Surveying the Landscape of Oral Antiplatelet Therapy in Acute Coronary Syndrome Management

Surveying the Landscape of Oral Antiplatelet Therapy in Acute Coronary Syndrome Management Jeffrey S Berger, MD, MS Assistant Professor of Medicine and Surgery Director of Cardiovascular Thrombosis

Disclosures AstraZeneca Research Support and Serve on the Executive Committee for the EUCLID trial in symptomatic PAD comparing ticagrelor versus clopidogrel

Audience Question 1 In acute coronary syndrome (ACS) patients, a reduction in death vs. clopidogrel was demonstrated with which drug in the PLATO trial? 40% 40% 0% 20% 1. Prasugrel 2. Ticagrelor 3. Aspirin 4. None of these drugs

Outcomes Question 2 A 76-year-old male experiences a STEMI, and primary PCI is undertaken with drug-eluting stent implantation. How long would you treat with an oral P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor)? 20% 40% 20% 20% 1. 1 month 2. 6 months 3. 12 months 4. Indefinitely

Antiplatelet Agents Desai NR, Bhatt DL. JACC Cardiovasc Intervention. 2010;3:571-83.

Vascular Death, n Aspirin is Effective in Acute Coronary Syndromes STEMI NSTE-ACS 400 300 Placebo 568/4300 (13.2%) 500 ASA 461/4295 (10.7%) SK 448/4300 (10.4%) SK + ASA 343/4292 (8.0%) 200 100 7 14 21 28 Days After STEMI 35 Lancet 1988;2:349-60 Cairns JA et al, NEJM 1985 313:1369

What is the optimal aspirin dose? N=25,086; 2-by-2 factorial design; 30 day follow-up Overall Cohort PCI Cohort Aspirin 325mg Aspirin 81mg P value MACE 4.2 4.4 0.61 CV death 2.1 2.3 0.22 Major Bleeding 2.3 2.3 0.9 Minor Bleeding 5.0 4.4 0.04 In the PCI cohort, the endpoint of definite or probable stent thrombosis did not differ between aspirin groups (1.9% vs 2.0%, P=0.36) NEJM 2010;363:930-42; Lancet 2010;376:1233-43

Cumulative Hazard Rate Dual Antiplatelet Therapy is Effective in the Setting of ACS: CURE 0.14 0.12 Placebo + ASA 20% Relative Risk Reduction 0.10 0.08 0.06 Clopidogrel + ASA 0.04 P < 0.0001 N = 12,562 0.02 0.00 0 3 6 9 12 Months of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Cumulative Hazard Rate PCI-CURE: Clopidogrel after NSTE-ACS Treated with PCI Composite of MI or cardiovascular death from randomization to end follow-up 0.15 0.10 Placebo + ASA* 12.6% 31% Overall Relative Risk Reduction 8.8% 0.05 Clopidogrel + ASA* P = 0.002 N = 2658 0.0 * In addition to other standard therapies. 0 100 200 300 400 Days of follow-up Mehta. et al for the CURE Investigators. Lancet. 2001;358:527-533.

CURE Trial Major Bleeding by ASA Dose ASA Dose Placebo + ASA Clopidogrel + ASA <100 mg 2.0% 2.6% 100 300 mg 2.3% 3.5% >300 mg 4.0% 4.9% Yusuf S, et al. N Engl J Med. 2001;345:494-502.

Death, MI Stroke (%) Dead (%) COMMIT: CLOPIDOGREL in 46,000 AMI Pts Death, Re-MI or Stroke Placebo + ASA: 2311 events (10.1%) Clopidogrel + ASA: 2125 events (9.3%) Placebo + ASA: 1846 deaths (8.1%) Mortality Clopidogrel +ASA: 1728 deaths (7.5%) 9% RRR (P=0.002) 7% RRR (P=0.03) Days since randomisation Days since randomisation Chen et al. Lancet. 2005;366:1607-1621.

What is the optimal clopidogrel dose? N=25,086; 2-by-2 factorial design; 30 day follow-up 600mg Load & Double Dose Clopidogrel 300mg Load & Standard Dose Clopidogrel P value MACE 4.2 4.4 0.3 CV death 2.1 2.2 0.57 Major Bleeding 2.5 2.0 0.01 Minor Bleeding 5.1 4.3 0.01 NEJM 2010;363:930-42; Lancet 2010;376:1233-43

Limitations of Clopidogrel Heterogenous antiplatelet response Genetic polymorphisms associated with poor response Drug-drug interaction Smoking interaction Bonello L, JACC 2010;56:919-33 Ho PM, JAMA 2009;301:937-44 Berger JS, Circulation 2009;120:2337-44

Impact of Platelet Reactivity after PCI: Meta-Analysis of Individual Patient Data 6 studies 3059 patients Brar et-al. JACC 2011; 58:1945

Proportion of Deaths or Recurrent ACS Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI 0.70 0.60 0.50 Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI 0.40 0.30 0.20 0.10 0 0 90 180 270 360 450 540 630 720 810 900 990 1080 Days Since Discharge Ho PM et al. JAMA. 2009;301(9):937-944. PPI = Proton Pump Inhibitor

COGENT Trial Design Non-STEMI, STEMI, or Elective Stent n=3627 Aspirin Clopidogrel 75 mg and Placebo Clopidogrel 75 mg and Omeprazole (Prilosec) 20 mg Planned enrollment: 5000; stopped due to bankruptcy Mean follow-up 133 days (maximum, 362 days) Bhatt D, et al. NEJM 2010;363:1909-17

Survival Probability Composite Cardiovascular Events COGENT Trial 1.00 0.98 0.96 N=3627 Placebo: 67 events; 1821 at risk Treated: 69 events; 1806 at risk HR=1.02 95% CI=0.70;1.51 0.94 Placebo 0.92 0.90 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Time (Days) Omeprazole Bhatt D, et al. NEJM 2010;363:1909-17 Adjusted with Cox Proportional Hazards Model for NSAID use and positive H. pylori status.

Probability of Freedom from Primary GI Endpoint COGENT Trial Effect of PPI on Composite GI Events 1.00 Omeprazole Placebo 0.90 HR = 0.34, 95% CI = 0.18-0.63 P < 0.001 by the log-rank test 0.00 0 50 100 150 180 200 Time (Days) No. at Risk Placebo 1885 1455 951 523 260 231 Omeprazole 1876 1500 987 553 250 215 Bhatt DL, et al. N Engl J Med. 2010;363(20):1909-1917.

CYP2C19 Genetic Polymorphisms and Outcomes With Clopidogrel Major Adverse CV Events (N=9684) Risk Ratio (95% CI) P Value Carriers vs Noncarriers 1.61 (1.28-2.02) <0.001 Heterozygotes vs Wildtype 1.50 (1.08-2.08) 0.016 Homozygotes vs Wildtype 1.81 (1.21-2.71) 0.004 Stent Thrombosis (N=5772) Carriers vs Noncarriers 2.76 (1.77-4.30) <0.001 Heterozygotes vs Wildtype 2.51 (1.59-3.98) <0.001 Homozygotes vs Wildtype 4.78 (2.01-11.39) <0.001 Risk Lower With CYP2C19 Variant 0.5 1.0 15.0 Relative Risk Risk Higher With CYP2C19 Variant Mega JL, et al. JAMA 2010; 304:1821-1830. Courtesy of JL Mega and MS Sabatine.

Clopidogrel Label Changes WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS See full prescribing information for complete boxed warning. Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1) Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5) Tests are available to identify a patient s CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5) Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1) http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s055lbl.pdf

Metabolism of P2Y 12 Receptor Blockers Schomig A. NEJM 361;11:1108-11 Ticagrelor and Prasugrel have Rapid Consistent /Greater IPA

PRINCIPLE TIMI 44: Comparison with Higher Dose Clopidogrel N=201 IPA (%; 20 mm ADP) P<0.0001 for each IPA (%; 20 mm ADP) P<0.0001 Prasugrel 60 mg Clopidogrel 600 mg Hours Wiviott SD et al. Circulation. 2007;116:2923-32. Clopidogrel 150 mg 14 Days Prasugrel 10 mg 22

TRITON-TIMI 38 Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA n=13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1 o endpoint: CV death, MI, stroke 2 o endpoints: CV death, MI, stroke, rehosp-rec isch CV death, MI, UTVR UTVR = urgent target vessel revascularization; NSTEMI = non-st segment elevation MI Wiviott SD et al. Am Heart J. 2006;152:627-635.

Endpoint (%) TRITON-TIMI 38 15 Prasugrel: Efficacy and Safety 10 CV Death / MI / Stroke Clopidogrel 12.1 9.9 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel 5 0 TIMI Major NonCABG Bleeds 0 30 60 90 180 270 360 450 Wiviott, et al, NEJM 2007;357:2001 Days Prasugrel Clopidogrel 2.4 1.8 HR 1.32 (1.03-1.68) P=0.03 24

Events (%) TRITON-TIMI 38: Bleeding Events 4 Clopidogrel Prasugrel ICH in patients w/ prior stroke/tia (N = 518) 2 1.8 2.4 1.4 0.9 0.9 1.1 Clop 0 (0%) Pras 6 (2.3%) (P = 0.02) 0 TIMI Major Bleeds ARD 0.6% HR = 1.32 P = 0.03 NNT =167 Life Threatening ARD 0.5% HR = 1.52 P = 0.01 0.1 0.4 0.3 0.3 Nonfatal Fatal ICH ARD 0.2% P = 0.23 ARD 0.3% P = 0.002 ARD 0% P = 0.74 ICH = intracranial hemorrhage; ARD = absolute risk difference; TIA = transient ischemic attack. Wiviott SD et al. N Engl J Med. 2007:357:2001-2015.

TRITON-TIMI 38: Summary of the results Mod/high-risk ACS (n=13,608) scheduled for PCI randomized to: Prasugrel (60 mg LD and 10 mg daily MD) or Clopidogrel (300 mg LD and 75 mg daily MD) for 6-15 months Primary end point (CV death, nonfatal MI, nonfatal stroke) 9.9% prasugrel vs 12.1% clopidogrel (HR: 0.81; p<0.001) Prasugrel significant MI (7.4% vs. 9.7%; p<0.001) and stent thrombosis (1.1% vs. 2.4%) Prasugrel significantly increased risk of major bleeding, including fatal bleeding Cardiovascular mortality and overall mortality did not differ significantly between groups Wiviott SD, et al. for TRITON-TIMI 38 Investigators. NEJM 2007;357:2001 15.

TRITON-TIMI 38 Prior Stroke / TIA Yes No Net Clinical Benefit Bleeding Risk Subgroups Post-hoc analysis P int = 0.006 Risk (%) + 54-16 Age >=75 < 75 P int = 0.18-1 -16 Wgt < 60 kg +3 >= 60 kg P int = 0.36-14 OVERALL -13 0.5 1 2 Prasugrel Better Wiviott SD, et al. NEJM 2007;357:2001-2015. HR Clopidogrel Better

Black Box Warning with Prasugrel Prasugrel can cause significant, sometimes fatal, bleeding Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack or stroke In patients age 75 and older, prasugrel is generally not recommended because of the increased risk of intracranial and fatal bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI). In these situations, the drug's effect appears to be greater, and its use may be considered. Additional risk factors for bleeding include: body weight < 60 kg propensity to bleed concomitant use of medications that increase the risk of bleeding http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022307s003lbl.pdf

Ticagrelor Cyclopentyl-triazolopyrimidine Rapid oral absorption (30 minutes to onset) No transformation to active metabolite Reversibly binds to P2Y 12 Peak platelet inhibition within 1.5-3 hours Half life of 7-8 hours -> twice a day dosing

IPA (%; 20 mm ADP, Final) Clopidogrel vs. Ticagrelor ONSET/OFFSET Study Loading Maintenance and Offset 100 80 * * * Ticagrelor 180mg * 60 40 20 * Clopidogrel 600 mg 0 0.5 4 8 12 16 20 24 Hours Gurbel PA et al. Circulation. 2009;120:2577-85. *P<0.0001; P<0.005;, P<0.05, ticagrelor vs clopidogrel.

PLATO: Study Design NSTE-ACS (moderate-to-high risk) or STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-pci) 6 12-month exposure (median 9 mos) Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding Wallentin L, et al. NEJM. 2009;361:1045-57.

Cumulative incidence (%) PLATO: K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 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 0 60 120 180 240 300 360 11.7 9.8 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 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L et al. NEJM.2009;361:1045-57

% of Events Aspirin with: PLATO: Individual Endpoints Ticagrelor Clopidogrel N = 18,624 Started study drug at median 11.3 hours after chest pain began 12 month follow-up 12 10 8 6 4 2 0 11.7 9.8 6.9 5.8 5.1 4 1.5 1.3 All CV Events MI Stroke CV Death NEJM 2009;361:1045-57 P<0.001 P=0.005 P=0.22 P=0.001

PLATO Bleeding Data Ticagrelor Clopidogrel 14% p=0.43 12% 10% p=0.57 8% p=0.70 6% 4% p=0.02 2% p=0.66 0% PLATO Major Bleeding TIMI Major Bleeding Life-Threatening or Fatal Bleeding Fatal Bleeding TIMI non-cabg Major Bleeding Wallentin L et al. NEJM 2009;361:1045-57.

PLATO: Summary of the results NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Ticagrelor (180 mg LD and 90 mg bid MD) or Clopidogrel (300-600 mg LD and 75 mg daily MD) for 6-12 months Primary end point (CV death, nonfatal MI, nonfatal stroke), 9.8% ticagrelor vs 11.7% clopidogrel (HR: 0.84; p<0.001) Ticagrelor significant MI (7.4% vs. 9.7%; p<0.001), CV death (4% vs. 5.1%) and stent thrombosis (1.1% vs. 2.4%) Ticagrelor significantly increased risk of non-cabg major bleeding Fatal bleeding was not significantly different between groups Overall mortality was significantly decreased with ticagrelor (4.5% vs. 5.9%; p<0.001) Wallentin L, et al. for PLATO Investigators. NEJM 2009;361:1045-57.

Primary Efficacy Outcome US and ROW by aspirin dose Mahaffey KW et al. Circulation.2011;124:544-554.

Ticagrelor FDA Label Boxed Warning WARNING: BLEEDING RISK Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding (5.1, 6.1). Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage (4.1, 4.2). Do not start ticagrelor in patients planned to undergo urgent coronary bypass graft surgery (CABG). When possible, discontinue ticagrelor at least 5 days prior to any surgery (5.1). Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of ticagrelor (5.1). If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events (5.5). WARNING: Aspirin Dose and Ticagrelor Effectiveness Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After any initial dose, use with aspirin 75-100 mg per day (5.2, 14). http://www.pdr.net/drugpages/productlabeling.aspx?mpcode=04020155

How Do Different Antiplatelets Compare in the Setting of ACS? Event CURE TRITON TIMI 38 PLATO Clopidogrel (vs placebo) RR (95% Cl) Prasugrel (vs Clopid) RR (95% Cl) Ticagrelor (vs Clopid) RR (95% Cl) MACE 9.3 vs 11.4 0.80 (0.72-0.90) MI 5.2 vs 6.7 0.77 (0.67-0.89) Stroke 1.2 vs 1.4 0.86 (0.63-1.18) Any Death 5.7 vs 6.2 0.93 (0.81-1.07) CV Death 5.1 vs 5.5 0.93 (0.79-1.08) 9.9 vs 12.1 0.81 (0.73-0.90) 7.3 vs 9.5 0.76 (0.67-0.85) 1.0 vs 1.0 1.02 (0.71-1.45) 3.0 vs 3.2 0.95 (0.78-1.16) 2.1 vs 2.4 0.89 (0.70-1.12) 9.8 vs 11.7 0.84 (0.77-0.92) 5.8 vs 6.9 0.84 (0.75-0.95) 1.5 vs 1.3 1.17 (0.91-1.52) 4.5 vs 5.9 0.78 (0.69-0.89) 4.0 vs 5.1 0.79 (0.69-0.91) Major Bleeding 3.7 vs 2.7 1.38 (1.13-1.67) 2.5 vs 1.7 1.45 (1.15-1.83) 11.6 vs 11.2 1.04 (0.95-1.13) C = Clopidogrel Pl = Placebo Pr = Prasugrel Ti = Ticagrelor

What About Medical Therapy in ACS?

TRILOGY ACS: Primary Efficacy Endpoint to 30 Months (Age < 75 years) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Roe MT et al. N Engl J Med. 2012;367:1297-1309.

CV death, MI or stroke (%) PLATO Non-Invasive and Invasive: Primary Outcome 20 15 10 Non-invasive HR, 0.85, 95% CI: (0.73 1.0) 14.3% 12.0% 10.7% 9.0% 5 0 Invasive HR, 0.84, 95% CI: (0.75 0.94) Number at risk Invasive Days after randomization Ticagrelor 6732 6236 6134 5972 4889 3735 3048 Clopidogrel 6676 6129 6034 5881 4815 3680 2965 Non-invasive Ticagrelor 2601 2392 2326 2247 1854 1426 1099 Clopidogrel 2615 2392 2328 2243 1835 1416 1109 James S et al. BMJ 2011;342:d3527 0 60 120 180 240 300 360

Antiplatelet Rx after ACS I IIa IIb III I IIa IIb III I IIa IIb III After PCI, aspirin should be continued indefinitely. It is reasonable to use 81 mg of aspirin daily in preference to higher maintenance doses (IIa-B). In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y 12 inhibitor therapy should be given for at least 12 months. Options include: - clopidogrel 75 mg daily, - prasugrel 10 mg daily, or - ticagrelor 90 mg twice daily. For UA/NSTEMI patients in whom an initial conservative strategy is selected, clopidogrel or ticagrelor should be administered for up to 12 months. 2011 ACCF/AHA PCI Guidelines & 2012 ACCF/AHA UA/NSTEMI Focused Update

Risk of Any Event Optimizing Antiplatelet Therapy: Balancing Safety and Efficacy High risk of ischemic events Sweet spot High risk of bleeding events Ischemic risk Bleeding risk Risk of Any Event Inhibition of Platelet Aggregation Ferreiro JL, et al. Thromb Haemost. 2010;103:1128-1135.

Concept of Platelet Biosignature Treatment Consideration Patient A Patient B Platelet Genetics and/or Platelet phenotype Biosignatures Outcome A or Treatment A Outcome B or Treatment B

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