on Behalf of the COGENT Investigators The COGENT Trial Deepak L. Bhatt MD, MPH, Byron Cryer MD, Charles F. Contant PhD, Marc Cohen MD, Angel Lanas MD, DSc, Thomas J. Schnitzer MD, PhD, Thomas L. Shook MD, Pablo Lapuerta MD, Mark A. Goldsmith, MD, PhD, Benjamin M. Scirica MD, Robert P. Giugliano MD, Christopher P. Cannon MD, on Behalf of the COGENT Investigators

Disclosure for Dr. Bhatt Dr. Bhatt has served as a consultant to: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi aventis, Schering Plough, Takeda, The Medicines Company, Vertex. Principal Investigator for several potentially related studies. His institution has received funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, The Medicines Company. This presentation discusses off-label and/or investigational uses of various drugs and devices. The trial was funded by Cogentus, though no funding received for these analyses.

Algorithm to Assess GI Risk With Antiplatelet Therapy Need for antiplatelet therapy Yes Assess GI risk factors GI bleeding Dual antiplatelet therapy Concomitant anticoagulant Test for H pylori; treat if infected Yes History of ulcer complication History of ulcer disease (nonbleeding) According to the consensus document: If a patient needs antiplatelet therapy, the clinician should assess the patient’s GI risk factors. [Bhatt p7] If the patient has a history of ulcer complication or of nonbleeding ulcer disease, evaluate whether H pylori infection is present and treat if indicated, before starting chronic antiplatelet tharapy. [Bhatt p7,8] Proton pump inhibitors should be prescribed if the patient has GI bleeding, is receiving dual antiplatelet therapy, or is receiving a concomitant anticoagulant. [Bhatt p7] If none of these risk factors are present, the patient should still receive a proton pump inhibitor if more than one of the following apply: [Bhatt p7] The patient is age 60 or older The patient uses corticosteroids The patient has dyspepsia or symptoms of gastroesophageal reflux disease. No Yes More than one risk factor: Aged 60 years or more Corticosteroid use Dyspepsia or GERD symptoms PPI Yes Bhatt DL, Scheiman J, Abraham NS, et al. JACC 2008:52:1502–17. Circulation 2008. AJG 2008. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation 2008 in press; epub Oct 3 ahead of print. 3

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.

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, Maddox TM, Wang L, 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.

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, Braunwald E, Antman EM, et al. Lancet. 2009. 6

Aims To determine whether PPI versus placebo reduced important GI events in patients on dual antiplatelet therapy To determine if there was any cardiovascular interaction between clopidogrel and PPI

Methods Multicenter, international, randomized, double-blind, double-dummy, placebo-controlled, parallel group, phase 3 efficacy and safety study of CGT-2168, a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), compared with clopidogrel. Patients were stratified based on two baseline factors: H. pylori serology (positive or negative) and concomitant use of any NSAID. All patients were to receive enteric coated aspirin at a dose of 75 to 325 mg.

Methods The GI endpoint was upper GI bleeding, bleeding of presumed occult GI origin with decrease in hemoglobin of ≥ 2 g/dL or decrease in hematocrit ≥ 10%, symptomatic gastroduodenal ulcer confirmed by endoscopy or radiography, pain of presumed GI origin with underlying multiple erosive disease confirmed by endoscopy, obstruction, or perforation. The cardiovascular endpoint was the composite of cardiovascular death, non-fatal MI, CABG or PCI, or ischemic stroke. Adjudication of events was performed by an independent committee of cardiologists and gastroenterologists. The initial planned sample size was 3200 patients, an accrual period of 1 year, and maximum follow up of 2 years. As a low rate of gastrointestinal events was observed as the trial was ongoing, the sample size target was increased to 4200 and then ~5000 (143 GI events). The study ended when the sponsor declared bankruptcy.

Inclusion Criteria Patients ≥ 21 years of age Clopidogrel therapy with concomitant aspirin was anticipated for at least the next 12 months acute coronary syndrome undergoing placement of a coronary stent

Exclusion Criteria Hospitalized patients for whom discharge was not anticipated within 48 hours of randomization Requirement for current or chronic use of a proton pump inhibitor, H2 receptor blocker, sucralfate or misoprostol Erosive esophagitis, esophageal, or gastric variceal disease, or non-endoscopic gastric surgery Receipt of > 21 days of clopidogrel or another thienopyridine prior to randomization Oral anticoagulation that cannot be safely discontinued for duration of study Recent fibrinolytic therapy Scheduled PCI or recent (< 30 days prior to randomization) CABG Active bleeding or a history of a hemostatic disorder Systemic corticosteroids except low-dose oral corticosteroids equivalent to prednisone ≤ 5 mg/day

Results 3627 patients (above the initial target of 3200) 393 sites Median follow-up 133 days (maximum 362 days) 136 adjudicated cardiovascular events (preliminary) 105 adjudicated GI events (preliminary) 143 had been planned

Baseline Characteristics Variable Treated n (%) Placebo n (%) p-value for difference H. Pylori Positive 923 (49.2) 926 (49.0) 0.938 Used NSAIDs 116 (6.2) 105 (5.6) 0.456 Sex – Male 1251 (66.7) 1313 (69.6) 0.061 White/Black/Other 1756/68/51 1769/63/56 0.808 History of ACS 669 (36.1) 699 (37.5) 0.382 History of MI 484 (26.1) 466 (25.0) 0.468 History of PAD 172 (9.3) 158 (8.5) 0.426 History of Stroke 208 (5.8) 114 (6.1) 0.757 Mean (SD) Median Age 67.2 years (10.8) 68.7 years 67.2 years (11.1) 68.6 years 0.984 BMI 29.2 kg/m2 (5.6) 28.4 29.2 kg/m2 (5.3) 28.3 0.655

Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk HR = 1.02 95% CI = 0.70; 1.51 Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 0.96 95% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk Treated: 36 events, 1839 at risk Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 0.95 95% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

Composite Cardiovascular Event Hazard Ratios for Baseline Variables Vertical Line is Overall Hazard

Vertical Line is Overall Hazard Composite Cardiovascular Event Hazard Ratios for Medical History Variables Vertical Line is Overall Hazard

HR = 0.55 95% CI = 0.36; 0.85 p=0.007 (preliminary) Placebo: 67 events, 1895 at risk Treated: 38 events, 1878 at risk

Limitations Due to premature termination of trial, limited follow-up However, most relevant for GI events, as most cardiac events early after ACS or PCI No current PPI/clopidogrel data set has more adjudicated CV endpoints May not be directly applicable to PPIs other than omeprazole Most commonly used PPI One most indicted by ex vivo studies Special formulation of clopidogrel/PPI with different release kinetics, so may not be the same as taking clopidogrel and omeprazole off the shelf If a major concern, then take the clopidogrel in the morning and the PPI at night

Conclusions COGENT is the first, randomized assessment of clopidogrel and PPIs on clinical events The data provide strong reassurance that there is no clinically relevant adverse cardiovascular interaction between clopidogrel and PPIs The results call into question the exact relationship between ex vivo platelet assays and clinical outcomes, especially with respect to assessing drug interactions Platelet assays and observational data are not a substitute for RCT data Further research is needed to define the optimal strategy to reduce GI events in patients on antithrombotic therapy, though prophylactic PPIs seem very promising