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

Test for H pylori; Yes History of ulcer complication

treat if infected History of ulcer disease (nonbleeding)
GI bleeding
Dual antiplatelet therapy
Concomitant anticoagulant

No Yes
More than one risk factor: PPI
Aged 60 years or more
Corticosteroid use Yes
Dyspepsia or GERD symptoms

Bhatt DL, Scheiman J, Abraham NS, et al. JACC 2008:52:1502–17. Circulation 2008. AJG 2008.
 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)
0
-5
-10
-15
-20
Omeprazole (n=64)
-25
Placebo (n=60)
-30
-35 -32.6
(%
n
ritoR
IV
P

-40
) a

-45 -43.3
-50 p<0.0001

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

 Risk of All-Cause Mortality and Recurrent
ACS in Patients Taking Clopidogrel and PPI
0.70 Neither clopidogrel nor PPI
PPI without clopidogrel
0.60 Clopidogrel + PPI
Deaths or Recurrent ACS

Clopidogrel without PPI

0.50
Proportion of

0.40

0.30

0.20

0.10

0
0 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.

 Primary endpoint stratified by use of a PPI
PPI use at randomization (n= 4529)

Clopidogrel
CV death, MI or stroke

Prasugrel

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.
 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 Placebo p-value for difference
n (%) n (%)
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) Mean (SD)
Median Median
Age 67.2 years (10.8) 67.2 years (11.1) 0.984
68.7 years 68.6 years
BMI 29.2 kg/m2 (5.6) 29.2 kg/m2 (5.3) 0.655
28.4 28.3
 Survival Curves for PPI Treated vs Placebo
Composite Cardiovascular Events
1.00
0.98
Survival Probability

0.96
0.94

Placebo: 67 events, 1821 at risk

HR = 1.02 Treated: 69 events, 1806 at risk
95% CI = 0.70; 1.51
Placebo
0.92

Treated

Adjustment through Cox Proportional Hazards Model

0.90

Adjusted to Positive NSAID Use and Positive H. Pylori Status

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

Days
 Survival Curves for PPI Treated vs Placebo
MI Events
1.00

Treated
0.98

Placebo
Survival Probability

0.96
0.94

HR = 0.96
95% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk
Treated: 36 events, 1839 at risk
0.92

Adjustment through Cox Proportional Hazards Model

0.90

Adjusted to Positive NSAID Use and Positive H. Pylori Status

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

Days
 Survival Curves for PPI Treated vs Placebo
Revascularization
1.00
0.98

Treated
Placebo
Survival Probability

0.96
0.94

HR = 0.95
95% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
0.92
0.90

Adjustment through Cox Proportional Hazards Model

Adjusted to Positive NSAID Use and Positive H. Pylori Status

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

Days
Composite Cardiovascular Event Hazard
Hazard Ratios for Baseline Variables

Ratios for Baseline Variables

Composite Cardiovascular Events

Overall

BMI > 30

BMI <= 30
Age > 70

Age <= 70

White

Black

Other Race

Female

Male

NSAIDs Used

No NSAIDs Used Vertical Line is Overall Hazard

H. pylori Negative

H. pylori Positive or Indeterminate

0 2 4 6 8 10

Hazard Ratio
Composite Cardiovascular Event Hazard
Hazard Ratios for Medical History Variables

Ratios for Medical History Variables

Composite Cardiovascular Events

Overall

History of Other Positive

History of Other Negative

History of Stroke Positive

History of Stroke Negative

History of PAD Positive

History of PAD Negative

History of MI Positive

History of MI Negative
Vertical Line is Overall Hazard
History of ACS Positive

History of ACS Negative

0 1 2 3 4

Hazard Ratio
 Survival Curves for PPI Treated vs Placebo
1.00
0.98
Composite GI Events

Treated
Survival Probability

0.96
0.94

Placebo
HR = 0.55
95% CI = 0.36; 0.85
p=0.007 Placebo: 67 events, 1895 at risk
0.92

Treated: 38 events, 1878 at risk

(preliminary)
0.90

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

Days
 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