New Approaches to, and Indications for, Antiplatelet Therapy

New Approaches to, and Indications for, Antiplatelet Therapy Kenneth A. Bauer, MD Professor of Medicine, Harvard Medical School Chief, Hematology Section, VA Boston Healthcare System Director, Thrombosis Clinical Research, Beth Israel Deaconess Medical Center

Disclosures Consultant Bayer Healthcare Janssen Pharmaceuticals Bristol Myers Squibb Pfizer Boehringer Ingelheim Instrumentation Laboratory Acknowledgement Deepak Bhatt, MD

Atherothrombosis: Clinical Manifestations Acute coronary syndromes STEMI NSTEMI Unstable angina Stable CAD Angioplasty Bare metal stent Drug eluting stent CABG Abdominal aortic aneurysm (AAA) Stroke/TIA Carotid artery disease Renal artery stenosis Peripheral arterial disease Acute limb ischemia Claudication Endovascular stenting Peripheral bypass Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

Platelet and Thrombus Formation: Vascular Injury Meadows TA, Bhatt DL. Circ Res. 2007;100:1261

Desai NR, Bhatt DL. JACC Intervention 2010 Antiplatelet Agents

Mechanism Of Aspirin In Reducing Risks Of Cardiovascular Disease Aspirin irreversibly acetylates the active site of cyclooxygenase (COX-1 and COX-2), which is required for the production of thromboxane A2 by platelets, which promotes platelet aggregation.

Efficacy of Aspirin at Various Doses in Reducing Vascular Events in High-Risk Patients Aspirin (mg daily) No. of Trials % Odds Reduction Odds Ratio 500-1500 34 19 160-325 19 26 75-150 12 32 <75 3 13 Any aspirin 65 23 Vascular events included nonfatal MI, nonfatal stroke, and death from vascular causes. Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86. 0 0.5 1.0 1.5 2.0 Antiplatelet Antiplatelet Better Worse Treatment effect P<.0001

Effect of Antiplatelet Therapy in Reducing Vascular Events in Diabetic Patients Adjusted (%) of pts (+1 SD) with vascular events 30 20 10 0 No Diabetes Diabetes Control Antiplatelet therapy Benefit/1000 pts (SD): 36 (3) 38 (12) 2P: <0.00001 <0.002 Antiplatelet Trialists Collaboration BMJ 1994

ADP Receptors Receptor subtype Clopidogrel P2X 1 P2Y 1 P2Y 12 Active metabolite G protein G protein Molecular structure Intrinsic ion channel GPCR G q GPCR G i Secondary messenger system [Na + /Ca 2+ ] i PLC/IP 3 [Ca 2+ ] i AC [camp] Functional response Shape change aggregation Shape change transient aggregation Sustained aggregation secretion Bhatt DL et al. Nat Rev Drug Discov. 2003;2:15-28.

Ticlopidine Thienopyridine derivative: converted to active metabolites by liver cytochrome P450 isozymes Irreversible P2Y 12 receptor inhibitor Labeled indication: To reduce the risk of recurrent stroke in patients who have had a stroke or a TIA Dosage: 250 mg bid In combination with aspirin, demonstrated to be more effective than anticoagulation (heparin/warfarin) in the prevention of stent thrombosis Replaced by clopidogrel due to hematologic side effects: Neutropenia (2%) Thrombotic thrombocytopenic purpura (TTP)

CAPRIE: Superior Efficacy of Clopidogrel versus ASA Patients with recent ischemic stroke, recent MI or symptomatic PAD Cumulative event rate* (%) 20 16 12 8 4 ASA Clopidogrel 8.7% RRR (p=0.043) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of follow-up *MI, ischemic stroke or vascular death Intent-to-treat analysis (n=19,185) CAPRIE Steering Committee. Lancet 1996; 348: 1329 1339.

CAPRIE: Clopidogrel Provided Amplified Benefit in Patients with Diabetes 38 Event rate*/year (%) 25 20 15 10 5 21 9 p=0.042 p=0.096 17.7% 15.6% 12.7% 11.8% p=0.106 21.5% 17.7% ASA Clopidogrel 0 Patients without diabetes (n=15,233) Patients with diabetes (n=3866) Patients treated with insulin (n=1134) *MI, stroke, vascular death or rehospitalization for ischemic events/bleeding Number of events prevented per 1000 patients per year compared with ASA Bhatt DL et al. Am J Cardiol 2002; 90: 625 628.

Dual Antiplatelet Therapy Clopidogrel adds to the benefit of aspirin in some circumstances (coronary artery disease). Benefits and risks: Aspirin + Clopidogrel Issues with Clopidogrel Clopidogrel versus Prasugrel Clopidogrel versus Ticagrelor Cangrelor (investigational) P2Y 12 receptor antagonist Aspirin + Dipyrimadole (Aggrenox) sustained release ASA (25 mg bid)/dipyrimadole (200 mg bid) Approved indication: ischemic stroke or TIA

Issues with Clopidogrel Irreversible P2Y 12 receptor: dosage 75 mg qd Pharmacokinetics: Oral absorption 1 h, t 1/2 8 h Onset: 4-6 hours (after loading dose) Offset: 5-7 days Variable response: 25-30% of patients achieve less than 25% inhibition of platelet activity Undergoes 2 step metabolism (CYP3A4/2C19 mediated) to active agent (genetic variability) Potential drug interaction (e.g., PPIs)

CURE: Primary Efficacy Results (MI/Stroke/CV Death) Randomized trial in acute MI Cumulative Hazard Rate 0.14 0.12 0.10 0.08 0.06 0.04 0.02 Placebo * (n = 6,303) Clopidogrel * (n = 6,259) 20% Relative risk reduction p = 0.00009 N=12,562 0.00 0 3 6 9 12 Months of follow-up *On top of standard therapy (including ASA) Yusuf S et al. N Engl J Med 2001; 345: 494 502.

CURE: Clopidogrel in Patients with ACS and Diabetes Myocardial Infarction, Stroke, or Vascular Death 18 16.7% 25 * Cumulative event rate (%) 16 14 12 10 8 6 4 2 9.9% 20 * 7.9% 14.2% Placebo Clopidogrel No previous diabetes n = 9,721 Diabetes n = 2,840 *Number of events prevented/1,000 patients treated/9 months On top of standard therapy (including ASA) Yusuf S et al. N Engl J Med 2001; 345: 494 502.

CHARISMA A randomized, double-blind placebo controlled trial of 15,603 patients (79% ) with established CVD and 21% with multiple risk factors designed to test whether clopidogrel should be continued beyond 1 year in addition to aspirin. All patients received daily aspirin (75-162 mg) and were randomized to daily clopidogrel (75 mg) or placebo Clopidogrel patients had an event rate of 6.8% and placebo patients had an event rate of 7.3%. CHARISMA demonstrated no significant benefit long term when clopidogrel is added to aspirin. Rates of severe bleeding were similar, but clopidogrel patients experienced significantly higher rates of moderate bleeding. Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717

CHARISMA: Proportion of Diabetic Patients in Subgroups N=15,613 N=12,153 N=3,284 Non Diabetics 58% Non Diabetics 69% Diabetics 42% Diabetics 31% Diabetics 83% Non Diabetics 17% Overall population Secondary prevention Primary prevention

Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) p value Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046 (n=12,153) Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20 (n=3,284) Overall Population 0.93 (0.83, 1.05) 0.22 (n=15,603) 0.4 0.6 0.8 1.2 1.4 Clopidogrel + ASA Better 1.6 Placebo + ASA Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these prespecified subgroups of patients 166 patients did not meet any of the main inclusion criteria Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

Primary Efficacy Diabetics vs Non Diabetics Overall population Secondary prevention Primary prevention N=15,603 N=12,152 N=3,284 p-value for interaction: 0.283 p-value for interaction: 0.923 p-value for interaction: 0.255 10.04% 10% 8.24% 8.17% 9.23% 8% 6.7% 5.87% 6.73% 5.89% 6.98% 5.97% 6.69% 6% 5.14% 4% 2% 0% Non Diabetics Diabetics Non Diabetics Diabetics Non Diabetics Diabetics N=9,047 N=6,556 N=8,380 N=3,773 N=569 N=2,715 Placebo + ASA Clopidogrel + ASA

Mechanism of Action of Prasugrel Bhatt DL. N Engl J Med 2009.

15 Primary Endpoint CV Death,MI,Stroke Primary Endpoint (%) 10 5 HR 0.77 P=0.0001 HR 0.80 P=0.0003 Clopidogrel Prasugrel 12.1 (781) 9.9 (643) HR 0.81 (0.73-0.90) P=0.0004 NNT= 46 0 Wiviott et al. NEJM 2007. ITT= 13,608 LTFU = 14 (0.1%) 0 30 60 90 180 270 360 450 Days

Stent Thrombosis (ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 Clopidogrel 2.4 (142) Endpoint (%) 2 1 Prasugrel 1.1 (68) HR 0.48 P <0.0001 NNT= 77 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al NEJM 2007. Slide courtesy of Dr. Elliott Antman

% Events 4 2 Bleeding Events - Safety Cohort (N=13,457) Clopidogrel Prasugrel 1.8 2.4 1.4 0.9 0.9 1.1 ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02) 0 TIMI Major Bleeds Life Threatening 0.1 0.4 0.3 0.3 Nonfatal Fatal ICH ARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74 Slide courtesy of Dr. Elliott Antman

Diabetic Subgroup N=3146 Endpoint (%) 18 16 14 12 10 8 CV Death / MI / Stroke Clopidogrel Prasugrel 17.0 12.2 HR 0.70 P<0.001 NNT = 21 6 4 2 0 TIMI Major NonCABG Bleeds Clopidogrel 2.6 Prasugrel 0 30 60 90 180 270 360 450 Days Wiviott et al. Circulation 2008. 2.5

Mechanism of Action of Ticagrelor (a cyclopentyl triazolopyrimidine) Bhatt DL. Nature Reviews Cardiology. 2009;6:737-38.

CV Death, MI, or Stroke Cumulative incidence (%) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 0 60 120 180 240 300 360 No. at risk Days after randomisation Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 Wallentin L, et al. N Engl J Med. 2009.

Secondary Efficacy Endpoints Myocardial infarction Cardiovascular death 7 Clopidogrel 6.9 7 Cumulative incidence (%) 6 5 4 3 2 1 0 5.8 Ticagrelor HR 0.84 (95% CI 0.75 0.95), p=0.005 Cumulative incidence (%) 6 5 4 3 2 1 0 Clopidogrel 5.1 4.0 Ticagrelor HR 0.79 (95% CI 0.69 0.91), p=0.001 0 60 120 180 240 300 360 0 60 120 180 240 300 360 No. at risk Days after randomisation Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364 Wallentin L, et al. N Engl J Med. 2009.

Ticagrelor in Patients with Diabetes Mellitus PLATO Study James S et al. EHJ 2010.

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 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. Ferreiro JL, Angiolillo DJ. Circulation 2011. 123:798-813.

DUAL ANTIPLATELET THERAPY AND INCREASED RISKS OF BLEEDING In a meta-analysis of 18 randomized trials which included 129,314 patients Those assigned to dual antiplatelet therapy have about a 50% increase in risk of major bleeding compared with those given single agent therapy The magnitude of this excess risk is about as high as the approximately 60% increase observed in the trials comparing single antiplatelet agents to placebo These excess risks of major bleeding should be considered in relation to the benefits on occlusive CVD events in choosing the optimal antiplatelet strategy, especially for long-term treatment of patients with prior events or those at high risk of developing CVD. Fund Clin Pharm 2008; 22:315-321

Conclusions Increased platelet activation/aggregation in diabetic patient contributes to their increased rate of ischemic events Clear role for aspirin in secondary prevention,? primary prevention Dual antiplatelet therapy indicated for at least 1 year after ACS or PCI More potent P2Y12 receptor antagonists likely of greater benefit in diabetics, if bleeding risk not too high