Drug eluting stents From revolution to evolution. Current limitations

Transcription

1 Drug eluting stents From revolution to evolution Current limitations Eric Eeckhout Centre Hospitalier Universitaire Vaudois Lausanne - Switzerland eric.eeckhout@chuv.ch

2 Overview Historical perspective Current limitations From revolution to evolution

3 Historical perspective The first stent in a human being J. Puel Toulouse

4 Historical perspective

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6 Historical perspective Vessel closure after PTCA After successful stent placement

7 Historical perspective Serruys PW, et al. NEJM 1991;324:13-17

8 Historical perspective Restenosis : 14%

9 Historical perspective Trial & error RCT BENEstent-1 STRESS

10 Benestent I BENESTENT-1 Serruys PW, et al. NEJM 1994 Serruys PW, et al. NEJM 1994;331:

11 Historical perspective Trial & error RCT Confirmation BENEstent-1 STRESS BENEstent II Thienopyridines Better deployment

12 Historical perspective Serruys PW, et al. Lancet 1998;352: Event-free survival (Kaplan-Meier curves at 12 months of all patients (n=823) included in intention-to-treat analysis and of patients assigned clinical and angiographic follow-up or clinical follow-up alone.

13 Historical perspective Trial & error RCT Confirmation Stent-mania BENEstent-1 STRESS BENEstent II Thienopyridines Better deployment Customized stents In-stent restenosis

14 Historical perspective

15 Historical perspective Trial & error RCT Confirmation Revolution to Stent-mania BENEstent I STRESS I BENEstent II Thienopyridines Better deployment Customized stents In-stent restenosis

16 Historical perspective July 1999 Start of a phase 2 program with a stent eluting rapamycine - First in Man (FIM study). -QCA, quantitative IVUS, motorized, ECG-gated pull back -Rotterdam : Sao Paulo : 15 patients slow release (6month follow up) 15 slow release patients (4month follow up) 15 fast release patients (4month follow up)

17 First-In-Man study with a stent eluting rapamycine stent : Sao Paulo, Dec Robert Falotico The father of the sirolimus stent 5 40 Courthesy P. Serruys

18 Sirolimus-Coated stent Sousa JE, at al. Circulation 2001;103; Rensing, B.J. et al. European Heart Journal 2001;22: Sousa JE, at al. Circulation 2001;104:

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20 RAVEL : the radical abolition of restenosis Morice MC et al. NEJM 2002 The RAVEL study : presented in Stockholm 2001 at the ESC annual meeting

21 Historical perspective The DES revolution RAVEL SIRIUS And more The ENDEVEOR & SPIRIT series The TAXUS series

22 Overview Historical perspective Current limitations From revolution to evolution

23 Event-Free Survival (%) Trial design 100% 95% 90% 88.8% 85% 80% 75% 70% without Angio f/u (N=205) with Angio f/u (N=208) 79.3% Benestent II : Event-Free Survival at One year with and without angio follow-up (stent group)

24 Trial design RAVEL 95.0% 85.6% P (FE) = 0.02 P (LR) = 0.01 Morice MC et al. NEJM 2002

25 Freedom from events (%) Trial design The SIRIUS trial (Moses J, et al NEJM 2003) Trial design affects clinical results DES do not abolish restenosis SIR TLR Control TLR SIR MACE Control MACE SIR TVF Control TVF At 270 days, reduction in TLR of 12.5% At 360 days, reduction in TLR of 15.1% In segment restenosis : 8.9% Time after initial procedure (days)

26 Stent thrombosis Lausanne

27 Safety of DES Meta-Analyses Relative excess death/q-wave MI of 1st generation DES vs BMS (%) % % 5 0 SirolimusES PaclitaxelES E. Camenzind, CH, 992 World Congress of Cardiology 2006

28 Stent thrombosis First report in 4 patients of late stent thrombosis in DES after discontinuation of antiplatelet therapy Lancet 2004; 364: In 2006 patients, angiographically proven late stent thrombosis occurs with an incidence of at least 0.35% JACC 2005

29 Cumulative incidence, % Late Angiographic Coronary Stent Thrombosis of DES in Routine Clinical Practice; 4-year follow up of 8146 patients from Berne and Rotterdam Median 56 Days Cumulative Incidence of Stent Thrombosis 3.3% Time since PCI in years 27% late ST on dual antiplatelet therapy Days Cumulative incidence, % Patients at risk J. Daemen, NL, 3098 Daemen J et al, Lancet 2007 ESC Congress 2007 World Congress of Cardiology 2006

30 Discontinuation of Thienopyridine and Risk of Stent Thrombosis: Milan-Siegburg Cohort Study Airoldi F et al. Circulation 2007;116: ,021 patients with 5,389 lesions treated with DES ( ) HR= P<0.001 HR= P=0.92

31 Stent thrombosis The New Engl J Med issue of March 8, 2007

32 In-Vivo Mechanisms of Late Drug Eluting Stent Thrombosis. Optical Coherence Tomography, Intravascular Ultrasound and Thrombus Aspirated Findings case Positive Remodeling - - Uncovered/Total Struts/section>30 % Aggressive restenosis Eosinophil Fraction V.Sirbu, IT, 827 ESC Congress 2008

33 Stent thrombosis 4 year F.U. of FIM patient Pt # 4 (Fast release) SEM showed > 95% endothelized stent surface. Uncovered stent strut (arrow). Courtesy of R. Virmani

34 Coronary Aneurysms After Drug-Eluting Stent Implantation: Clinical, Angiographic and Intravascular Ultrasound Findings 1197 Follow-up angiograms of patients treated with 9 months (71% late angiographic FU) 15 Pts (1.25%) were found to have coronary aneurysms F. Alfonso, ES, 316 ESC Congress 2008

35 Coronary Aneurysms After Drug-Eluting Stent Implantation: Clinical, Angiographic and Intravascular Ultrasound Findings F. Alfonso, ES, 316 ESC Congress 2008

36 PERCENT CHANGE (%) PERCENT CHANGE (%) Vasodilation Exercise Sirolimus-Eluting Stents Associated With Paradoxical Coronary Vasoconstriction Vasoconstriction *P<0.001 vs control * * Prox.Ref. Prox. Stent Distal Distal Ref. Nitroglycerin Sirolimus group Control group Togni M et al. J Am Coll Cardiol 2005, 46: Sirolimus group Control group Prox.Ref. Prox. Stent Distal Distal Ref.

37 Safety Late stent thrombosis is (was) an important limitation of first generation drug eluting stents Mechanism multifactorial : Delayed/incomplete neointimal coverage Hypersensitivity Late malapposition Abnormal vasomotion (?) Premature discontinuation of antiplatelet t Resistance to thienopyridines Stent fracture Prolonged dual antiplatelet t is mandatory

38 Optimal revascularization strategy in patients with three-vessel disease and/or left main disease The 2-year Outcomes of the SYNTAX Trial A. Pieter Kappetein, MD PhD Erasmus MC, Rotterdam, NL On behalf of the SYNTAX investigators Clinical Trial Update III 2 September 2009, Room Barcelona Zone 2 9:24 AM to 9:37 AM Conflicts of Interest: None

39 Cumulative Event Rate (%) Repeat Revascularization to 2 Years CABG (N=897) TAXUS (N=903) P< Before 1 year * 5.9% vs 13.5% P<0.001 After 1 year * 3.7% vs 5.6% P= % 8.6% Months Since Allocation Cumulative KM Event Rate ± 1.5 SE; log-rank P value;*binary rates ITT population

40 Cumulative Event Rate (%) Myocardial Infarction to 2 Years CABG (N=897) TAXUS (N=903) Before 1 year * 3.3% vs 4.8% P=0.11 P=0.01 After 1 year * 0.1% vs 1.2% P= Months Since Allocation 5.9% 3.3% Cumulative KM Event Rate ± 1.5 SE; log-rank P value;*binary rates ITT population

41 Real-world experience with TAXUS Liberté: One-year results from the 22,000 patient OLYMPIA global post-approval registry. Incidence (%) Cardiac Events 1.2 TAXUS Liberté Stent- Related n=450 n=256 n=160 n=522 n=793 n=161 All Death Cardiac Death MI Reintervention Cardiac Thrombosis Composite Stent Events O. Mendiz, AR, 3288 ESC Congress 2008

42 ESC Congress 2008

43 SYRTAX late : In-Stent Late Loss Cumulative Distribution Curve 8 month years late loss in stent (mm) late loss (5 years), SES late loss (8 months), SES late loss (5 years), PES late loss (8 months), PES

44 Efficacy Uncertainties remain in certain patient subsets : Primary PCI SVG interventions Marked variations in outcome reporting in large registries using data validation Medium term efficacy much less than expected in patients with complex multivessel disease Late erosion of initial luminal gain with first generation DES

45 From revolution to evolution The DES revolution RAVEL SIRIUS And more The ENDEVEOR & SPIRIT series The DES evolution The TAXUS series

46 Historical Perspective Stents and Thrombosis 24 ASA and Oral Anticoagulation ASA and Ticlopidine New generation DES 7,6 6,0 3,5 1,4 0,5 ASA and Clopidogrel 1,5 0,9 1,6 1,0 0,4 0,3 Prasugrel Ticagrelor

47 Stent Thrombosis in Perspective Definite Stent Thrombosis in All Comer 12 Months Early Generation DES Newer Generation DES 4 3,3 3 % 2 2,0 2,0 1,2 1 0,3 0,3 0,4 0 CYPHER SIRTAX CYPHER LEADERS TAXUS SYNTAX ENDEAVOR RESOLUTE RAC XIENCE RAC XIENCE SPIRIT IV XIENCE COMPARE

48 %changes in diameter %changes in diameter %changes in diameter %changes in diameter Different DES, different vasomotor responses al segment A Proximal segment B Distal segment C P=0.005 C PES SES BES ZES BMS PES SES BES ZES BMS Reference segment P=NS PES SES BES ZES BMS P= P S B Z B 5 0 Hamilos et al Circulation Interv 2009

49 New Stent Technology New Generation DES Endothelial Progenitor Cell Capture Biodegradable Polymers Polymer Free Surface Bioabsorbale Stents Polymer coating Stent Strut Stent Strut Biodegradable Polymer abluminal only After release of polymer