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Progress in Oral Anti-Platelet Therapy

Progress in Oral Anti-Platelet Therapy. Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital. GP IIb/IIIa Receptor Activation Pathway. ADP. Thrombin. TXA 2. PAF. PLATELET. ASPIRIN. Vasopressin. Epi. ASPIRIN. ASPIRIN. HEPARINS. ASPIRIN. CLOPIDOGREL.

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Progress in Oral Anti-Platelet Therapy

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  1. Progress in Oral Anti-Platelet Therapy Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital

  2. GP IIb/IIIa Receptor Activation Pathway ADP Thrombin TXA2 PAF PLATELET ASPIRIN Vasopressin Epi ASPIRIN ASPIRIN HEPARINS ASPIRIN CLOPIDOGREL ASPIRIN ASPIRIN 5HT ASPIRIN Collagen GP IIb/IIIa Thickness of lineindicates strengthof activator Fibrinogen GP IIb/IIIa PLATELET

  3. Role of Thienopyridines • Inhibit platelet aggregation • Improve cardiovascular outcome • Decrease the risk of MI • Decrease the risk of stent thrombosis • Decrease the risk of death

  4. What is the Effect of Clopidogrel on Platelet Aggregation?

  5. Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days) Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)

  6. Why is the onset of action of clopidogrel late and why is the response to clopidogrel variable?

  7. Is There a Correlation Between Poor Platelet Inhibition and Adverse Cardiovascular Outcome?

  8. Can We Improve the Outcome by Improving Platelet Inhibition?

  9. TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET REACTIVITY MONITORING DECREASE EARLY STENT THROMBOSIS L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli. Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCE Laboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCE Service de cardiologie, Hôpital d’aubagne, Aubagne; FRANCE Service de cardiologie, Clinique clairval, Marseille; FRANCE Service de cardiologie, Clinique Bouchard, Marseille; FRANCE Service de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCE Laboratoire de statistique, Faculté de la Timone, Marseille; FRANCE Service de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE Am J Cardiol 2009;103:5-10

  10. Non-emergent PCI : ACS and Stable angina (n= 1122) Loading dose (LD) -ASA 250mg -Clopidogrel 600mg DESIGN VASP ≥ 50% Randomization (n=429) CONTROL (n =215) VASP-guided LD (n =214) Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCI Maintenance dose -ASA 160 mg -Clopidogrel 75 mg 1° endpoint: Definite stent thrombosis (ARC definition) 2° endpoints: MACE including CV death, MI and U-TVR TIMI major and minor bleeding at 30 days

  11. VASP after first LD 66 ± 11 67 ± 10 VASP after sensitization  37 ± 12† † p <0.01 Platelet reactivity monitoring 17 patients (8%)

  12. Timing of early stent thrombosis All early stent thrombosis occured during the first 7 days Am J Cardiol 2009;103:5-10

  13. How Can We Solve the Problem Caused by Clopidogrel Resistance? Is the answer by increasing the dose?

  14. TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38 Study funded by Daiichi Sankyo Company, Limited and Eli Lilly and Company

  15. TRITON-TIMI 38: Study Objective and Hypothesis To test the hypothesis that an antiplatelet agent that results in higher and less variable IPA reduces ischemic events1 To evaluate the safety of a regimen that produces higher IPA1 To determine in ACS subjects with planned PCI whether:2 Prasugrel is superior to clopidogrel in reducing occurrence of CV death, nonfatal MI, or nonfatal stroke Prasugrel has a similar safety profile to clopidogrel ACS=Acute Coronary Syndrome; CV=Cardiovascular; IPA=Inhibition of Platelet Aggregation; MI=Myocardial Infarction; PCI=Percutaneous Coronary Intervention 1.Wiviott SD et al. New Engl J Med 2007;357:2001-20152. Wiviott SD et al. Am Heart J 2006;152:627-635

  16. TRITON-TIMI 38: Study Design and Primary Efficacy End Points R Prasugrel 60 mg LD/ 10 mg MD ASA UA/NSTEMI (TIMI Risk Score ≥ 3) 12.0 month planned median & Planned PCI Double-blind treatment 6 - 15 months planned follow-up 14.5 month actual median STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days) ASA Clopidogrel 300 mg LD/ 75 mg MD Day 3 Day 30 Day 90 Day 450 Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke = Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR = Key safety end point: non-CABG related TIMI Major Bleeding ASA=Acetylsalicylic Acid; CABG=Coronary Artery Bypass Graft surgery; LD=Loading Dose; MD=Maintenance Dose; MI=Myocardial Infarction; NSTEMI=Non-ST-Elevation Myocardial Infarction; PCI=Percutaneous Coronary Intervention; R=Randomization; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; UTVR=Urgent Target Vessel Revascularization Wiviott SD et al. New Engl J Med 2007;357:2001-2015Wiviott SD et al. Am Heart J 2006;152:627-635

  17. TRITON-TIMI 38: TIMI Bleeding Definitions Hgb=Hemoglobin; PRBC=Packed Red Blood Cells; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. Am Heart J 2006;152:627-635

  18. TRITON-TIMI 38: Key Enrollment Criteria Inclusion Criteria Moderate-high risk ACS patients with planned PCI: UA/NSTEMI (TIMI Risk Score ≥3) within 72 hours of symptom onset STEMI: Primary PCI (within 12 hours) STEMI: Primary PCI not planned (>12 hours to ≤14 days) Exclusion Criteria Any thienopyridine within 5 days of randomization Daily treatment with NSAID or Cox-2 inhibitor Fibrin-specific fibrinolytic therapy <24 hours Increased bleeding risk History of hemorrhagic stroke; or ischemic stroke ≤3 months ACS=Acute Coronary Syndrome; NSTEMI=Non–ST-Elevation Myocardial Infarction; CI=Percutaneous Coronary Intervention; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; NSAID=Non-steroidal Anti-Inflammatory Drug Wiviott SD et al. Am Heart J 2006;152:627-635

  19. TRITON-TIMI 38: Baseline Characteristics * P=0.02 NSTEMI=Non–ST-Elevation Myocardial Infarction; STEMI=ST-Elevation Myocardial Infarction; UA=Unstable Angina 1. Wiviott SD et al. New Engl J Med 2007;357:2001-2015 2. Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

  20. TRITON-TIMI 38: Study Drug and Pharmacotherapies *P=0.03 Wiviott SD et al. New Engl J Med 2007;357:2001-2015 PCI=Percutaneous Coronary Intervention

  21. TRITON-TIMI 38: Primary End Point All ACS Population 15 HR 0.77 (0.67-0.88)P<0.001 Clopidogrel 12.1(n=781) 9.9 (n=643) 10 Prasugrel CV Death/MI/Stroke (%) HR 0.81 (0.73-0.90)P<0.001ARR=2.2NNT=46 HR 0.80 (0.71-0.90)P<0.001 5 Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%) 0 0 30 60 90 180 270 360 450 Days ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  22. TRITON-TIMI 38: Timing of Benefit (Primary Endpoint, All ACS– 3-Day Landmark Analysis) 8 6.9 5.6 6 Clopidogrel 5.6 Clopidogrel 4.7 CV Death/MI/Stroke (%) Prasugrel Prasugrel 4 HR 0.82 (0.71-0.96)P=0.01 RRR 18% ARR 0.9% HR 0.80 (0.70-0.93)P=0.003 RRR 20% ARR 1.3% 2 0 0 1 2 3 3 30 90 180 270 360 450 Loading Dose Maintenance Dose Days ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; RRR=Relative Risk Reduction Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  23. TRITON-TIMI 38: Rates of Key Study End Points (All ACS) 15 12.1(n=781) Clopidogrel CV Death, MI, Stroke 9.9 (n=643) 10 P<0.001 Prasugrel ↓138 events End Point (%) P=0.03 5 ↑ 35 events Non-CABG TIMI Major Bleeds 2.4 (n=146) Prasugrel 1.8 (n=111) Clopidogrel 0 0 30 60 90 180 270 360 450 120 Days After Randomization CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  24. TRITON-TIMI 38: Net Clinical Benefit(All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed) 15 13.9 12.2 Clopidogrel HR 0.87 (0.79-0.95)P=0.004 10 Prasugrel End Point (%) 5 ITT=13,608 0 0 30 60 90 180 270 360 450 Days After Randomization MI=Myocardial Infarction; CABG=Coronary Artery Bypass Graft surgery; Hazard Ration; ITT=Intent To Treat; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  25. TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent 3 2 1 0 0 30 60 90 180 270 360 450 Any Stent at Index PCI n=12,844 2.4 Clopidogrel Stent Thrombosis (%) 1.1 Prasugrel HR 0.48 (0.36-0.64)P<0.001 RRR 52% ARR 1.22% NNT=77 Days ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363

  26. TRITON-TIMI 38: Primary Endpoint (CVD/MI/Stroke) Not Related to Stent Thrombosis 0 50 100 150 200 250 300 350 400 450 12 10.3% 10 RRR 15% Clopidogrel 8.7% 8 HR 0.85p=0.005 % of Subjects 6 Prasugrel 4 2 0 Days CVA=cerebrovascular accident; HR=hazard ratio; MI=myocardial infarction Wiviott SD et al. Lancet2008;371:1353-1363

  27. TRITON-TIMI 38: Net Clinical Benefit: MI and Non-CABG TIMI Major Bleeds Events per 1,000 patients on prasugrelversus clopidogrel Myocardial Infarction +6 # of Events -23 Non-CABG TIMI Major Bleed CABG=Coronary Artery Bypass Graft surgery; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  28. TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146) 18 17.0 Clopidogrel CV Death, MI, Stroke 16 Prasugrel 14 12.2 12 HR 0.70P<0.001 10 End Point (%) NNT=21 8 6 Non-CABG TIMI Major Bleeds 4 2.6 2.5 2 0 0 30 60 90 180 270 360 450 Days CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT= Number Needed to Treat; TIMI=Thrombolysis In Myocardial Infarction Adapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

  29. TRITON-TIMI 38: Net Clinical BenefitPost-hoc Analyses in Selected Subgroups P* value P** interaction All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed Yes 0.04 - History of stroke or TIA No <0.001 0.006 Any of the following: Age >75 y, Body wt. <60 kg, History stroke/TIA 0.43 - Yes <0.001 0.006 No 0.5 0.8 1.0 1.3 1.5 1.8 2.0 2.3 2.5 HR Clopidogrel Better Prasugrel Better *Tests hazard ratio =1.0 within subgroups; **Tests equality hazard ratio between subgroups MI=Myocardial infarction; HR=Hazard Ratio; TIA=Transient Ischemic Attack; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  30. TRITON-TIMI 38: Clinical Implications For every 1,000 patients treated with prasugrel compared with clopidogrel 23 MI’s are prevented 6 more non-CABG TIMI major bleeds are experienced Over 15 months Number needed to treat is 46 to prevent one CV death, nonfatal MI or nonfatal stroke Number needed to harm is 167 to cause one non-CABG TIMI major bleed CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  31. Conclusions The TRITON-TIMI 38 Trial demonstrated that prasugrel is more effective at preventing ischemic events than clopidogrel in moderate to high-risk patients with ACS with scheduled PCI Prasugrel was also more effective at preventing stent thrombosis The beneficial effect of intensive inhibition of platelet aggregation is accompanied by increased risk of major bleeding Analysis of net clinical benefit favored prasugrel over clopidogrel In patients with STEMI and those with Diabetes the superiority of prasugrel compared to clopidogrel was more important with SAME bleeding risk ACS= Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention Wiviott SD et al. New Engl J Med 2007;357:2001-2015

  32. ACC/AHA 2009 STEMI/PCI Guidelines Focused Update Based on the ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (STEMI) and the ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (PCI): A Report of the ACC/AHA Task Force on Practice Guidelines

  33. IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III I I I I I I C B MODIFIED Recommendation Recommendations for the use of Thienopyridines STEMI A loading dose of thienopyridine is recommended for STEMI patients for whom PCI is planned. Regimens should be one of the following: Prasugrel 60 mg should be given as soon as possible for primary PCI. Clopidogrel at least 300 mg to 600mg† should be given as early as possible before or at the time of primary or non-primary PCI.

  34. Recommendations for the timing of Angiography and Antiplatelet Therapy in UA/NSTEMI

  35. IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III III III III III I I I I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III III III III III I I I I I I I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III III III III III III III III III I I I I I I I I I I I I A B A B Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive …dual-antiplatelet therapy on presentation, ASA should be initiated on presentation The choice of a second antiplatelet therapy to be added to ASA on presentation includes 1 of the following: Before PCI: ● Clopidogrel; or ● An IV GP IIb/IIIa inhibitor. (Level of Evidence: A) IV eptifibatide or tirofiban are the preferred GP IIb/IIIa inhibitors. At the time of PCI: ● Clopidogrel if not started before PCI; or ● Prasugrel; or ● An IV GP IIb/IIIa inhibitor (Level of Evidence: A) JACC Vol. 57, No. 18, March 2011

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