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

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

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

What is the Effect of Clopidogrel on Platelet Aggregation?

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)

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

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

Can We Improve the Outcome by Improving Platelet Inhibition?

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

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

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

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

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

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

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

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:

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

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

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

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:

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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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)

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

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:

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

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:

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:

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

Eff-SK-2-MENA-07/10

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

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:

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:

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

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.

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

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