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MANAGING ATHERO-THROMBOTIC RISK Early impact and long-term benefit of antiplatelet therapy

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 2008. www.metcardio.org.

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MANAGING ATHERO-THROMBOTIC RISK Early impact and long-term benefit of antiplatelet therapy

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  1. MANAGING ATHERO-THROMBOTIC RISK Early impact and long-term benefit of antiplatelet therapy What is the optimal duration of antiplatelet therapy? Giuseppe BiondiZoccai, M.D. Division of Cardiology, University of Turin, Turin, Italy EFIM-7, Rome, 7-10 May 2008 www.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 Scientific Consultant Bristol Myers Squibb Speaker bureau Cephalon Consultant/Speaker bureau Cordis Speaker bureau Invatec Consultant Mediolanum Cardio Research Consultant/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: • 1 month • 6 months • 9 months • 12 months • 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: • 1 month • 6 months • 12 months • 24 months • 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) 0.14 Placebo + ASA 20% Relative Risk Reduction P=0.00009 0.12 0.10 Clopidogrel + ASA Study subjects had ACS (UA/non–ST-elevation MI) 0.08 Cumulative Hazard Rate 0.06 The primary outcome occurred in 9.3% of patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group 0.04 0.02 0.00 9 0 6 12 3 Months of Follow-up CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  11. 15 11.5% Placebo n=1063 10 Death, MI, or Stroke, % 8.5% Clopidogrel n=1053 5 P=.02 0 0 3 6 9 12 Months CREDO – 1-year primary outcome 27% Relative RiskReduction Adapted from Steinhubl SR, et al. JAMA.2002;288:2411-2420.

  12. CURE safety Bleeding Results † 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. REACH – 1/4 of patients with CAD also have polyvascular disease ~ 1/4 of the 40,258 patients with CAD also have atherothrombotic disease in other arterial territories (%s are of total population, n=67,888) Multiple risk factors only population Patients with CAD = 59.3% of the REACH Registry population CAD 44.6% 8.4% CVD 16.6% 1.6% 4.7% PAD 4.7% CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease 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 25 23.1 CAD alone (n=28,867) 20 17.4 PAD alone (n=3,246) CAD + PAD (n=3,264) 15 13.0 1-year event rate (%) 10 5.5 3.6 5 3.1 3.2 1.6 1.2 1.4 1.5 1.4 1.0 0.9 0.8 0 CV death Non-fatal MI Non-fatal stroke CV death, MI or CV death, MI, stroke stroke or hospitalisation* *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.

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

  17. CHARISMA overall population – primary efficacy outcome (MI, stroke, or CV death)* Placebo + ASA† 7.3% 8 Clopidogrel + ASA† 6.8% 6 Cumulative event rate (%) 4 RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 2 0 0 6 12 18 24 30 Months since randomization‡ *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.

  18. CHARISMA primary end point (MI/stroke/CV death) in pts with previous MI, stroke or PAD* 10 N=9,478 Placebo + ASA 8.8% Clopidogrel + ASA 7.3% 8 6 Primary outcome event rate (%) 4 RRR: 17.1 % [95% CI: 4.4%, 28.1%] P=0.01 2 * Post hoc analysis 0 0 6 12 18 24 30 Months since randomization Bhatt DL, et al.J Am Coll Cardiol 2007;49:1982–8

  19. CHARISMA overall population – safety results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=7,802) (n=7,801) P-value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 0.17 Primary ICH 26 (0.3) 27 (0.3) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) <0.001 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. ICH=Intracranial hemorrhage. • Adjudicated outcomes by intention to treat analysis. Adapted from Bhatt DL et al. N Engl J Med. 2006;354:1706-1717.

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

  21. CAPRIE - efficacy of clopidogrel in MI, ischemic stroke, or vascular death (N=19,185) Median Follow-up=1.91 years 8.7%* Aspirin Overall Relative RiskReduction 16 Clopidogrel 12 Aspirin Cumulative Event Rate (%) P=0.045 8 Clopidogrel Study subjects had either recent MI, recent ischemic stroke, or established peripheral arterial disease. 4 0 36 0 3 6 9 12 15 18 21 24 27 30 33 Months of Follow-Up • ITT analysis. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

  22. CAPRIE post hoc analysis - benefit enhanced in pts with previous ischemic events* The absolute risk reduction (ARR) among patients with a history of acute events favored the clopidogrel group through the duration of the trial RRR 12.0% (95% CI 0.6-22.1) NNT 26 ARR 3.9% RRR 14.9% (95% CI 0.3-27.3) NNT 29 ARR 3.4% IS, MI, rehospitalization IS, MI, VD * 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.

  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 8146 patientstreatedwith DES (sirolimus or paclitaxel- elutingstents) followed for a meanof 1.7 years (up to 3) 0.6% per year • Stent thrombosis: • Cumulative incidence -> 2.9% rate • Late thrombosis -> costant 0.6% yearly rate Daemen J et al. Lancet 2007;369:667–78

  25. Duke Registry – clopidogrel and long-term outcomes after DES implantation Adjusted rates of death or MI starting at 6 months • 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 inthe DES without clopidogrel group • Among BMS patients, there were no differences in deathor MI Difference = -4.1 ± 3.5 p=0.02 Difference = -0.5 ± 2.7 p=0.70 Endpoint (%) 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 guidelines2007 update Bassand J-P et al. Eur Heart J 2007;28:1598–1660.

  28. NSTE-ACS - recommendations for oral antiplatelet drugs (2007) • 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) 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. PCI - recommendations for oral antiplatelet drugs (2005) • 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) 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. International updates – US PCI guidelines (2007) • 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) King SB III et al. Circulation 2008;117:261-95.

  33. Take home messages

  34. Take home messages • 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: • 1 month • 6 months • 9 months • 12 months • 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: • 1 month • 6 months • 12 months • 24 months • 36 months

  40. Manythanks for furtherslides on thistopic, pleasevisit the www.metcardio.org website

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