The COGENT TrialThe 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.

GI bleedingDual antiplatelet therapy

Concomitant anticoagulant

Algorithm to Assess GI Risk With Antiplatelet Therapy

Assess GI risk factors

History of ulcer complication History of ulcer disease (nonbleeding)

Test for H pylori; treat if infected

More than one risk factor:Aged 60 years or moreCorticosteroid useDyspepsia or GERD symptoms

Need for antiplatelet therapy

Yes

Yes

NoPPI

Yes

Yes

Bhatt DL, Scheiman J, Abraham NS, et al. JACC 2008:52:1502–17. Circulation 2008. AJG 2008.

Clopidogrel is a prodrug; requires conversion by the liver Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metaboliteprimarily via CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity

Clopidogrel is a prodrug; requires conversion by the liver Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metaboliteprimarily via CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity

Clopidogrel and PPIs – The OCLA studyClopidogrel and PPIs – The OCLA study

-32.6

-43.3-50-45-40-35-30-25-20-15-10-50

PR

I Var

iati

on

(%

)

Omeprazole (n=64)

Placebo (n=60)

PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)

Gilard et al. J Am Coll Cardiol 2008;51:256-60.

p<0.0001

Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI

Ho PM, Maddox TM, Wang L, et al. JAMA. 2009;301(9):937-944.

0.70

0.60

0.50

0.40

0.30

0.20

0.10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since Discharge

Pro

po

rtio

n o

f D

eath

s o

r R

ecu

rren

t A

CS

Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI

CV

dea

th,

MI

or

stro

ke

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

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 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 Treatedn (%)

Placebon (%)

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

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

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite Cardiovascular Events

Adjustment through Cox Proportional Hazards ModelAdjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori StatusAdjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 1.0295% CI = 0.70; 1.51

Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk

Hazard Ratio

0 2 4 6 8 10

H. pylori Positive or Indeterminate

H. pylori Negative

No NSAIDs Used

NSAIDs Used

Male

Female

Other Race

Black

White

Age <= 70

Age > 70

BMI <= 30

BMI > 30

Overall

Hazard Ratios for Baseline VariablesComposite Cardiovascular Events

Composite Cardiovascular Event Hazard Ratios for Baseline Variables

Vertical Line is Overall Hazard

Composite Cardiovascular Event Hazard Ratios for Medical History Variables

Hazard Ratio

0 1 2 3 4

History of ACS Negative

History of ACS Positive

History of MI Negative

History of MI Positive

History of PAD Negative

History of PAD Positive

History of Stroke Negative

History of Stroke Positive

History of Other Negative

History of Other Positive

Overall

Hazard Ratios for Medical History VariablesComposite Cardiovascular Events

Vertical Line is Overall Hazard

Days

Su

rviv

al P

rob

ab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.9

00

.92

0.9

40

.96

0.9

81

.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite GI Events

HR = 0.5595% CI = 0.36; 0.85

p=0.007

(preliminary)

Placebo: 67 events, 1895 at riskTreated: 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