Bhatt Cogent

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; treat if infected

Yes

History of ulcer complication History of ulcer disease (nonbleeding) GI bleeding Dual antiplatelet therapy Concomitant anticoagulant 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.

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

) (% n rito a IV R P

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

0 -5 -10 -15 -20 -25 -30 -35 -40 -45 -50

Omeprazole (n=64) Placebo (n=60)

-32.6

p<0.0001

-43.3

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 Proportion of Deaths or Recurrent ACS

0.70

Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI

0.60 0.50 0.40 0.30 0.20 0.10 0

0

90

180

270

360

450

540

630

720

Days Since Discharge

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

810

900

990 1080

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

CV death, MI or stroke

Clopidogrel

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 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

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

0.96 0.94

Placebo: Treated:

HR = 1.02 95% CI = 0.70; 1.51

67 events, 1821 at risk 69 events, 1806 at risk

0.92

Placebo Treated Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

0.90

Survival Probability

0.98

1.00

Survival Curves for PPI Treated vs Placebo Composite Cardiovascular Events

0

30

60

90

120

150

180

210 Days

240

270

300

330

360

390

1.00

Survival Curves for PPI Treated vs Placebo MI Events

0.96 0.94

HR = 0.96 95% CI = 0.59; 1.56

37 events, 1851 at risk 36 events, 1839 at risk

0.92

Placebo: Treated:

Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

0.90

Survival Probability

0.98

Treated Placebo

0

30

60

90

120

150

180

210 Days

240

270

300

330

360

390

0.98

1.00

Survival Curves for PPI Treated vs Placebo Revascularization

Treated 0.96 0.94

HR = 0.95 95% CI = 0.59; 1.55

Placebo: Treated:

67 events, 1821 at risk 69 events, 1806 at risk

0.92 0.90

Survival Probability

Placebo

Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status

0

30

60

90

120

150

180

210 Days

240

270

300

330

360

390

Composite Cardiovascular Event Hazard Hazard Ratios for Baseline Variables Composite Cardiovascular Events Ratios for Baseline Variables 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

Hazard Ratio

8

10

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

3

4

0.98

1.00

Survival Curves for PPI Treated vs Placebo Composite GI Events

0.96 0.94

Placebo

HR = 0.55 95% CI = 0.36; 0.85

0.92

p=0.007

Placebo: Treated:

67 events, 1895 at risk 38 events, 1878 at risk

(preliminary)

0.90

Survival Probability

Treated

0

30

60

90

120

150

180

210 Days

240

270

300

330

360

390

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