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

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

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

4. 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 Stent Thrombosis of DES Data from a large two institutional cohort study 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 % stent thrombosis All pts (n=804) Clop-Resp (n=699, 87%) Clop-nonResp (n=105, 13%) 2.3 (n=16) P <.0001 8.6 (n=9) 3.1 (n=25) 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) 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. 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 The perioperative dilemma

15.  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 Coronary stent thrombosis and noncardiac surgery

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

17. Continue dual antiplatelet therapy during and after surgery MINIMIZE THE RISK OF STENT THROMBOSIS Stop clopidogrel and aspirin and “bridge” with a short-acting GP IIb-IIIa inhibitor Continue aspirin, stop clopidogrel and restart it soon after surgery Risk of bleeding 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. Risk of discontinuing warfarin and increasing the possibility of stroke or thromboembolic events Risk of discontinuing clopidodrel and increasing the possibility of stent thrombosis The triple dilemma of triple therapy Risk of continuing warfarin + aspirin + clopidogrel and increasing the possibility of bleeding

20. Triple therapy and major bleeding @ 30 days 6.0% @ 6 months 13.3% @ ≥ 12 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 Gilard et al. J Am Coll Cardiol 2008;51:256-60. p<0.0001 clopidogrel clopidogrel + omeprazole

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. 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) The COGENT Trial

27. Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status HR = 1.02 95% CI = 0.70; 1.51 Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk

28. Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status HR = 0.96 95% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk Treated: 36 events, 1839 at risk

29. Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status HR = 0.95 95% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk

30. HR = 0.55 95% CI = 0.36; 0.85 p=0.007 Placebo: 67 events, 1895 at risk Treated: 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. CV death, MI or stroke Days CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PPI use at randomization (n= 4529) Clopidogrel Prasugrel PRASUGRELPPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20 Primary endpoint stratified by use of a PPI O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

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

35. - sympathetic activation - increased inflammatory mediator release - increased platelet adhesiveness and persistently high platelet counts - increase release of procoagulant factors - decreased/impaired fibrinolysis 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