Dual Antiplatelet Therapy Duration After Drug-Eluting Stent Placement: OPTIDUAL Trial

1. Twelve vs 48 months of dual antiplatelet therapy after drug-eluting stent placementThe OPTIDUAL randomized trial Gérard HELFT on behalf of the OPTIDUAL Investigators Institut de Cardiologie, Hôpital Pitié-Salpétrière, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie Paris, France IHU, Institute of Cardiometabolism And Nutrition, HôpitalPitié-Salpétrière Paris, France

2. Background (1) Stone G et al. N Engl J Med 2011;364 Wenaweser P et al. JACC 2008;52 The long-term risk of very late thrombosis after PCI does not decrease over time Nearly half of the recurrent MACE after PCI for ACS are associated with non-culprit lesions at the time of PCI

3. Background (2) DAPT trial: showed a reduction in rates of MACCE and stentthrombosis but an increase in bleeding Mauri L et al. N Engl J Med 2014;371:2155

4. Hypothesis • On a background of aspirin, continuing clopidogrel for up to 48 monthswould be superior to stopping clopidogrel at 12 months following drug-eluting stent (DES)implantation in reducing net adverse clinical events(composite of death, MI, stroke or major ISTH bleeding) • Randomized, multicentre, open-label study conducted in 58 sites in France (January 2009–January 2013) • Funded by the French Ministry of Health. Additional unrestricted research grants from Fédération Française de Cardiologie, Cordis, Boston, Medtronic, Terumo and Biotronik Helft G et al,Trials 2013;14:56

5. Patient selection Exclusion criteria • DES implantation in an unprotected left main coronary artery • Requirement for oral anticoagulation • Malignancies or other coexisting conditions associated with a life expectancy of <2 years Inclusion criteria • Patients with stable CAD or ACS • With ≥1 lesion with a significant stenosis in an artery ≥2.25 mm • Implanted with ≥1 DES of any type

6. Study design End of the study Randomizationof patients free of MACCE or bleed DESinsertion 0 12 months 48 months ASPIRIN + CLOPIDOGREL 12 ± 3 months ASPIRIN + CLOPIDOGREL ASPIRIN ALONE Follow-up (every 6 months between 12 and 48 months)

7. Methods • Primary endpoint • Net adverse clinical events: composite of all-cause death, non-fatal MI, stroke, or major bleeding (ISTH classification) • Secondary endpoints • Individual components of the primary outcome • Stent thrombosis (defined according to the Academic Research Consortium [ARC]) • Repeat revascularization of the treated vessel • Bleeding (ISTH, GUSTO, TIMI, BARC classifications)

8. Statistical analysis Superiority trial: • 983 patients per arm • 80% power, alpha type-I error of 5% • Significant reduction in the primary composite outcome at 3 years post-randomization from 7% with aspirin alone to 4% with extended DAPT Owing to lack of resources and slower enrolment than anticipated, the executive committee and sponsor recommended termination of follow-up at the end of September 2014

9. Patient flow chart (CONSORT)

10. Patient baseline characteristics

11. Procedural characteristics 34.4% 38.0% 65.6% 62.0% 33.5% 35.1%

12. Treatment at randomization

13. Primary outcome:Composite of death, MI, stroke, major bleed R 0.75, 95% CI 0.50-1.28 P=0.17 7.5% 5.8%

14. Components of the primary endpoint Death Stroke HR 0.69, CI 0.22-2.18 P=0.53 HR 0.65, CI 0.34-1.22 P=0.18 MI Major bleed HR 0.67, CI 0.31-1.44 P=0.31 HR 0.98, CI 0.47-2.05 P=0.95

15. Post-hoc analysis of ischaemic outcomes: death, stroke, or MI HR 0.64, 95% CI 0.40-1.02 P=0.06 6.4% 4.2%

16. Bleeding events

17. Meta-analysis of RCTs testing 12 months vs longer DAPT after DES: Death, stroke, MI

18. Meta-analysis of RCTs testing 12 months vs longer DAPT after DES: Death, stroke, MI

19. Study limitations • Only powered to detect major differences in ischaemic and bleeding events • Termination of the trial before enrolment and follow-up were completed reduced the trial power • Open-label trial, although all clinical outcomes were adjudicated by an independent clinical event committee blinded to treatment assignment

20. Conclusions (1) Extending DAPT duration for up to 48 months did not achieve statistical superiority compared with stopping clopidogrel at 12 months with regards to net adverse clinical outcomes, in patients free of MACCE and major bleed 12 months after stent implantation

21. Conclusions (2) • Borderline but non-statistically significant reduction in post-hoc analysis of ischaemic outcomes with extended DAPT • No apparent increase in bleeding and all-cause mortality with extended DAPT

22. Main recruiting sites Tarbes, Private office, N. Ley CH Bagnols sur Ceze, A. El Jabali CMC, Port Marly,, M. Brami CHU Kremlin Bicêtre,, A. Bouchachi, Villefranche de Rouergue, Private office, P. Beranger CH Nanterre, F Digne Cherbourg, Private office, P. Pon-Bache Gabrielsen CHU Nice, E Ferrari Creil, Private office, JPh Détienne CHU Caen, M Hamon Nantes, Private office, M. Benghanem Thionville, : P. Houplon CHU Bichat, Paris, G Steg Biarritz, M. Ducoudre Saint-Germain en Laye, Private office, M Sander And 27 other centres CHU Pitié-Salpétrière, Paris, G Helft CH Versailles, JL Georges CHU Toulouse, D Carrié Grenoble, Private office, X Dreyfus CHU Angers, A Furber CHU Montpellier, F Leclercq CHU Rouen, H Eltchaninoff Polyclinique de Bergerac, Falquier CHU Lariboisière, Paris, P Henry CH Le Raincy-Montfermeil, S Cattan Clinique Turin, Paris, L Sebagh CHU Tenon, Paris, PL Michel CH Cherbourg, A Tuambilangana CHU Nîmes, G Cayla CHU Bordeaux, H Douard CH Compiègne, A Luycx-Bore

23. Trial organization • Steering Committee • G. Helft, P.G. Steg, J.Ph. Metzger, C. Le Feuvre, E. Vicaut • Clinical Events Committee • L. Payot, O. Varenne, T. Petroni, O. Jobard, F. Laveau • Data Monitoring Committee • C. Elie, N. Mansencal, E. Durand • Study Staff • E. Berman , V. Raghavan, S. Djaileb