Debate: Clopidogrel - PPI Interaction: More Needs to Be Learned The Warning Is an Overreaction Peter Berger, MD Director, Center for Clinical Studies Interventional Cardiologist Geisinger Clinic CRT Feb. 2011

Potential Conflicts of Interest Consultant: AstraZeneca, Boehringer Ingelheim, Eli Lilly/Daiichi-Sankyo, Medicure, Accumetrics, Ortho McNeil (each for less than $10,000) Research funding for Geisinger Clinic for studies on which I am the Principle Investigator: Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, The Medicines Company, and Corgenix/Aspirinworks (all for more than $10,000).

OPTIMUS: Diabetic Pts Hyporesponsive to Clopidogrel 64.3±6 p=0.4 62.5±11 100 p<0.0001 100 p=0.5 64.9±9 67.4±6 80 63.1±7 80 52.3±13 Maximal ADP (20mmol/L) platelet aggregation (%) Maximal ADP (20mmol/L) platelet aggregation (%) 60 60 40 40 75 mg for 30 days 150 mg for 30 days 75 mg for 90 days 20 20 30 60 30 60 90 90 Day Day 64 pts are 66% of 98 studied; all hyporesponsive Angiolillo DJ et al. Circulation. 2007;115:708-716

OSASIS 7- CURRENT 25,087 ACS or STEMI Pts PCI planned < 24 hrs No restriction on GP IIb/IIIa inhibitors Clopidogrel 600 mg 150 mg from Day 2 to Day 7 75mg from Day 8 to 30 Clopidogrel 300 mg 75 mg from Day 2 to 30 CURRENT/OASIS-7 is a Phase III, multinational, multicenter, randomized, factorial design, parallel-group study comparing 2 regimens of clopidogrel (high vs. standard dose) in a double-blind fashion and 2 regimens of ASA (high vs. low dose) in an open-label fashion in patients with non-ST-segment elevation ACS managed with an early invasive strategy with intent for PCI as early as possible within 24 hours. Each patient will be treated and followed for 30 days. ASA 300 mg Day 1 75–100 mg from Day 2 to 30 ASA 300 mg Day 1 300 mg–325 mg from Day 2 to 30 ASA 300 mg Day 1 75–100 mg from Day 2 to 30 ASA 300 mg Day 1 300 mg–325 mg from Day 2 to 30 1o Outcome: Death / MI /stroke, 30 Days; 2o outcome: bleeding 5

Clopidogrel: Double vs Standard Dose Primary Outcome and Components HR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N=25,087) 4.4 0.95 0.84-1.07 0.370 MI 2.6 2.0 0.78 0.64-0.95 0.012 0.025 1.4 1.7 1.25 0.87-1.79 0.23 2.2 1.9 0.86 0.73-1.03 0.097 CV Death 0.96 0.77-1.19 0.68 1.0 2.8 2.7 0.74-1.26 0.77 2.1 0.81-1.14 0.628 Stroke 0.4 0.88 0.55-1.41 0.59 0.50 0.8 0.9 1.11 0.68-1.82 0.67 0.5 0.99 0.70-1.39 0.950

GRAVITAS Study Design R Elective or Urgent PCI with DES* (83 sites) VerifyNow P2Y12 Test 12-24 hours post-PCI PRU ≥ 230 R High-Dose Clopidogrel† clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel protocol-mandated to ensure steady-state at 12-24 hrs †Placebo-controlled All patients received aspirin (81-162mg daily) 7

Pharmacodynamics: Effect of SD vs HD Clopidogrel Standard-Dose High-Dose 500 P = 0.98 P < 0.001 400 Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001 PRU value 300 200 100 N=1105 N=1013 N=940 N=1109 N=1012 N=944 Post-PCI 30 d 6 mo Post-PCI 30 d 6 mo ITT population 8

Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test. 9

Prior Drug-Drug Interaction Studies Many studies (CURRENT-OASIS 7, GRAVITAS, CILON-t, etc.) have now shown that letting platelet function tests guide clinical decision making-choice of drug, dose of drug, etc- is misleading, and would be a mistake

Prior Drug-Drug Interaction Studies Virtually all studies have indicated a reduction in inhibition of aggregability when clopidogrel is administered with certain statins (ie, atorvastatin), and calcium channel blockers The existence of a negative interaction between atorvastatin and clopidogrel, has been thoroughly debunked; between calcium channel blockers and clopidogrel also appears to be false But what about PPIs?

Treatment Effect of Clopidogrel Reduction in 1o endpoint: 20% among ACS pts in CURE 20% among STEMI pts in CLARITY 9% among AMI pts in COMMIT 27% among elective PCI pts in CREDO 13% among pts with vascular disease in CHARISMA Therefore, if a polymorphism rendered clopidogrel completely ineffective, would expect ~20% increase in events

Registry Analysis of a PPI-Clopidogrel Interaction Methods All pts with ACS (MI or unstable angina) discharged from any VA Medical Center from 10/1/2003 through 1/31/2006 and prescribed clopidogrel at discharge Primary outcome: Death/re-hospitalization for ACS Secondary outcomes: 1. ACS hospitalization 2. Revascularization procedures: PCI or CABG 3. All-cause mortality Follow-up through 9/30/2006 Median follow-up was 521 days (IQ range 305-779) Ho P et al. JAMA. 2009;301:937-44

Clopidogrel with or without PPI at any point in time (n=8,205) Variable Clopidogrel with or without PPI at any point in time (n=8,205) Clopidogrel only (n=2,961) Clopidogrel + PPI (n=5,244) p-value Age, mean (SD) 65.7 (11.7) 67.7 (11.4) <0.001 Diabetes 38.0 45.5 Prior MI 20.1 26.4 CABG 19.8 26.3 Heart failure 16.1 26.2 Cerebrovascular disease 7.6 9.1 0.02 Peripheral vascular disease 16.2 25.7 Prior clopidogrel use 17.5 Cancer 5.6 7.3 <0.01 Chronic obstructive pulmonary disease 17.0 Renal disease 9.9 17.4 Liver disease 2.4 3.5 Dementia 10.2 13.8 Ho P et al. JAMA. 2009;301:937-44

Clopidogrel with or without PPI at any point in time (n=8,205) Variable Clopidogrel with or without PPI at any point in time (n=8,205) Clopidogrel only (n=2,961) Clopidogrel + PPI (n=5,244) p-value TIMI risk score, mean (SD) 2.8(1.2) 2.9(1.2) <0.001 LVEF<0.40 24.3 26.6 0.02 ACS presentation STEMI NSTEMI 21.7 68.8 16.7 70.5 PCI performed 55.5 46.3 CABG performed 2.5 2.6 0.83 Discharge medications Aspirin Β-blocker ACE-inhibitor Statin 91.2 92.7 79.0 95.4 89.4 93.3 78.4 95.9 0.01 0.64 0.09 0.25 Ho P et al. JAMA. 2009;301:937-44

Adverse Outcomes Following Hospital Discharge for Acute Coronary Syndrome Freq. of events Unadjusted OR (95 CI) Adjusted OR* Clopidogrel only (n=2961) Clopidogrel + PPI (n=5244) Death/ACS hospitalization 20.8 29.8 1.62 (1.45-1.80) 1.25 (1.11-1.41) ACS hospitalization 6.9 14.6 2.29 (1.95-2.69) 1.86 (1.57-2.20) Revascularization procedures 11.9 15.5 1.36 (1.19-1.55) 1.49 (1.30-1.71) Death 16.6 19.9 1.24 (1.10-1.40) 0.91 (0.80-1.05) Ho P et al. JAMA. 2009;301:937-44 * Adjusted for all important variables

Cumulative Hazard for Death/ACS, Re-Hospitalization Ho P et al. JAMA. 2009;301:937-44 Days Since Discharge

MEDCO Analysis: Baseline Characteristics No PPI (N=9862) PPI* (N=6828) Age - yrs; mean±SD 65.2±10.6 67.5±10.4 Age ≥65 years - no. (%) 4903 (49.7) 4076 (59.7) Female - no. (%) 2572 (26.1) 2596 (38.0) Prior cardiovascular event - no. (%) 2226 (22.6) 1845 (27.0) Congestive heart failure - no. (%) 1831 (18.6) 1719 (25.2) Diabetes mellitus - no. (%) 2238 (22.7) 1767 (25.9) Hypertension - no. (%) 4581 (46.5) 3454 (50.6) Dyslipidemia treatment - no. (%) 5190 (52.6) 3991 (58.5) Dyslipidemia diagnosis or treatment - no. (%) 6254 (63.4) 4630 (67.8) Chronic kidney disease - no. (%) 265 (2.7) 312 (4.6) Any upper gastrointestinal disease - no. (%) 474 (4.8) 1649 (24.2) Prior upper gastrointestinal bleeding - no. (%) 13 (0.1) 122 (1.8) Drug-eluting stent – no. (%) 3124 (31.7) 1964 (28.9) *all p<0.01 Stanek EJ et al SCAI LBCT 09

MEDCO Database (N=14,383 on Clopidogrel Post Stent) Association Between PPI Use and Clinical Outcomes Adjusted OR 1.79 (1.62-1.97) MACE , 1 Year (%) PPI No PPI (n=4321) (n=9862) Aubert RE et al. Circulation 2008;118:S-815

Clopidogrel And PPIs: Interaction? Several other registries reveal the same Possible Explanations: PPIs (at least some PPIs) do inhibit the conversion of clopidogrel to its active metabolite PPIs directly cause CV events Confounding

Clopidogrel and Proton Pump Inhibitors Competition at CYP 2C19? VASP-P (%) PPI (N=24) No PPI (N=81) Gilard M et al, J Thromb Hem. 2006:4:2508 21

VASP Before and After 7 Days of Clopidogrel in Pts on and Not On Omeprazole (Prilosec) Gilard M et al JACC 2008;51: 256-60

The Issue of Those Drug-Drug Interaction Studies But is there a clinical interaction between PPIs and clopidogrel? Proper subgroup analyses from every randomized trial examining the issue (CREDO, CHARISMA, PLATO, TRITON) indicate that there is not a clinically significant reduction in clinical efficacy (or increase in bleeding) among patients on clopidogrel taking these other drugs

CREDO Death, MI, and Stroke at 1 Yr And PPIs RRR= 0.77 (0.45, 1.33) RRR=0.75 (0.55, 1.03) CV Death, MI, Stroke (%) PPI (N=366) No PPI (N=1750) Placebo n=1063 Clopidogrel n=1053 Steinhubl S et al Circulation 2008 Abstract

CREDO Death, MI, and Stroke at 1 Yr And PPIs RRR= 0.77 (0.45, 1.33) RRR=0.75 (0.55, 1.03) CV Death, MI, Stroke (%) P-value for interaction between randomized therapy and baseline PPI P=0.69 PPI (N=366) No PPI (N=1750) Placebo n=1063 Clopidogrel n=1053 Steinhubl S et al Circulation 2008 Abstract

TRITON CV Death, Nonfatal MI, Nonfatal Stroke And PPIs RRR=0.82 (0.72, 0.95) RRR=0.82 0.68, 0.93 CV Death, MI, Stroke () PPI No PPI Prasugrel Clopidogrel FDA Website

TRITON Major Non-Cardiac Bleeding and PPIs PPI Inhibitor? H2 Blocker? 1.19 (0.70, 2.02) 1.11 (0.79, 1.56) 1.35 (0.94, 1.94) 1.23 (0.93, 1.63) Prasugrel Clopidogrel FDA Website

COGENT Aspirin Non-STEMI, STEMI, or Elective Stent n=3627 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)

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

COGENT No. of Events Clopidogrel with: Placebo Omeprazole N=3627 Mean follow-up 133 days (maximum, 362 days) Omeprazole N=3627 No. of Events Bhatt D et al NEJM 2010

Conclusion “There is no good evidence that the differences in surrogate markers resulting from concomitant PPI administration to pts on clopidogrel translate into meaningful differences in clinical outcomes.” ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010:2619-33.