www. Clinical trial results.org The RAVEL Study A RAndomised (double blind) study with the Sirolimus coated BX™ VElocity balloon expandable stent (CYPHER™) in the treatment of patients with De Novo native coronary artery Lesions M.C. Morice, P.W Serruys, J.E. Sousa, J. Fajadet, M. Perin, E. Ban Hayashi, A. Colombo, G. Schuler, P. Barragan, C. Bode on behalf of the RAVEL Study Group. A RAndomised (double blind) study with the Sirolimus coated BX™ VElocity balloon expandable stent (CYPHER™) in the treatment of patients with De Novo native coronary artery Lesions M.C. Morice, P.W Serruys, J.E. Sousa, J. Fajadet, M. Perin, E. Ban Hayashi, A. Colombo, G. Schuler, P. Barragan, C. Bode on behalf of the RAVEL Study Group.

www. Clinical trial results.org RAVEL: Background Sirolimus (Rapamune® - Wyeth Ayerst) is a naturally occurring macrocyclic antibiotic It is a potent immunosuppressive agent inducing late G1 cell cycle arrest

www. Clinical trial results.org Results of the RAVEL Trial Bx velocity™ stent coated with Sirolimus™ (Cypher™) versus placebo Inclusion Criteria S ingle de novo lesions Native coronary arteries <18mm in length Native coronary arteries 2.5 to 3.5mm in diameter Design: Double-blinded, placebo-controlled, randomized trial Enrolled 237 patients from several countries in Europe and Latin America All patients received Clopidogrel for a 2-month period Results: There was no case of restenosis in patients receiving the Sirolimus coated stent Rate was 26% in the uncoated stent group Late lumen loss of only 0.01mm with Sirolimus coated stent No reported cases of subacute thrombosis in patients treated with the Sirolimus coated stent Event-free survival was 97% with Sirolimus coated stent Bx velocity™ stent coated with Sirolimus™ (Cypher™) versus placebo Inclusion Criteria S ingle de novo lesions Native coronary arteries <18mm in length Native coronary arteries 2.5 to 3.5mm in diameter Design: Double-blinded, placebo-controlled, randomized trial Enrolled 237 patients from several countries in Europe and Latin America All patients received Clopidogrel for a 2-month period Results: There was no case of restenosis in patients receiving the Sirolimus coated stent Rate was 26% in the uncoated stent group Late lumen loss of only 0.01mm with Sirolimus coated stent No reported cases of subacute thrombosis in patients treated with the Sirolimus coated stent Event-free survival was 97% with Sirolimus coated stent

www. Clinical trial results.org RAVEL: Study Design 237 patients with single de novo lesions in native coronary arteries < 18 mm in length and 2.5 to 3.5 mm in diameter, randomized trial in Europe and Latin America to BX Velocity Stent Coated with Sirolimus (n=120) Uncoated BX Velocity Stent (n=118) Uncoated BX Velocity Stent (n=118) Clopidogrel for 2 months Major Adverse Cardiac Events (MACE) (Death / MI / Urgent TVR) Angiographic study

www. Clinical trial results.org Diabetes (%) Bare Stent Sirolimus Coated Sirolimus Coated N=118 N=120 P=NS Unstable Angina (%) P=NS Diabetes Unstable Angina Lesion Length (mm) P=NS Lesion Length RAVEL: Baseline Characteristics Bare Stent Sirolimus Coated Sirolimus Coated Bare Stent Sirolimus Coated Sirolimus Coated N=118 N=120 N=118 N=120

www. Clinical trial results.org RAVEL: Minimum Lumen Diameter (mm) Post MLD (mm) Follow-up MLD (mm) Late Loss (mm) Pre MLD (mm) P = NS P< Bare Stent Bare Stent Sirolimus Coated Sirolimus Coated Bare Stent Bare Stent Sirolimus Coated Sirolimus Coated Bare Stent Bare Stent Sirolimus Coated Sirolimus Coated Bare Stent Bare Stent Sirolimus Coated Sirolimus Coated

www. Clinical trial results.org Angiographic Restenosis (%) Bare Stent Sirolimus Coated Sirolimus Coated P<0.001 Target Vessel Revascularization (%) P< Restenosis TVR MACE Free Survival (%) P<0.001 MACE Free RAVEL: Results Bare Stent Sirolimus Coated Sirolimus Coated Bare Stent Sirolimus Coated Sirolimus Coated

www. Clinical trial results.org Angiographic Restenosis (%) Bare Stent Sirolimus Coated Sirolimus Coated P<0.001 Restenosis 1 Year MACE Free Survival (%) P<0.001 MACE Free RAVEL: Long-Term Results At 1 year Bare Stent Sirolimus Coated Sirolimus Coated

www. Clinical trial results.org Angiographic Restenosis (%) Bare Stent Sirolimus Coated Sirolimus Coated P<0.001 Restenosis Late Lumem Loss (mm) P<0.001 Late Loss RAVEL: QCA Results in Diabetic Patients Bare Stent Sirolimus Coated Sirolimus Coated

www. Clinical trial results.org RAVEL: Cautionary Notes In the First In Man study of 45 patients followed over 45 months, there was one stent thrombosis between months 12 and 13 While data is available to just over 6 months, more long term data is needed to exclude a risk of late thrombosis Fortunately, no aneuryms or pseudoaneurysms have been observed with 2 year follow-up in the First In Man study (FIM) RAVEL may be underpowered to demonstrate late safety signals, the ongoing SIRIUS trial enrolling 1101 patients at 53 centers will provide more information in this regard The efficacy of coated stenting in the management of in stent restenosis has not been studied to date In the First In Man study of 45 patients followed over 45 months, there was one stent thrombosis between months 12 and 13 While data is available to just over 6 months, more long term data is needed to exclude a risk of late thrombosis Fortunately, no aneuryms or pseudoaneurysms have been observed with 2 year follow-up in the First In Man study (FIM) RAVEL may be underpowered to demonstrate late safety signals, the ongoing SIRIUS trial enrolling 1101 patients at 53 centers will provide more information in this regard The efficacy of coated stenting in the management of in stent restenosis has not been studied to date

www. Clinical trial results.org RAVEL : Conclusions The treatment of a de novo lesion with CYPHER™ appears feasible and safe : no acute, subacute (30 days) or late occlusion occurred although clopidogrel / ticlopidine was administered for only 2 months Virtual elimination of neo-intimal in-stent proliferation: MLD post deployment (2.43 mm) remains essentially unchanged at 6 months (2.42 mm) with no measurable late loss (-0.05 mm) Restenosis (0%) and no evidence of edge effect The treatment of a de novo lesion with CYPHER™ appears feasible and safe : no acute, subacute (30 days) or late occlusion occurred although clopidogrel / ticlopidine was administered for only 2 months Virtual elimination of neo-intimal in-stent proliferation: MLD post deployment (2.43 mm) remains essentially unchanged at 6 months (2.42 mm) with no measurable late loss (-0.05 mm) Restenosis (0%) and no evidence of edge effect

www. Clinical trial results.org RAVEL: Conclusions Angiographic results are confirmed in a subset of patients evaluated with IVUS: Percentage of volume obstruction of the stent is less than 2%, No evidence of negative remodelling at the edges of the stent. This virtual elimination of neo-intimal hyperplasia was shown to be clinically translated into an absence of re- intervention so that event free survival at 6 months is close to 97% and significantly (P<0.0001) superior to the 72% event free survival of the patients treated with the bare stent. Angiographic results are confirmed in a subset of patients evaluated with IVUS: Percentage of volume obstruction of the stent is less than 2%, No evidence of negative remodelling at the edges of the stent. This virtual elimination of neo-intimal hyperplasia was shown to be clinically translated into an absence of re- intervention so that event free survival at 6 months is close to 97% and significantly (P<0.0001) superior to the 72% event free survival of the patients treated with the bare stent.