Dominick J. Angiolillo, MD, PhD Consulting Fees sanofi-aventis Bristol-Myers Squibb Eli Lilly and Company Daiichi Sankyo

Honoraria Bristol-Myers Squibb sanofi-aventis Eli Lilly and Company Daiichi Sankyo I intend to reference off label or unapproved uses of drugs or devices in my presentation. I intend to discuss ticagrelor, elinogrel, cangrelor, TRA

Clopidogrel - PPI Interaction: The Interaction Is Real and the Warning Is Justified! Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Director of Cardiovascular Research Associate Professor of Medicine University of Florida College of Medicine - Jacksonville

Clopidogrel – 2C19 specific PPI Interaction: The Interaction Is Real and the Warning Is Justified! Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Director of Cardiovascular Research Associate Professor of Medicine University of Florida College of Medicine - Jacksonville

PROTON PUMP INHIBITORS (PPIs) ASPIRIN + CLOPIDOGREL EFFECT prevention of cardiac damage EFFECT SIDE gastric bleeding PROTON PUMP INHIBITORS (PPIs) EFFECT prevention of gastric bleeding

2009 Updated Labeling for Clopidogrel–PPI Interaction FDA/p 1/para 1-5; US Plavix label/p 15/para 3; p 16/para 4 FDA-required label changes:2 Warning: “Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart” Drug-Drug Interactions: “Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine” Based on PK/PD studies showing concomitant omeprazole reduced clopidogrel active metabolite and effect on platelets1 Did not include COGENT study data2 EMEA warning extends to discourage concomitant use of all PPIs3 Concomitant use of drugs that inhibit CYP2C19 discouraged; concomitant use of any PPI “should be avoided unless absolutely necessary”4 Wathion/p 1/para 4, 6; EU Plavix label/p 4/para 2 Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Published November 17, 2009. Accessed January 22, 2010. Wathion N. Public statement on possible interaction between clopidogrel and proton pump inhibitors. European Medicines Agency. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf. Published May 29, 2009. Accessed January 22, 2010. Plavix [summary of product characteristics]. Paris, France: Sanofi Pharma Bristol-Myers Squibb SNC; 2009. http://www.ema.europa.eu/humandocs/Humans/EPAR/plavix/plavix.htm. Updated August 28, 2009. Accessed January 22, 2010. Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2009. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed January 22, 2010. EMEA=European Medicines Agency; FDA=Food and Drug Administration; PD=pharmacodynamic; PK=pharmacokinetic. 1Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafety InformationforHeathcareProfessionals/ucm190787.htm. Published November 17, 2009. Accessed January 22, 2010. 2Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2009. 3Wathion N. http://www.emea.europa.eu/humandocs/PDFs/ EPAR/Plavix/32895609en.pdf. Published May 29, 2009. Accessed January 22, 2010. 4Plavix [summary of product characteristics]. Paris, France: Sanofi Pharma Bristol-Myers Squibb SNC; 2009. 6

(oral ingestion of pro-drug) Pharmacogenetics of Cardiovascular Antithrombotic Therapy N S O Cl CH3 C Clopidogrel (oral ingestion of pro-drug) MDR-1 Platelet membrane receptors P2Y12 , GP IIb/IIIa, GP Ia Genetic targets CYP enzyme system Two sequential steps: One step: CYP3A4, CYP3A5, CYP2C9, CYP1A2 Both steps: CYP2B6, CYP2C19 Intestinal absorption Hepatic generation of active metabolite HOOC * HS N O Cl OCH3 Platelet inhibition Marin F & Angiolillo DJ. J Am Coll Cardiol 2009 ;54:1041-57

Clopidogrel and PPIs – The OCLA study Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite PPIs are strong inhibitors of CYP2C19 activity PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) Poor responders = 16 placebo and 39 in omeprazole PRI was measured at Day 1 and omeprazole vs. placebo was given for 7 days plus clopidogrel, PRI rechecked Graph represents change from baseline; omeprazole clearly attenuates the antiplatelet effect of clopidogrel, but is this significant clinically? p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:256-60.

Results of a Prospective Randomized Crossover Study Pharmacodynamic Effects of Concomitant versus Staggered Clopidogrel and Omeprazole Intake: Results of a Prospective Randomized Crossover Study p=0.02 p<0.001 p=0.08 P2Y12 reactivity index (PRI) % VASP Ferreiro & Angiolillo. Circ Cardiovasc Interv 2010;3:436-41

Insights on FDA decision making Angiolillo DA, et al. Clin Pharmacol Ther 2011 89:65-74.

Insights on FDA decision making Four randomized, placebo-controlled, crossover PK/PD studies (n=282 healthy subjects) to investigate the interaction between: Clopidogrel (300-mg LD/75-mg MD) & omeprazole (80 mg) administered simultaneously. Clopidogrel (300-mg LD/75-mg MD) & omeprazole (80 mg) given 12 hours later. Increasing the clopidogrel dose to 600-mg LD/150-mg MD & omeprazole (80 mg) administered simultaneously. Clopidogrel (300-mg LD/75-mg MD) & pantoprazole (80 mg) administered simultaneously. Angiolillo DA, et al. Clin Pharmacol Ther 2011 89:65-74.

Standard-Dose Clopidogrel + Omeprazole versus Standard-Dose Clopidogrel + Pantoprazole: VASP-PRI Data Mean ± SEM of Vasodilator-Stimulated Phosphoprotein Phosphorylation-Platelet Reactivity Index (%) Clopidogrel ± Omeprazole Clopidogrel ± Pantoprazole VASP-PRI (%) was higher in the clopidogrel + omeprazole group (left panel): omeprazole decreased the effect of clopidogrel on platelet reactivity at Day 5. There was a numerically small, statistically insignificant increase in VASP-PRI when clopidogrel was coadministered with pantoprazole, with the CI for the effect including zero (increase of 3.86% with 90% CI, -2.71 to 10.44) (P=0.3319). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. After coadministering omeprazole (left panel) or pantoprazole (right panel) with clopidogrel (300-mg LD/75-mg/day MD), the estimated treatment differences (90% CIs) at Day 5 were: 20.7% (90% CI, 14.1% to 27.2%; P<0.0001) for omeprazole and 3.9% (–2.7% to 10.4%; P=0.3319) for pantoprazole. D, day; LD, loading dose; LOQ, lower limit of quantification; MD, maintenance dose; SEM, standard error of the mean; T, sampling time; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index. Angiolillo DA, et al. Clin Pharmacol Ther 2011 89:65-74.

Double-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4 Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 600-mg Loading Dose (Left) and 150-mg Maintenance Dose (Right) Plasma Active Metabolite Concentrations (ng/mL) 60 0 1 2 3 4 Nominal time (h) Day 1: 600 mg 50 40 30 20 10 Nominal time (h) Day 5: 150 mg 0 1 2 3 4 25 20 15 10 5 Plasma Active Metabolite Concentrations (ng/mL) Clopidogrel alone Clopidogrel + omeprazole LOQ = 0.500 ng/mL Clopidogrel alone Clopidogrel + omeprazole LOQ = 0.500 ng/mL The pharmacokinetic population included 65 subjects. Based on AUC(0-24) ratios (double-dose clopidogrel + omeprazole vs double-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 48% following a 600-mg loading dose of clopidogrel given concomitantly with 80 mg omeprazole (AUC0-24 ratio of 0.52; 90% CI, 0.49-0.56; P<0.001) and by 41% following an additional 4-day 150-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.59; 90% CI, 0.56-0.63; P<0.001). After a 600-mg clopidogrel loading dose given concomitantly with omeprazole, the Cmax ratio was 0.54 (90% CI, 0.49-0.59; P<0.001); after an additional 4 days of clopidogrel 150 mg/day given concomitantly with omeprazole, the Cmax ratio was 0.50 (90% CI, 0.46-0.56; P<0.001). Simultaneous administration of a 600-mg clopidogrel loading dose with omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, 1.09-1.31; P=0.002), and after 4 days of clopidogrel 150 mg/day, unchanged clopidogrel exposure increased by 44% (AUC0-24 ratio, 1.44; 90% CI, 1.27-1.63; P<0.001). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. After coadministering omeprazole with clopidogrel (600-mg LD/150-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by: 46% on Day 1 (P<0.001) and 50% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and 48% on Day 1 (P<0.001) and 41% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24). LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation. Angiolillo DA, et al. Clin Pharmacol Ther 2011 89:65-74.

Drug-drug interactions Nat Rev Cardiol. 2009;6:392-394

Deaths or Recurrent ACS Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI 0.70 0.60 0.50 0.40 0.30 0.20 0.10 Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI Deaths or Recurrent ACS Proportion of In this retrospective cohort study by Ho and colleagues, concomitant use of clopidogrel and a proton pump inhibitor (PPI) after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without a PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS. Of 8205 patients with ACS taking clopidogrel after hospital discharge, 63.9% (n=5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n=2961) were not prescribed PPI. Median follow-up after hospital discharge was 521 days (interquartile range, 305-779 days). Death or rehospitalization for ACS occurred in 20.8% (n=615) of patients prescribed clopidogrel without PPI and 29.8% (n=1561) of patients prescribed clopidogrel plus PPI. In multivariable analysis, use of clopidogrel plus PPI at any point in time was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio, 1.25; 95% CI, 1.11-1.41). In multivariable analyses with medication use as a time-varying covariate, periods of use of clopidogrel without PPI were associated with a significantly lower risk of adverse events compared with periods without the use of either clopidogrel or PPI (P<.001). However, this association appeared to be attenuated when comparing periods of use of clopidogrel plus PPI use with periods without use of either clopidogrel or PPI (shown in figure on slide). 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. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):937-944.

TRITON-TIMI 38: Primary endpoint stratified by use of a PPI PPI use at randomization (n= 4529) Clopidogrel Prasugrel CV death, MI or stroke CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20 Days O'Donoghue ML et al. Lancet. 2009;374:989-97. 16

Primary Outcome by Randomized Treatment and PPI Use Clopidogrel/PPI vs. Clopidogrel/no PPI: *HR 1.20 (1.04-1.38) 13.03 10.92 Pinteraction for P2Y12 * PPI=0.72 Ticagrelor/PPI vs. Ticagrelor/no PPI: *HR 1.24 (1.07-1.25) 10.96 9.19 *Propensity Adjusted Hazard Ratio (95% Cls) Goodman SG et al. AHA 2010

Impact of PPI Co-administration With Clopidogrel on MACE Subgroup N Studies Total N Odds Ratio P value Patients (95% CI) High-risk 6 33768 1.49 (1.41-1.57) <0.001 Patients Low-risk 7 12269 1.01 (0.88-1.16) 0.84 patients High-risk patients defined as an annual rate of MACE >10% in the control group. CI=confidence interval; MACE=major adverse cardiovascular events. Hulot JS, et al. J Am Coll Cardiol. 2010 18

Clopidogrel and the Optimization of GI Events Trial – COGENT K–M Estimates of the Probability of Remaining Free of Primary Gastrointestinal Events K–M Estimates of the Probability of Remaining Free of Primary Cardiovascular Events HR: 0.34; 95% CI: 0.18-0.63 HR: 0.99; 95% CI: 0.68-1.44 Bhatt DL et al. N Engl J Med 2010;363:1909-1917.

COGENT - Major Limitations Trial interrupted prematurely for bankruptcy. Not powered for CV events (“There was no a priori sample-size calculation or explicit noninferiority hypothesis for the CV endpoint”) Definition of CV endpoint (CV death, non-fatal MI, ischemic stroke, or coronary revascularization) Low CV event rate (109 overall events), thus broad CI (HR:0.99; 95% CI: 0.68-1.44). Cannot exclude a clinically important increase in risk up to 44%. Low major CV event rate (43 major events) –HR 1.15 favoring placebo. Authors conclusions: “Our results do not rule out a clinically meaningful difference in CV events due to the use of a PPI.” PPI used in COGENT: combo-pill (not available) with different PK profiles than commercially available omeprazole.

Clopiodgrel FDA Box Warnings The Code of Federal Regulations (21CFR 201.57 [e]) requires that “labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved. Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box. The boxed warning ordinarily shall be based on clinical data.” Murphy S, Roberts R. "Black box" 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk. J Allergy Clin Immunol. 2006;117:34-9.

The Statin Story Only PD (no PK) interactions shown with CYP 3A4 interfering statins in the acute phase of treatment with standard (300mg) loading-dose. No PD interactions observed with high (600mg) loading-dose or in maintenance phase (75mg). CYP 3A4 not as important on clopidogrel metabolism compared with CYP 2C19. Clinical outcome data never concerning. The PPI story is a different animal.

Clopidogrel – 2C19 specific PPI Interaction PD and PK interaction between clopidogrel and 2C19 specific PPI is real! The clinical implications of this interaction are still controversial / not fully defined. Therefore, this implies increased risk for harm (potentially life- threatening), justifying the “boxed warning”.

There are reasons for warnings!

There are reasons for warnings!

Clopidogrel – 2C19 specific PPI Interaction PD and PK interaction between clopidogrel and 2C19 specific PPI is real! The clinical implications of this interaction are still controversial / not fully defined. Therefore, this implies increased risk for harm (potentially life- threatening), justifying the “boxed warning”. Don’t risk-the stakes are high! Other “roads” are available that are safer and equally efficacious (non 2C19 specific PPI, H2RA) to prevent bleeding. Follow the “boxed warning”!