The Big Antiplatelet Debate Why I Prefer Prasugrel Over Ticagrelor Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Director of Cardiovascular Research Associate Professor of Medicine University of Florida College of Medicine - Jacksonville

Dominick J. Angiolillo, MD, PhD Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Merck, Evolva Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson&Johnson, Bristol Myers Squibb, Sanofi-Aventis

TRITON vs PLATO: Is there a winner?

TRITON vs PLATO Proof of concept: Higher IPA to Support ACS Differences between trials Patient Population TRITON: ACS undergoing PCI PLATO: Full spectrum ACS 2. Pretreatment TRITON: No pretreatment (except STEMI) PLATO: Pretreatment 3. Clopidogrel Loading Dose TRITON: 300mg PLATO: 300-600mg 4. Duration of trial (median) TRITON: 14.5 months PLATO: 9 months

(prasugrel vs clopidogrel) (ticagrelor vs clopidogrel) TRITON TIMI 38 (prasugrel vs clopidogrel) PLATO (ticagrelor vs clopidogrel)

Why I prefer prasugrel STEMI-PCI Diabetes Mellitus with ACS Recurrent ACS while on Clopidogrel Stent thrombosis

Why I prefer prasugrel 1. STEMI-PCI 2. Diabetes Mellitus with ACS 3. Recurrent ACS while on Clopidogrel 4. Stent thrombosis

Death, MI or Stroke in STEMI-PCI % P=0.11 N=6364 N=7544 N=3534 Drug Double dose clopidogrel Ticagrelor Prasugrel Follow-up 1 month 6-12 months 15 months

Primary Efficacy Endpoint Primary Efficacy Endpoint STEMI TRITON PLATO Primary Efficacy Endpoint Time (Days) 5 10 15 50 100 150 200 250 300 350 400 450 Proportion of patients (%) 9.5 12.4 10.0 HR=0.79 (0.65–0.97) NNT=41 p=0.02 RRR=21% p=0.002 RRR=32% 6.5 N=3534 P=0.02 N=7544 P=0.07 Primary Efficacy Endpoint 2 4 8 12 6 10 Clopidogrel Ticagrelor Cumulative incidence (%) 10.8 9.4 p=0.07 RRR=13% Clopidogrel Prasugrel HR=0.87 (0.75 to 1.01) NNT=71 Time (Months)

Why I prefer prasugrel 1. STEMI-PCI 2. Diabetes Mellitus with ACS 3. Recurrent ACS while on Clopidogrel 4. Stent thrombosis

Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85) PLATO 16.2 14.1 0.88 (0.76 – 1.03) CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15) (PCI Cohort) 0.5 1 1.5 New Drug/Approach Better Standard Clopidogrel Better CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction. Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011; 123: 798-813.

TRITON TIMI-38: Diabetic Subgroup 18 Clopidogrel 17.0 16 CV Death/MI/Stroke 14 12.2 12 HR 0.70 P<0.001 Prasugrel 10 Endpoint (%) NNT = 21 8 6 TIMI Major Non-CABG Bleeds 4 Clopidogrel 2.6 2 2.5 Prasugrel 30 60 90 180 270 360 450 Days Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-36.

TRITON TIMI-38: CV Death/MI/Stroke by Diabetic Status Pras Clop Reduction in Risk No DM 9.2% 10.6% 14% DM No Insulin 11.5% 15.3% 26% DM on Insulin 14.3% 22.2% 37% 0.3 1 2 Prasugrel better Clopidogrel better Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-36.

Diabetes N=4662 Primary endpoint 16.2% 14.1% CV death, MI or stroke (%) 10.2% 8.4% No diabetes Number at risk Diabetes Ticagrelor 6999 6507 6407 6252 5143 3955 3191 Clopidogrel 6952 6434 6318 6153 5044 3869 3097 No diabetes Ticagrelor 2326 2113 2045 1959 1593 1199 953 Clopidogrel 2336 2084 2041 1968 1604 1225 975 Days after randomization James S, Angiolillo DJ, Cornel JH et al. Eur Heart J 2010; 31: 3006-16

Why I prefer prasugrel 1. STEMI-PCI 2. Diabetes Mellitus with ACS 3. Recurrent ACS while on Clopidogrel 4. Stent thrombosis

TRITON: 2nd Event following a Nonfatal Primary Endpoint CVD/MI/Stroke CV Death Murphy SA, et al. Eur Heart J 2008;29:2473-2479

Total Events: CVD / MI / Stroke RECURRENT EVENTS Total Events P<0.001 Additional Events P=0.40 First Events P=0.002

Why I prefer prasugrel STEMI-PCI Diabetes Mellitus with ACS Recurrent ACS while on Clopidogrel Stent thrombosis

NEW APPROACHES: STENT THROMBOSIS Hazard Ratio [95% confidence interval] Study 0.48 [0.36 - 0.64] 0.73 [0.57 - 0,94] 0.69 [0.56 - 0,87] TRITON-TIMI 38 PLATO CURRENT-OASIS 7 % of events Standard New Drug / Approach 3,0 2.2 2.3 1.6 2.4 1.1 Better Standard Clopidogrel Ferreiro JL, Angiolillo DJ. Circ Cardiovasc Interv 2012

Why I prefer prasugrel STEMI-PCI Diabetes Mellitus with ACS Recurrent ACS while on Clopidogrel Stent thrombosis Common factors: - High thrombotic risk - Benefits strongly outweigh the risk (increased ischemic benefit, minimal/no differences in bleeding) - Cost-effective

Novel P2Y12 receptor antagonists: When “NOT to Use” or “Use with Caution”? Prasugrel. Contraindicated: high-risk bleeding; prior TIA/stroke; hypersensitivty Precautions: elderly, low-weight; CABG/surgery (7days). Ticagrelor. Contraindicated: high-risk bleeding; prior hemorrhagic stroke; severe hepatic dysfunction Precautions: COPD/asthma (dyspnea 14% of patients), bradyarrythmia without pacemaker; aspirin dose (<100mg); compliance (b.i.d. administration); drug interactions (CYP 3A4 interfering agents); CABG/surgery (5-7days).

Unraveling some myths! Bleeding Mortality

(prasugrel vs clopidogrel) (ticagrelor vs clopidogrel) TRITON TIMI 38 (prasugrel vs clopidogrel) PLATO (ticagrelor vs clopidogrel)

Non-CABG and CABG-related major bleeding 9 NS Ticagrelor Clopidogrel 7.9 8 Prasugrel vs Clopidogrel 2.4% vs 1.8% ARD 0.6% HR 1.32 P=0.03 NNH=167 Ticagrelor vs Clopidogrel 2.8% vs 2.2% ARD 0.6% HR 1.25 P=0.03 NNH=167 Non-CABG TIMI major bleeding TRITON PLATO 7.4 7 NS 5.8 6 5.3 p=0.026 K-M estimated rate (% per year) 5 4.5 4 3.8 p=0.03 2.8 3 2.2 2 1 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

Balance of Efficacy/Safety in patients <75 yrs, >60 kg, No prior TIA/stroke

CV Mortality in TRITON and PLATO TRITON 2.4 vs. 2.1%; HR 0.89 (0.70 – 1.12); P = 0.31 PLATO 5.0 vs. 4.1%; HR 0.79 (0.69-0.91); P < 0.001 If you apply the HR to the other population HR necessary for P < 0.05 in TRITON = 0.78 (PLATO 0.79 → P = 0.06) HR necessary for P < 0.05 in PLATO = 0.87 (TRITON 0.89 → P = 0.08) Courtesy of Steve Wiviott

Adjusted HR* for Cardiovacular Death By MI Classification Type 1 MI – 2.6—3.9—5.7 Type 2 MI ? Type 4a MI – 1.6—2.4—3.6 Type 4b MI – 5.3—8.3—13.0 Type 4 MI – 2.7—3.7—5.2 Type 5 MI ? All MI ? *adjusted for age, gender, diabetes, hx of CHF, hx of MI, hypertension, dyslipidemia, renal dysfunction, prior MI, randomization group, severity of CAD and index event

Is there room for ticagrelor? A. In patients with prior TIA/Ischemic stroke and: Primary PCI- STEMI Diabetes Mellitus with ACS Recurrent ACS while on Clopidogrel Stent thrombosis B. High-risk medically managed ACS C. Clopidogrel allergy

Elderly and Low-weight Patients Facts: Both populations are associated with increased bleeding regardless of management Bleeding risk is further increased with both prasugrel and ticagrelor Limited data on clinical effects associated with dose modification (e.g. 5mg prasugrel). Overall, good experience with clopidogrel. Practical perspective: I continue to use clopidogrel, particularly for long-term management, in my elderly and low-weight patients.

Conclusions: This is Why I Prefer Prasugrel Prasugrel was specifically studied in ACS patients undergoing PCI, showing significant ischemic benefit with a favorable safety profile. Fact #1: We cannot use new agents in all our ACS patients (cost-prohibitive!! ... and clopidogrel, now generic, is still a very good option) Fact #2: The benefit of prasugrel is enhanced where we really need a new agent (STEMI, DM, recurrent events, stent thrombosis)! Facts #3-5: Prasugrel is a PCI drug. I am an interventional cardiologist This is an interventional meeting