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Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease

Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease. פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון. דצמבר 2005. Acute Coronary Syndromes . Acute Coronary Syndrome. No ST Elevation. ST Elevation. Non ST Elevation MI. Myocardial Infarction Non Q MI Q wave MI.

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Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease

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  1. Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease פרופ’ יוסף רוזנמן מכון הלב, בי"ח וולפסון דצמבר 2005

  2. Acute Coronary Syndromes Acute Coronary Syndrome No ST Elevation ST Elevation Non ST Elevation MI Myocardial Infarction Non Q MIQ wave MI Unstable Angina Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.

  3. Initial Treatment Strategy ACS ST Elevation Non ST Elevation Culprit plaque stabilization Reperfusion and culprit plaque stabilization • Anti-thrombotic Rx (+ Fibrinolysis) • 2. Early / Primary PCI • Anti-thrombotic Rx • Early PCI The best way to stabilize a culprit plaque is with a stent

  4. Goals of Peri – PCI Medical Treatment (short and long term) 1 • Minimize peri-procedural complications (related to the treated plaque) • Thrombosis etc • Stabilize the rest of the non-occlusive narrowings • Prevent progression • Prevent atherothrombosis 2

  5. The Clinical QuestionsCombination Rx. (ASA + Clopidogrel) When angiography / PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month improving long-term outcome 1 2

  6. 1 Clopidogrel before coronary angiography - Patients with ACS • Goals of therapy • Prevent ischemic events until coronary angiography / PCI • Before plaque stabilization was achieved • Prevent PCI / stent related ischemic complications

  7. 1 Clopidogrel before coronary angiography -Patients with ACS • ST Elevation • CLARITY • Non ST Elevation • CURE

  8. 1 Clopidogrel before coronary angiography -Patients with ACS • ST Elevation • CLARITY • Non ST Elevation • CURE

  9. Study Design Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Clopidogrel 300 mg + 75 mg qd Placebo Study Drug Primary endpoint: Occludedartery (TIMI Flow Grade 0/1) or D/MI by timeof angio Coronary Angiogram (2-8 days) Open-label clopidogrel per MD inboth groups 30-day clinical follow-up

  10. Primary Endpoint:Occluded Artery (or D/MI by time of angio) Odds Ratio 0.64(95% CI 0.53-0.76) 36% Odds Reduction P=0.00000036 0.4 0.6 0.8 1.0 1.2 1.6 Clopidogrel better Placebo better Clopidogrel Placebo n=1752 n=1739

  11. Need for Urgent orAdditional Treatment 16%  P=0.07 21%  P=0.005 21%  P=0.01 Early Angio(w/in 48 hrs) Urgent Revasc(index hosp) GP IIb/IIIaif PCI

  12. CV Death, MI, RI  Urg Revasc 15 Placebo 20% 10 Clopidogrel Percentage with endpoint (%) Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 5 1 0 0 5 10 15 20 25 30 days

  13. CLARITY: Patient Management • Clopidogrel Placebo • Parameter (n=1,752) (n=1,739) • Symptom onset to fibrinolytic (hours) 2.72.6 • Fibrinolytic to study drug (minutes) 1010 • Median doses of study medication 44 • Angiography performed (%) 9494 • Study drug to angiography (hours) 8484 • Coronary revascularization (%): 6363 • PCI 57.256.6 • CABG 5.96.0 Sabatine M et al. New Engl J Med 2005; 352: 1179–1189.

  14. 41% p=0.001 15 No Pretreatment (n=930) 12.0 Clopidogrel Pretreatment (n=933) 46% p=0.008 38% p=0.03 10 7.5 Patients with endpoint (%) 6.2 6.2 4.0 5 3.6 0 Overall Events* Pre-PCI Events** Post-PCI Events* PCI-CLARITY: MI, Stroke, or CV DeathEvents pre and post PCI ***MI or Stroke M Sabatine, et al. JAMA 2005,

  15. Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction: The Clarity Ambulance Substudy

  16. Substudy Sites and Patient Numbers France: 172 patients • L Soulat: 57 • Y Lambert: 48 • F Lapostolle: 28 • F Thieuleux: 21 • C Gully: 10 • D Pollet: 5 • D Galley: 2 • L Olliver: 1 • UK: 40 patients • J Adgey: 27 • J Purvis: 13 • Sweden: 5 patients • J-E Karlsson: 5 217 patients in total

  17. 2.0 1.5 1.0 0.5 0 2.5 3.0 Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance Event rate (%) Odds ratio (95% CI) Ambulance Non-ambulance p value Ambulance better Non-ambulance better *Complete considered to be >70%; ECG=electrocardiogram

  18. Primary Endpoint of TIMI Flow Grade 0/1, MI or Death Odds ratio (95% CI) 0.60 (0.301.17) Ambulance 0.65 (0.540.77) Non-ambulance Overall 0.64 (0.530.76) 0 0.5 1.0 1.5 2.0 Clopidogrel better Placebo better

  19. 1 Clopidogrel before coronary angiography -Patients with ACS • ST Elevation • CLARITY • Non ST Elevation • CURE

  20. CURE Study Design Clopidogrel 300 mg loading dose Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.* (6259 patients) Patients with Acute CoronarySyndrome R 3 months £ double-blind treatment £ 12 months (unstable angina or non-ST-segment elevation MI) Placebo + ASA 75-325 mg q.d.* (6303 patients) Day 1 3 m. Visit 1 m. Visit 6 m. Visit 9 m. Visit 12 m.or Final Visit Discharge Visit Placebo loading dose The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. R = Randomization* In combination with other standard therapy

  21. CURE Primary End Point - MI/Stroke/CV Death 11.4% Placebo + ASA* 9.3% Clopidogrel + ASA* 20% RRR P < 0.001 N = 12,562 0 3 6 9 12 Months of Follow-Up * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  22. CURE MI/Stroke/CV Death within 30 Days 1 Placebo + ASA* Clopidogrel + ASA* 21% RRR P = 0.003 N = 12,562 0 10 20 30 Days of Follow-Up * In combination with standard therapy The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  23. CURE MI/Stroke/CV Death or severe Ischemia at 24 hours 1 34% CV death, nonfatal MI,stroke or refractory orsevere ischemia NEJM 2001; 345:495-502

  24. CURE Need for Additional Anti-Thrombotic After Randomization 1 GP IIb/IIIa Inhibitor Thrombolysis P= 0.003 P< 0.001 18% 43% % patients requiringGP IIb/IIIa inhibitors % patients requiringthrombolytic therapy NEJM 2001; 345:495-502

  25. Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before coronary angiography (“upstream”) ? • Is there additional benefit to clopidogrel that would justify: • Increased CABG bleeding or alternatively • Need to postpone CABG for 3-5 days No data in the literature however

  26. The Role of Platelets in Atherothrombosis Adhesion Aggregation 1 3 Activation 2 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

  27. 1 Conclusions: Early Clopidogrel Therapy • Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome • ST elevation and non ST elevation • Treatment is effective to reduce ischemic complications • Before coronay angiography • During and after PCI

  28. 1 Conclusions: Early Clopidogrel Therapy • Loading dose should be 600mg to achieve early optimal antiplatelet effect • ?? 300mg in patients after fibrinolytic therapy • It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists • Especially in high risk patients in whom the likelihood for CABG is high

  29. Goals of Peri – PCI Medical Treatment (short and long term) 1 • Minimize peri-procedural complications (related to the treated plaque) • Thrombosis etc • Stabilize the rest of the non-occlusive narrowings • Prevent progression • Prevent atherothrombosis 2

  30. The Clinical QuestionsCombination Rx. (ASA + Clopidogrel) When PCI is planned in a patient already treated with ASA: Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer) Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome 1 2

  31. I IIa IIb III 2 Discharge/Post-Discharge Medications - Guidelines ASA, if not contraindicated Clopidogrel, when ASA contraindicated Aspirin + Clopidogrel for up to 9 months -blocker, if not contraindicated Lipid  agents + diet, if LDL >130 mg/dL ACE Inhibitor: CHF, EF < 40%, DM, or HTN

  32. PCI-CURE Overall Study Design: PCI-CURE PCI-CURE N = 2,658 patients undergoing PCI Pretreatment Open-label thienopyridine PLACEBO + ASA * N = 1345 Question 2 End of follow-up Up to 12 months after randomization Question 1 PCI 30 days post PCI R N = 1313 CLOPIDOGREL + ASA * Open-label thienopyridine Pretreatment Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  33. Overall Study Design: CREDO PCI* 28 Days 12 Months Randomization - Pre-treatment Open label clopidogrel continuation Clopidogrel Arm Clopidogrel 300 mg+ ASA† (325 mg) Clopidogrel 75 mg QD+ ASA† 325 mg QD Clopidogrel 75 mg QD+ ASA† (81-325 mg) QD R Clopidogrel 75 mg QD+ ASA† 325 mg QD Placebo QD+ ASA† (81-325 mg) QD Placebo Arm Placebo + ASA† (325 mg) Question 1 Question 2 1 2 Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

  34. Methodological Pitfall • Can a study with a single randomization provide an answer to two questions? Alternatively • Should a second randomization be done in order to answer the second question?

  35. PCI-CURE Study Designsingle randomization PCI-CURE Continuation Pretreatment Open-label thienopyridine PLACEBO + ASA * N = 1345 End of follow-up Up to 12 months after randomization PCI 30 days post PCI R N = 1313 CLOPIDOGREL + ASA * Open-label thienopyridine Continuation Pretreatment Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  36. PCI-CURE Alternative Study Designtwo randomizations PCI-CURE Continuation Pretreatment Open-label thienopyridine PLACEBO + ASA * N = 1345 R2 Clop. 2 Question 2 PCI R1 Placebo R2 N = 1313 CLOPIDOGREL + ASA * Open-label thienopyridine Continuation Pretreatment Mehta, SR. et al for theCURE Trial Investigators. N Engl J Med. 2001;345:494-502.

  37. Is it just methodology? Can we really expect long term benefit from early antiplatelet therapy?

  38. Adjunct antiplatelet therapy for PCI • EPISTENT • Randomized study designed to determine the effect of treatment with abciximab • TARGET • Randomized study designed to show that tirofiban is not inferior to abciximab • Post-hoc nonrandomized comparison among those who were or were not pre-treated with clopidogrel • PCI-CURE • Subgroup of CURE patients who underwent PCI • Randomized comparison of pre-treatment and continued clopidogrel therapy vs. placebo

  39. Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS Absolute reduction of Death or MI at 1 month and 1 year • Abciximab • Early clopidogrel • Early and continued • clopidogrel % reduction * * 6 month data in TARGET

  40. 2 Long Term Clopidogrel Post PCI • Clinical guidelines: 9 months to 1 year in patients with ACS • However, current data does not fully support this recommendation • What should we do?

  41. Comulative event rate in primary prevention stable CAD and ACS ACS Stable Primary

  42. Risk of vascular event after ACS Commulative risk Risk of event Risk per time Stable CAD Time after ACS

  43. Risk of vascular event after ACShigh and low risk High risk Risk of event Low risk Time after ACS

  44. Risk of bleeding after initiation of clopidogrel (high and low risk) • Fixed, except for the initial few days • heparin, catheterization Risk of event High risk Low risk Time after clopidogrel

  45. Risk of event (vascular/bleeding) after ACS and clopidogrel vascular Risk of event bleeding 3 months ?? Time after ACS

  46. Risk of event (vascular/bleeding) after ACS and clopidogrel vascular High vascular risk Risk of event bleeding 3 months ?? > 1 year Time after ACS

  47. Risk of event (vascular/bleeding) after ACS and clopidogrel vascular High bleeding risk e.g. coumadin Risk of event bleeding < 1 months 3 months ?? Time after ACS

  48. Risk of event (vascular/bleeding) after ACS and clopidogrel • Long term clopidogrel for patients with • High risk for vascular event • Low bleeding risk • Short term clopidogrel for patients with • Low risk for vascular event • High bleeding risk vascular Risk of event bleeding 3 months ?? Time after ACS

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