%) Reduction p-valueIn-Stent Restenosis041.9100%p

1.2 Studies in In-Stent Restenosis1.2.1 In-Stent Restenosis RegistryThe Pioneering First-In-Man Experience of the CYPHER Sirolimus-eluting Stent in In-Stent RestenosisInvestigators:E Sousa, P Serruys, AC Abizaid, AS Abizaid, A Sousa, M Costa, E Regar, B Rensing, M Degertekin, R Staico, J Popma.Aims of the study:To assess the feasibility and safety of the CYPHER Stent in the treatment of in-stent restenosisStudy design• Open-label safety study of the CYPHER Stent (140µg sirolimus/cm 2 ) in in-stent restenosis• Involving 41 patients from 2 centers• Vessel size 2.5-3.5mmSitesInst. Dante Pazzanese, São Paulo, BrazilThoraxcenter, Rotterdam, The NetherlandsPatientsn=25n=16All patients received:• One or two 18mm CYPHER Stents• Aspirin (325mg) indefinitely• Clopidogrel (75mg) for 60 daysEndpoints:• MACE at 30 days, 4 months and yearly up to 5 years• QCA F/U at 4 and 12 months• IVUS F/U at 4 and 12 monthsData analysis by independent core laboratories:• QCA: Brigham and Women’s Hospital, Boston, USA• IVUS: Cardialysis BV, Rotterdam, The NetherlandsPatient demographics (n=41*)Mean age (years)Male genderPrevious MIIDiabetesHyperlipidemiaHypertension5781%56%27%71%63%* Includes three vascular brachytherapy failures and one heart transplant patient with diffuse vasculopathy19

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical RevolutionBaseline angiography and initial QCA results (4 months), n=413.02.52.72.72.5CYPHER StentLumen Diameter (mm)2.01.51.00.50.90RVD(mm)In-StentMLD Pre (mm)In-StentMLD Post (mm)In-StentMLD F/U (mm)Restenosis:• 2.5% In-Stent• 7.5% In-LesionInitial IVUS results (4 months)% Volume obstruction0.95%Initial clinical results (4-6 months, n=41)DeathMITLR (clinically-driven)TVRThrombosisMACE (clinically-driven)1 (2.4%)1 (2.4%)0001 (2.4%)ConclusionsThe implantation of the CYPHER Stent for the treatment of in-stent restenosis is safe, feasible, and elicited practically noneointimal hyperplasia. The 4-month QCA and IVUS results appear to be better than what has been achieved by any othertechnique or drug therapy.These findings need to be confirmed by larger, randomised clinical trials in order to define the real impact of this strategy in thetreatment of in-stent restenosis.20

Chapter 2High-Risk Subgroups

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution2.1 Diabetes2.1.1 Diabetic Subgroup Analysis from RAVELQCA results (6 months)CYPHER Stent (n=19)Control (n=25)p-valueLesion Length (mm)9.749.42NSRVD (mm)2.522.51NSIn-Stent MLD (mm)Pre0.990.93NSPost2.372.36NSF/U2.291.56p

Clinical results (9 months)CYPHER Stent (%) n=131Control (%) n=148Reductionp-valueTLR6.922.369%p

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution2.2.2 Vessel Size Sub-Analysis from SIRIUSQCA results (8 months)*CYPHERStentControlCYPHERStentControlCYPHERStentControlRVD (mm)In-Stent Late Loss (mm)In-Lesion Late Loss (mm)In-Stent Restenosis (%)In-Lesion Restenosis (%)~2.3mm ~2.8mm ~3.3mm0.210.315.318.40.990.7741.942.90.150.212.46.31.040.8635.736.50.150.191.91.80.990.8029.530.2* p

2.2.3 Small Vessel Bifurcation Feasibility StudyThe First Study of the CYPHER Sirolimus-eluting Stent in Bifurcated LesionsInvestigators:A Colombo, MC Morice, J Ludwig, MB Leon, DR Holmes, J MosesAim of the study:To assess the feasibility and safety of implanting the CYPHER Stent in de novo bifurcated lesions in native coronary arteriesStudy design• Multi-centre, prospective, two-arm, randomised, controlled study of the CYPHER Stent (140µg sirolimus/cm 2 )• Involved 86 patients from 5 centres (Europe and USA)• Main branch vessel size 2.5-3.5mmTwo study arms:• DES + DES = CYPHER Stent implantation in both the main branch and side branch• DES + PTCA = CYPHER Stent implantation in the main branch and PTCA in the side branchAll patients received:• One or two 8mm/18mm CYPHER Stents• Antiplatelet therapy for 3 monthsEndpoints:• Primary endpoint: % Residual diameter stenosis in the stented branch (measured by QCA) at 6 months• QCA F/U at 6 months• Clinical F/U at 1, 6, 12, and 18 months, and yearly from 2-5 yearsBaseline populations• Intention-to-treat: DES + DES n=43; DES + PTCA n=43• Per protocol: DES + DES n=63; DES + PTCA n=23• Side branch lesions with unsatisfactory PTCA results crossed over to the DES + DES arm• One third of the DES + DES arm involved cross-over patients, biasing the results due to more difficult-to-treat cases in theDES + DES armBaseline characteristicsPer Protocol PopulationDES+DESDES+PTCAMain Branchn=63Side Branchn=65Main Branchn=23Side Branchn=23Diabetes21%26%RVD (mm)2.632.062.622.12Lesion Length (mm)10.85.512.15.0Procedural characteristicsBifurcation TechniqueT-StentingStent in side branch firstStent in main branch firstSimultaneousV-StentingY-StentingDES+DES (n=63)541511121225

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical RevolutionBifurcated Lesions TreatedType 1n=14(16.3%)Type 2n=42(48.8%)Type 3n=9(10.5%)Type 4n=11(12.8%)Type 4an=6(7.0%)Type 4bn=4(5.0%)QCA results (6 months) by actual treatment received: In-Lesion Late Loss1.3Historical Bare Metal Late Loss=1.25mm*In-Lesion Late Loss (mm)1.00.80.50.30.1487%Reduction0.2978%Reduction0.4450%ReductionCYPHER Stent0Main BranchDES+PTCAMain BranchDES+DESSide BranchDES+DES* Reimers & Colombo et al. Bifurcation Lesions, Techniques in Coronary Stenting Ch.10, Martin Dunitz Publishers, 2000DES+DESDES+PTCAMain BranchSide BranchMain BranchSide BranchIn-Stent Restenosis1.9%22.6%0%N/AVs. Historical Bare Metal100% reduction72% reduction100% reductionN/ARestenosis (50-60%)** Reimers & Colombo et al. Bifurcation Lesions, Techniques in Coronary Stenting Ch.10, Martin Dunitz Publishers, 200026

Location of in-stent restenosis:• 12 out of 13 in-stent restenoses occurred in the ostium of the side branchClinical results (6 months)DeathMI Q-waveMI Non Q-waveTLR-PTCATLR-CABGMACEOverall Stent ThrombosisDES+DES (%)n=631.61.611.17.91.619.03.5DES+PTCA (%)n=2304.34.34.3013.0ConclusionsBifurcated lesions are among the most challenging to treat. Implantation of the CYPHER Stent resulted in an absence of in-stentrestenosis in the main branch. In the side branch, the majority of in-stent restenoses occurred in the ostium. These preliminary resultssuggest that reductions in side branch restenosis may be possible through a refinement in bifurcation stenting technique.27

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution2.3 Long Lesions/Overlapping Stents2.3.1 Long Lesion and Overlapping Stent Analyses from SIRIUSOverlapping stent subgroup baseline angiographyRVD (mm)Lesion Length (mm)CYPHER Stent(n=176)2.7718.2Control(n=168)2.8018.1Overlapping stent subgroup procedural characteristicsStented Length (mm)Stent Overlap (mm)CYPHER Stent(n=176)28.34.6Control(n=168)27.94.0Overlapping stent subgroup QCA results (8months): Late Loss1.2p

Overlapping stent subgroup clinical results (9 months)CYPHER Stent (%)n=176Control (%)n=168p-valueIn-Hospital MACE4.54.2NSTLR4.517.9p

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution2.4 LAD Lesions2.4.1 LAD Subgroup Analysis from SIRIUSBaseline angiographyTotal Population(n=462)RVD (mm)Lesion Length (mm)2.7314.0QCA results (8 months): Late LossLate Loss (mm)1.21.00.80.60.40.2p

Chapter 3Long-Term Follow-Up

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution3.1 Studies in De Novo Coronary Artery Lesions3.1.1 First-In-Man Pilot StudyQCA results (4-24 months): In-Stent Late Loss0.8CYPHER StentIn-Stent Late Loss (mm)0.60.40.20-0.10.110.280.09 0.08-0.090.25FR= fast-releaseSR= slow-release0.2-0.24months12months24months4months12months24months6months18monthsG1 (FR) n=15 G2 (SR) n=15 G3 (SR) n=15In-Stent and In-Lesion Restenosis:• 0% in all groupsClinical results (6-36 months)6 monthsn=4524 monthsn=4536 monthsn=30 (G1 & G2)Death1 (2.2%)1 (2.2%)0MI1 (2.2%)2 (4.4%)1 (3.3%)TLR (clinically-driven)03 (6.7%)2 (6.7%)TVR1 (2.2%)3 (6.7%)2 (6.7%)Thrombosis001 (3.3%)MACE (clinically-driven)2 (4.4%)5 (11.1%)2 (6.7%)ConclusionsThese long-term results demonstrate the beneficial and sustained antiproliferative effects of CYPHER Stent in eliminating in-stentneointimal hyperplasia while showing low rates of MACE. If these findings are confirmed in large, randomised, placebo-controlledtrials, this technology is likely to have a major impact on the treatment of coronary artery disease in the near future.32

3.1.2 RAVELClinical results (hierarchical ranking of MACE at 12 and 24 months)CYPHER Stent (%)n=120Control (%)n=11812 months 24 months 12 months 24 monthsCardiac Death0.00.00.81.7Non Cardiac Death1.75.00.80.8MI3.32.53.43.4CD TLR*0.8**2.513.613.6All TLR*0.8**3.323.723.7No MACE (CD)94.290.081.480.5No MACE (All)94.289.271.270.3Stent Thrombosis0.00.00.00.0* CD – clinically driven revascularisations only; All – all revascularisations included** CABG for progression ostial LAD/LM, no restenosis in stentEvent-Free Survival TLR10097.5%Patients without TLR (%)90807060504096.7%86.4%76.5%300 60 120 180 240300 360 420 480 540 600 660 720Time (Days)CYPHER Stent all TLR (n=120)CYPHER Stent clin. driven TLR (n=120)Control all TLR (n=118)Control clin. driven TLR (n=118)ConclusionsThe results at two-year follow-up demonstrate the sustained efficacy of the CYPHER Stent, with a superior event-free survivalrate compared to control and an extremely low rate of TLR at 720 days. The safety profile remains comparable to the bare stentgroup, and the thrombosis rate remains at 0%.33

THE CYPHER STENT CLINICAL TRIALS The Summary of a Clinical Revolution3.1.3 SIRIUSClinical results (9-12 months)CYPHER Stent (%)n=533Control (%)n=5259 months 12 months 9 months 12 monthsDeath (%)0.91.30.60.8MI (%)2.83.03.23.4TLR (%)4.14.916.620.0TVF (%)8.89.821.024.8MACE (%)7.18.318.922.3Stent Thrombosis (%)0.40.40.80.8TLRp

3.2 Studies in In-Stent Restenosis3.2.1 In-Stent Restenosis RegistryQCA and IVUS results (4 and 12 months), n=390.830Lumen Diameter (mm)0.60.40.200.120.380.95% 1.53%2520151050Volume Obstruction (%)4 months 12 monthsIn-Stent Late Loss (mm) and Volume Obstruction (%)CYPHER StentClinical results (4 and 12 months, n=41)4 months (%) 12 months (%)DeathMITLR (clinically-driven)TVR (non TL)ThrombosisMACE (clinically-driven)2.42.40002.44.94.94.902.47.3ConclusionsThe early clinical benefits of CYPHER Stent implantation for the treatment of in-stent restenosis appear durable at late follow-up(1 year). These findings need to be confirmed by larger, randomised clinical trials that will be able to define the real impact of thisstrategy in the treatment of this very serious condition, in-stent restenosis.35

Ongoing Clinical TrialsFREEDOMUS/Canadian multicentre, prospective, randomised trial to comparethe effectiveness of the CYPHER Sirolimus-eluting Stent and bypasssurgery in diabetic patients (75 centres, n=2,500)Principal Investigator: V FusterSVELTEEuropean multicentre, prospective, non randomised, study to assessthe safety and effectiveness of the CYPHER Sirolimus-eluting Stentin reducing in-lesion late loss in de novo coronary artery lesions insmall vessels (2.25 - 2.75 mm) as compared to the uncoatedBX VELOCITY balloon-expandable stent (10 centres, n=100)Principal Investigator: B MeierARTS IIEuropean multicentre, open, non-randomised trial to assess theeffectiveness of the CYPHER Sirolimus-eluting Stent in patientswith multivessel disease who are candidates for either bypass surgeryor multivessel stenting, using patients who underwent bypass surgeryin ARTS I as a historical control (47 centres, n=600)Principal Investigator: P SerruysTROPICALMulticentre, non-randomised study of the CYPHER Sirolimus-elutingStent in the treatment of patients with an in-stent restenotic nativecoronary artery lesion. Results of this study will be compared withthe outcome of GAMMAI/II as a historical control (12 sites, n=160)Principal Investigators: F Neumann, W DesmetISR IISingle centre, non-randomised study to assess the performance andsafety of the CYPHER Sirolimus-eluting Stent in patients within-stent restenotic native coronary artery lesions (1 site, n=23)Principal Investigator: P BarraganATLAS (ULTIMA)Multicentre, prospective, non-randomised study to assess the safetyand effectiveness of the CYPHER Sirolimus-eluting Stent in reducingangiographic binary restenosis (>50% diameter stenosis) in patientswith unprotected left main coronary artery lesions as compared to anobjective performance criterion (10 sites, n=100)Principal Investigator: J Fajadet, S Ellis, PL WithlowSICTOMulticentre, prospective, non-randomised study to assess the feasibilityand restenosis/reocclusion rates of coronary stenting with a CYPHERSirolimus-eluting Stent in totally occluded native coronary arteries(5 sites, n=25)Principal Investigator: C LotanSINO-SIRIUSAsian Pacific non-randomized trial to assess the efficacy and safetyof the CYPHER Stent in de novo native coronary artery lesions(2 centres, n=50)Principal Investigators: R Gao, J Y ChenARGENTINASingle-centre, non-randomised trial to assess the efficacy and safetyof the CYPHER Stent (1 centre, n=20)Principal Investigator: D BerrocalREALITYProspective, Randomized, Multi-Center Comparison Study of theCYPHER Sirolimus-Eluting and TAXUS Paclitaxel-Eluting StentSystems in patients with up to two de novo native coronary arterylesions in a maximum of two vessels, 2.25 to 3.00 mm in diameter(85 centres, n=1000)Principal Investigator: MC Morice37

ImplicationsSince the introduction of angioplasty, restenosis has been a majorfactor limiting the long-term success of percutaneous coronaryrevascularisation. In the past decade, refinements in stenting techniquehave substantially improved the overall results of the procedure.Despite previous efforts to prevent the development of restenosis,including systemic and local delivery of drugs and the use of variousdevices, additional target vessel revascularisation is required in morethan 15 percent of patients. Although catheter-based brachytherapyis effective in the treatment of in-stent restenosis, its value in thetreatment of primary lesions is less clear. Furthermore, the use ofbrachytherapy is limited by its high cost and burdensomeinstrumentation and by the risks inherent in the use of radioisotopes.In this context, the benefit of the CYPHER Stent in several largemulticentre, randomised, controlled clinical trials is particularly striking.The CYPHER Stent clinical trial programme has set a new standardin coronary artery stent investigation. No other stent in this categoryhas been studied so extensively in such a wide range of high-riskpatients with difficult-to-treat lesions. In all subgroups, this new deviceappears to virtually eliminate the development of neointimal proliferation.Yet it does not require special implantation techniques orinstrumentation, and has appeared innocuous within the time frameof long-term follow-up to date. This broad utility may confer aconsiderable reduction in the need for repeat revascularisation inclinical practice, including bypass surgery, and thus avoid associatedcosts and patient morbidity.38

Presented as a service to interventional cardiology by Cordis,a Johnson & Johnson Company.© Johnson & Johnson Medical NV/SA,Europe, 2003

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