The COGENT Trial

1. 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

2. 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.

3. Algorithm to Assess GI Risk With Antiplatelet Therapy Need for antiplatelet therapy Yes Assess GI risk factors GI bleedingDual antiplatelet therapyConcomitant anticoagulant Yes Test for H pylori; treat if infected History of ulcer complication History of ulcer disease (nonbleeding) No Yes PPI More than one risk factor: Aged 60 years or more Corticosteroid use Dyspepsia or GERD symptoms Yes Bhatt DL, Scheiman J, Abraham NS, et al. JACC 2008:52:1502–17. Circulation 2008. AJG 2008.

4. 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 Clopidogrel and PPIs – The OCLA study PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP) p<0.0001 Gilard et al. J Am Coll Cardiol 2008;51:256-60.

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

6. 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.

7. 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

8. 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.

9. 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.

10. 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

11. 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

12. 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

13. Baseline Characteristics

14. Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk HR = 1.0295% CI = 0.70; 1.51 Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status

15. HR = 0.9695% CI = 0.59; 1.56 Placebo: 37 events, 1851 at riskTreated: 36 events, 1839 at risk Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status

16. HR = 0.9595% CI = 0.59; 1.55 Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk Adjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status

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

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

19. HR = 0.5595% CI = 0.36; 0.85 p=0.007 (preliminary) Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at risk

20. 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

21. 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