Giovanni Maria Santoro S. C. Cardiologia Ospedale San Giovanni di Dio Firenze

1. Gestione del paziente con stent coronarico. Il mantenimento della doppia antiaggregazione a lungo termine Giovanni Maria Santoro S. C. Cardiologia Ospedale San Giovanni di Dio Firenze

2. Efficacy of Dual Antiplatelet Therapy in Reducing Coronary Events after Stenting

3. Early stent thrombosis in patients treated with BMS Subacute stent thrombosis 24 h - 1 month Acute stent thrombosis < 24 h Cutlip et al. Circulation 2001;103:1967-71

4. Stent Thrombosis of DES Data from a large two institutional cohort study Cumulative incidence at 3 yrs 2.9% Predictors of stent thrombosis ACS HR 2.28 95% CI 1.29-4.03 Diabetes HR 2.07 95% CI 1.07-3.83 Daemen J et al. Lancet 2007;369:667-668

5. Histological characterization of DES vs BMS

6. Endhotelialization in DES vs BMS

8. Independent predictors of stent thrombosis Iakovou I, Colombo A, et al. JAMA 2005; 293:2126-30

9. Long-term dual antiplatelet therapy Main open issues • Clopidogrel low responsiveness • Perioperative management • Chronic oral anticoagulation • Interaction with PPIs

10. Clopidogrel absorption, metabolism and target

11. Definite/Probable DES thrombosis at 6-month FU • 804 unselected consecutive pts with CAD (2/3 UA/STEMI) with DES implanted, on ASA and clopidogrel (600 mg loading dose + 75 mg/day chronically for almost six months) P < .0001 % stent thrombosis 8.6 (n=9) 3.1 (n=25) 2.3 (n=16) Clop-nonResp (n=105, 13%) Clop-Resp (n=699, 87%) All pts (n=804) Buonamici et al. J Am Coll Cardiol 2007;49:2312

13. Long-term dual antiplatelet therapy Main open issues • Clopidogrel low responsiveness • Perioperative management • Chronic oral anticoagulation • Interaction with PPIs

14. The perioperative dilemma Risk of discontinuing antiplatelet therapy and increasing the possibility of perioperative stent thrombosis Risk of continuing antiplatelet therapy and increasing the possibility of surgical bleeding

15. Coronary stent thrombosis and noncardiac surgery • noncardiac surgery increases the risk of stent thrombosis • early surgery carries significantly greater risk than delayed surgery • the risk increases when antiplatelet therapy is discontinued

16. DELAY SURGERY ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery

17. MINIMIZE THE RISK OF STENT THROMBOSIS Continue dual antiplatelet therapy during and after surgery Risk of bleeding Continue aspirin, stop clopidogrel and restart it soon after surgery Stop clopidogrel and aspirin and “bridge” with a short-acting GP IIb-IIIa inhibitor Heparin probably ineffective because stent thrombosis is primarily a platelet-mediated phenomenon.

18. Long-term dual antiplatelet therapy Main open issues • Clopidogrel low responsiveness • Perioperative management • Chronic oral anticoagulation • Interaction with PPIs

19. The triple dilemma of triple therapy Risk of discontinuing clopidodrel and increasing the possibility of stent thrombosis Risk of continuing warfarin + aspirin + clopidogrel and increasing the possibility of bleeding Risk of discontinuing warfarin and increasing the possibility of stroke or thromboembolic events

20. Triple therapy and major bleeding @ ≥ 12 months 13.3% @ 30 days 6.0% @ 6 months 13.3% Rubboli et al. Ann Med 2008;40:428-36

21. What to do in patients with DES who need warfarin? DO NOT STOP CLOPIDOGREL PREMATURELY • Add warfarin to clopidogrel and aspirin if < 1 month after BMS or < 1 year after DES implantation. • Limit the time of triple therapy as much as possible, containing aspirin dose to ≤100 mg and targeting INR to 2.0-2.5. • A combination of warfarin and one antiplatelet agent seem to be a better choice for long-term treatment after stent implantation. • Since the most frequent bleeding site is gastro-intestinal, strategies to reduce GI events are recommended.

22. Long-term dual antiplatelet therapy Main open issues • Clopidogrel low responsiveness • Perioperative management • Chronic oral anticoagulation • Interaction with PPIs

24. Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite PPIs are strong inhibitors of CYP2C19 activity Clopidogrel and PPIs – The OCLA study PRI: Platelet Reactivity Index – change at day 7 from baseline clopidogrel clopidogrel + omeprazole p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:256-60.

25. Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI Of 8205 patients with ACS taking clopidogrel after hospital discharge, 63.9% (n=5244) were prescribed PPI at discharge Clopidogrel + PPI Clopidogrel / noPPI Ho et al. JAMA. 2009;301(9):937-944.

26. The COGENT Trial • Multicenter, international, randomized, double-blind, placebo-controlled trial • Comparison of a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), with clopidogrel (75 mg) alone. • All patients were to receive enteric coated aspirin at a dose of 75 to 325 mg. • 3627 patients included, median follow-up 133 days (max 366 days)

27. Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk HR = 1.0295% CI = 0.70; 1.51 Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status

28. HR = 0.9695% CI = 0.59; 1.56 Placebo: 37 events, 1851 at riskTreated: 36 events, 1839 at risk Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status

29. HR = 0.9595% CI = 0.59; 1.55 Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status

30. HR = 0.5595% CI = 0.36; 0.85 p=0.007 Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at risk

31. Conclusions • COGENT is the first, randomized assessment of clopidogrel and PPIs on clinical events • The data provide strong reassurance that there is no clinically relevant adverse cardiovascular interaction between clopidogrel and omeprazole • The results support the use of prophylactic PPIs, although the optimal strategy to reduce GI events in patients on antithrombotic therapy is still needed to define.

33. Primary endpoint stratified by use of a PPI PPI use at randomization (n= 4529) Clopidogrel Prasugrel CV death, MI or stroke CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20 Days O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

34. Major bleeding risk Triple therapy vs Double therapy Major bleeding Relative Risk 4.16 (95% CI 2.08-8.33) Sourgounis et al. Circulation 2009;119:1682-88

35. Noncardiac surgery and risk of stent thrombosis • incomplete endhotelialization of the stent • rebound after interruption of antiplatelet therapy - increased platelet adhesion and aggregation - increased inflammatory prothrombotic state • increased prothrombotic and inflammatory state associated with surgery - sympathetic activation - increased inflammatory mediator release - increased platelet adhesiveness and persistently high platelet counts - increase release of procoagulant factors - decreased/impaired fibrinolysis