1. MANAGING ATHERO- THROMBOTIC RISK Early impact and long-term benefit of antiplatelet therapy What is the optimal duration of antiplatelet therapy? Giuseppe Biondi Zoccai, M.D. Division of Cardiology, University of Turin, Turin, Italy EFIM-7, Rome, 7-10 May 2008www.metcardio.org

2. Disclosure Within the past 5 years, the presenter or his partner have had a financial interest/arrangement or affiliation with the organizations listed below: Company Name:Relationship: Boston ScientificConsultant Bristol Myers SquibbSpeaker bureau CephalonConsultant/Speaker bureau CordisSpeaker bureau InvatecConsultant Mediolanum Cardio ResearchConsultant/Speaker bureau

3. Introduction: sample case studies

4. Case study 1 67-year-old man admitted for unstable angina, known for diabetes and symptomatic peripheral artery disease. Coronary angiography showed multivessel disease, subsequently treated with bypass surgery

5. Case study 1 In such a patient, provided that he is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last: A.1 month B.6 months C.9 months D.12 months E.24 months

6. Case study 2 71-year-old woman with stable angina, known for previous ischemic stroke; coronary angiography showed right coronary artery disease treated with percutaneous paclitaxel-eluting stent implantation

7. Case study 2 In such a patient, provided that she is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last: A.1 month B.6 months C.12 months D.24 months E.36 months

8. Learning goals of this presentation What is the evidence supporting dual antiplatelet therapy for 12 months? What is the rationale in favor of dual antiplatelet therapy for more than 12 months? Is there any risk of late thrombosis with drug-eluting stents? What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?

9. Learning goals of this presentation What is the evidence supporting dual antiplatelet therapy for 12 months? What is the rationale in favor of dual antiplatelet therapy for more than 12 months? Is there any risk of late thrombosis with drug-eluting stents? What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?

10. CURE – primary end point of MI/stroke/CV death (N=12,562) CURE Trial Investigators. N Engl J Med. 2001;345:494-502. The primary outcome occurred in 9.3% of patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group Months of Follow-up Clopidogrel + ASA 3 6 9 Placebo + ASA 0 12 Cumulative Hazard Rate 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 20%Relative Risk Reduction P=0.00009 Study subjects had ACS (UA/non–ST-elevation MI)

11. CREDO – 1-year primary outcome 27% Relative Risk Reduction Months 306912 0 5 15 10 Death, MI, or Stroke, % P=.02 8.5% 11.5% Clopidogrel n=1053 Placebo n=1063 Adapted from Steinhubl SR, et al. JAMA. 2002;288:2411-2420.

12. CURE safety Bleeding Results Clopidogrel + Aspirin (+ standard therapy*) N=6,259 Placebo + Aspirin (+ standard therapy*) N=6,303 Major Bleeding † 3.7%2.7% Life-threatening ‡ 2.2%1.8% Fatal 0.2% 5 g/dL hemoglobin drop 0.9% Requiring surgical intervention 0.7% Hemorrhagic strokes 0.1% Requiring transfusion (≥4 units) 1.2%1.0% Other Major Bleeding § 1.6%1.0% Significantly disabling 0.4%0.3% Intraocular bleeding with significant loss of vision 0.05% 0.03% Requiring 2–3 units of blood 1.3%0.9% Minor Bleeding || 5.1%2.4% † P=0.001. ‡ P=NS. § P=0.005. || P<0.001. CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

13. Learning goals of this presentation What is the evidence supporting dual antiplatelet therapy for 12 months? What is the rationale in favor of dual antiplatelet therapy for more than 12 months? Is there any risk of late thrombosis with drug-eluting stents? What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?

14. ~ 1/4 of the 40,258 patients with CAD also have atherothrombotic disease in other arterial territories REACH – 1/4 of patients with CAD also have polyvascular disease CAD PAD 4.7% 8.4% 1.6% CVD 16.6% 44.6% (%s are of total population, n=67,888) Patients with CAD = 59.3% of the REACH Registry population CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease 4.7% Multiple risk factors only population Adapted from Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295:180–189.

15. REACH – pts with CAD + PAD have ↑ event rates than those with PAD or CAD alone 1-year event rate (%) *TIA, UA, other ischaemic arterial event including worsening of PAD Rates adjusted for age and sex CAD, coronary artery disease; MI, myocardial infarction; REACH, Reduction of Atherothrombosis for Continued Health; TIA, transient ischaemic attack; UA unstable angina Steg PG et al. JAMA 2007;297:1197–1206. 1.6 1.4 0.9 3.6 13.0 1.4 1.0 0.8 3.1 17.4 3.2 1.5 1.2 5.5 23.1 0 5 10 15 20 25 CV deathNon-fatal MINon-fatal strokeCV death, MI or stroke CV death, MI, stroke or hospitalisation* CAD alone (n=28,867) PAD alone (n=3,246) CAD + PAD (n=3,264)

16. Benefit of clopidogrel amplified in patients with polyvascular disease – CREDO subgroup analysis Adapted from Mukherjee D et al. Heart 2006;92:49–51. 2116 patients with planned PCI TVR, target vessel revascularisation Relative risk reduction with clopidogrel (%)

17. CHARISMA overall population – primary efficacy outcome (MI, stroke, or CV death)* *First occurrence of MI, stroke (of any cause), or cardiovascular death. † All patients received ASA 75-162 mg/day. ‡ The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Adapted from Bhatt DL et al. N Engl J Med. 2006;354:1706-1717. Cumulative event rate (%) 0 2 4 6 8 Months since randomization ‡ 0 612182430 Placebo + ASA † 7.3% Clopidogrel + ASA † 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22

18. CHARISMA primary end point (MI/stroke/CV death) in pts with previous MI, stroke or PAD* RRR: 17.1 % [95% CI: 4.4%, 28.1%] P=0.01 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 612182430 Clopidogrel + ASA 7.3% Placebo + ASA 8.8% N=9,478 Bhatt DL, et al. J Am Coll Cardiol 2007;49:1982–8 * Post hoc analysis

19. CHARISMA overall population – safety results Clopidogrel Placebo + ASA+ ASA + ASA+ ASA Safety Outcome* - N (%) (n=7,802) (n=7,801) P- value GUSTO Severe Bleeding130 (1.7)104 (1.3)0.09 Fatal Bleeding26 (0.3)17 (0.2)0.17 Primary ICH26 (0.3)27 (0.3)0.89 GUSTO Moderate Bleeding164 (2.1)101 (1.3)<0.001 ICH=Intracranial hemorrhage. Adjudicated outcomes by intention to treat analysis. Adapted from Bhatt DL et al. N Engl J Med. 2006;354:1706-1717. There was one documented nonfatal case of thrombotic thrombocytopenic purpura among the clopidogrel-treated patients; this patient died one month later from end-stage chronic obstructive pulmonary disease.

20. Primary End Point ▪First occurrence of ischemic stroke, MI, or vascular death Primary End Point ▪First occurrence of ischemic stroke, MI, or vascular death Follow-up 1 to 3 years N=19,185 n=9,586 Aspirin 325 mg n=9,599 Clopidogrel 75 mg 384 centers 16 countries Patient Population ▪Patients with recent MI, recent ischemic stroke, or established PAD Patient Population ▪Patients with recent MI, recent ischemic stroke, or established PAD CAPRIE - design CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

21. CAPRIE - efficacy of clopidogrel in MI, ischemic stroke, or vascular death (N=19,185) Months of Follow-Up Cumulative Event Rate (%) 0 4 8 12 16 Clopidogrel Aspirin Overall Relative Risk Reduction 8.7%* 03691215182124273033 36 Aspirin Clopidogrel P=0.045 ITT analysis. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339. Median Follow-up=1.91 years Study subjects had either recent MI, recent ischemic stroke, or established peripheral arterial disease.

22. CAPRIE post hoc analysis - benefit enhanced in pts with previous ischemic events* *Self-reported history of IS or MI. ARR=absolute risk reduction; RRR=relative risk reduction; NNT=number needed to treat; IS=ischemic stroke; MI=myocardial infarction; VD=vascular disease. Ringleb PA et al for the CAPRIE Investigators. Stroke. 2004;35:528-532. The absolute risk reduction (ARR) among patients with a history of acute events favored the clopidogrel group through the duration of the trial RRR 14.9% (95% CI 0.3-27.3) NNT 29 ARR 3.4% IS, MI, rehospitalization RRR 12.0% (95% CI 0.6-22.1) NNT 26 ARR 3.9% IS, MI, VD

23. Learning goals of this presentation What is the evidence supporting dual antiplatelet therapy for 12 months? What is the rationale in favor of dual antiplatelet therapy for more than 12 months? Is there any risk of late thrombosis with drug-eluting stents? What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?

24. Rotterdam-Bern Registry – long-term incidence of DES thrombosis Daemen J et al. Lancet 2007;369:667–78 8146 patients treated with DES (sirolimus or paclitaxel- eluting stents) followed for a mean of 1.7 years (up to 3) Stent thrombosis: Cumulative incidence -> 2.9% rate Late thrombosis -> costant 0.6% yearly rate 0.6% per year

25. Duke Registry – clopidogrel and long- term outcomes after DES implantation Endpoint (%) Adjusted outcomes were analyzed at 24 months Patients in the DES with clopidogrel group had significantly lower rates of death or MI than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in death or MI Adjusted rates of death or MI starting at 6 months Difference = -4.1 ± 3.5 p=0.02 Difference = -0.5 ± 2.7 p=0.70 Eisenstein EL et al. JAMA 2007;297:159–68

26. Learning goals of this presentation What is the evidence supporting dual antiplatelet therapy for 12 months? What is the rationale in favor of dual antiplatelet therapy for more than 12 months? Is there any risk of late thrombosis with drug-eluting stents? What does the European Society of Cardiology recommend in patients with acute coronary syndromes/stents?

27. ESC NSTE-ACS guidelines 2007 update Bassand J-P et al. Eur Heart J 2007;28:1598–1660.

28. Aspirin is recommended for all patients presenting with NSTE-ACS without contraindication at an initial loading dose of 160 - 325mg (non-enteric) (I- A), and at a maintenance dose of 75 to 100mg long- term (I-A) For all patients immediate 300mg loading dose of clopidogrel is recommended, followed by 75mg clopidogrel daily (I-A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding (I-A) For all patients with contraindication to aspirin, clopidogrel should be given instead (I-B) 28 NSTE-ACS - recommendations for oral antiplatelet drugs (2007) Bassand J-P et al. Eur Heart J 2007;28:1598–1660.

29. ESC PCI 2005 guidelines Silber S et al. Eur Heart J 2005;26:804-47.

30. Aspirin is recommended for all patients undergoing PCI (I-A) For all stable patients clopidogrel is recommended after bare-metal stents for 1 month (I-A), drug- eluting stents for 6–12 months and brachytherapy for 12 months or (I-C) For patients with NSTE-ACS clopidogrel is recommended for 9–12 months (I-B) PCI - recommendations for oral antiplatelet drugs (2005) Silber S et al. Eur Heart J 2005;26:804-47.

31. International updates King SB III et al. Circulation 2008;117:261-95.

32. For all patients receiving a DES, clopidogrel 75 mg daily should be given for >12 months if patients are not at high risk of bleeding (I-B) For those receiving a BMS, clopidogrel should be given for >1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for >2 weeks) (I-B) Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement (IIb-C) International updates – US PCI guidelines (2007) King SB III et al. Circulation 2008;117:261-95.

33. Take home messages

34. The benefit of dual antiplatelet therapy for 12 months following NSTE-ACS is well established in patients without excessive bleeding risk Most recent data and guidelines support dual antiplatelet therapy for 12 months in subjects treated with DES without high bleeding risk Given the long-term increased risk of thrombotic events among patients with polyvascular disease or treated with DES, dual antiplatelet therapy beyond 12 months can be considered on a case by case basis in this setting

35. Conclusions: sample case studies

36. Case study 1 67-year-old man admitted for unstable angina, known for diabetes and symptomatic peripheral artery disease. Coronary angiography showed multivessel disease, subsequently treated with bypass surgery

37. Case study 1 In such a patient, provided that he is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last: A.1 month B.6 months C.9 months D.12 months E.24 months

38. Case study 2 71-year-old woman with stable angina, known for previous ischemic stroke; coronary angiography showed right coronary artery disease treated with percutaneous paclitaxel-eluting stent implantation

39. Case study 2 In such a patient, provided that she is not at excessive bleeding risk, how long should dual antiplatelet therapy (ie aspirin and clopidogrel) last: A.1 month B.6 months C.12 months D.24 months E.36 months

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