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

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Presentation on theme: "Progress in Oral Anti- Platelet Therapy Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital 1."— Presentation transcript:

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

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3 GP IIb/IIIa Receptor Activation Pathway ASPIRIN ASPIRIN HEPARINS ASPIRIN ASPIRIN ASPIRIN ASPIRIN GP IIb/IIIa Thickness of line indicates strength of activator 5HT PAF Epi Thrombin ADP TXA 2 ASPIRIN Vasopressin Collagen Fibrinogen PLATELET PLATELET CLOPIDOGREL

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6 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

7 What is the Effect of Clopidogrel on Platelet Aggregation?

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9 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)

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

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

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15 Can We Improve the Outcome by Improving Platelet Inhibition?

16 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

17 DESIGN Non-emergent PCI : ACS and Stable angina (n= 1122) Loading dose (LD) -ASA 250mg - Clopidogrel 600mg 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

18 Platelet reactivity monitoring VASP after first LD66 ± 1167 ± 10 VASP after sensitization  37 ± 12 † 17 patients (8%) † p <0.01

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

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

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26 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

27 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: Wiviott SD et al. Am Heart J 2006;152: 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 events 1  To evaluate the safety of a regimen that produces higher IPA 1  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

28 TRITON-TIMI 38: Study Design and Primary Efficacy End Points & Planned PCI ASA 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 Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke = UA/NSTEMI (TIMI Risk Score ≥ 3) STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days) R Day 3 Day 30Day 90 Prasugrel 60 mg LD/ 10 mg MD Clopidogrel 300 mg LD/ 75 mg MD Day 450 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 = 14.5 month actual median 12.0 month planned median Double-blind treatment months planned follow-up Key safety end point: non-CABG related TIMI Major Bleeding Wiviott SD et al. New Engl J Med 2007;357: Wiviott SD et al. Am Heart J 2006;152:

29 TIMI Category Intracranial hemorrhage Clinically Overt (including imaging) Hgb drop (g/dL) MajorXX≥5 MinorX3 to <5 MinimalX<3 TRITON-TIMI 38: TIMI Bleeding Definitions Wiviott SD et al. Am Heart J 2006;152: Hgb=Hemoglobin; PRBC=Packed Red Blood Cells; TIMI=Thrombolysis In Myocardial Infarction Life Threatening: Any TIMI major bleeding event meeting any of the following criteria: Fatal Leads to hypotension requiring I.V. inotropic agents Requires surgical intervention for ongoing bleeding Necessitates transfusion of ≥ 4 units of blood (whole or PRBC) over 48 hour time period Any symptomatic intracranial bleed

30 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: 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

31 TRITON-TIMI 38: Baseline Characteristics Clopidogrel (n=6,795) Prasugrel (n=6,813) UA/NSTEMI (%) 1 74 STEMI (%) 1 26 Median age (years) 1 ≥75 years (%) Median weight (kg) 2 <60 kg (%) Female (%) 1 27*25 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: Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL * P=0.02

32 TRITON-TIMI 38: Study Drug and Pharmacotherapies Clopidogrel (n=6,795) % Prasugrel (n=6,813) % Timing of study drug loading dose Pre-PCI (before 1 st wire)2526 During PCI (1 st wire to 1 hr after leaving lab)7473 Post-PCI (>1 h after leaving lab)11 Pharmacotherapies (during index event) Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker 75*76 Beta-blocker88 Statin92 Calcium channel blocker1718 Aspirin99 PCI=Percutaneous Coronary Intervention *P=0.03 Wiviott SD et al. New Engl J Med 2007;357:

33 ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat Days Prasugrel Clopidogrel Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%) HR 0.81 ( ) P<0.001 ARR=2.2 NNT= (n=781) 9.9 (n=643) HR 0.77 ( ) P<0.001 HR 0.80 ( ) P<0.001 CV Death/MI/Stroke (%) Wiviott SD et al. New Engl J Med 2007;357: TRITON-TIMI 38: Primary End Point All ACS Population

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35 ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; RRR=Relative Risk Reduction Days CV Death/MI/Stroke (%) Loading Dose Maintenance Dose HR 0.82 ( ) P=0.01 RRR 18% ARR 0.9% HR 0.80 ( ) P=0.003 RRR 20% ARR 1.3% Clopidogrel Prasugrel Wiviott SD et al. New Engl J Med 2007;357: TRITON-TIMI 38: Timing of Benefit (Primary Endpoint, All ACS– 3-Day Landmark Analysis)

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

37 Days After Randomization MI=Myocardial Infarction; CABG=Coronary Artery Bypass Graft surgery; Hazard Ration; ITT=Intent To Treat; TIMI=Thrombolysis In Myocardial Infarction End Point (%) HR 0.87 ( ) P= ITT=13,608 Prasugrel Clopidogrel TRITON-TIMI 38: Net Clinical Benefit ( All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed ) Wiviott SD et al. New Engl J Med 2007;357:

38 TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent 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: HR 0.48 ( ) P<0.001 RRR 52% ARR 1.22% Prasugrel Clopidogrel Days Stent Thrombosis (%) Any Stent at Index PCI n=12, NNT=77

39 TRITON-TIMI 38: Primary Endpoint (CVD/MI/Stroke) Not Related to Stent Thrombosis Days % of Subjects 10.3% 8.7% RRR 15% HR 0.85 p=0.005 Clopidogrel Prasugrel CVA=cerebrovascular accident; HR=hazard ratio; MI=myocardial infarction Wiviott SD et al. Lancet 2008;371:

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

41 TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146) 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 HR 0.70 P<0.001 Days End Point (%) CV Death, MI, Stroke NNT= Non-CABG TIMI Major Bleeds Prasugrel Clopidogrel

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

45 CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction 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 Wiviott SD et al. New Engl J Med 2007;357:

46 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:

47 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 47 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

48 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 48 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: MODIFIED Recommendation 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. Prasugrel 60 mg should be given as soon as possible for primary PCI.

49 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 49 Recommendations for the timing of Angiography and Antiplatelet Therapy in UA/NSTEMI

50 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive 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) 50 JACC Vol. 57, No. 18, March 2011 …dual-antiplatelet therapy on presentation, ASA should be initiated on presentation


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