Bhatt Cogent

8/14/2019 Bhatt Cogent

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The COGENT TrialThe COGENT Trial

Deepak L. Bhatt MD, MPH, Byron Cryer MD, Charles F. ContantPhD, 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


2/21

Disclosure for Dr. Bhatt

Dr. Bhatt has served as a consultant to: Arena, Astra Zeneca, Bristol-MyersSquibb, 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 hasreceived funding from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, SanofiAventis, The Medicines Company.

This presentation discusses off-label and/or investigational uses of various drugsand devices.

The trial was funded by Cogentus, though no funding received for these analyses.


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GI bleedingDual antiplatelet therapy

Concomitant anticoagulant

Algorithm to Assess GI Risk WithAntiplatelet Therapy

Assess GI risk factors

History of ulcer complicationHistory 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 2008:52:150217. Circulation 2008. AJG 2008.


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Clopidogrel is a prodrug; requires conversion by theClopidogrel is a prodrug; requires conversion by theliver primarily via CYP3A4 and CYP2C19 to anliver primarily via CYP3A4 and CYP2C19 to anactive metaboliteactive 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

P R I V a r i a t i o n ( % )

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


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Risk of All-Cause Mortality and RecurrentACS 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

P r o p o r t

i o n o

f

D e a

t h s o r

R e c u r r e n

t A C S

Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI


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C V d e a

t h ,

M I o r s

t r o

k e

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

ODonoghue ML, Braunwald E, Antman EM, et al. Lancet . 2009.


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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


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Methods

Multicenter, international, randomized, double-blind,double-dummy, placebo-controlled, parallel group, phase3 efficacy and safety study of CGT-2168, a fixed-dosecombination of clopidogrel (75 mg) and omeprazole (20mg), compared with clopidogrel.

Patients were stratified based on two baseline factors: H. pylori serology (positive or negative) and concomitant useof any NSAID.

All patients were to receive enteric coated aspirin at a

dose of 75 to 325 mg.


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Methods

The GI endpoint was upper GI bleeding, bleeding of presumed occult GI

origin with decrease in hemoglobin of 2 g/dL or decrease inhematocrit 10%, symptomatic gastroduodenal ulcer confirmed byendoscopy or radiography, pain of presumed GI origin with underlyingmultiple 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, thesample size target was increased to 4200 and then ~5000 (143 GI

events). The study ended when the sponsor declared bankruptcy.


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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


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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


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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


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Baseline Characteristics

0.0611313 (69.6)1251 (66.7)Sex Male

0.65529.2 kg/m 2 (5.3)

28.3

29.2 kg/m 2 (5.6)

28.4

BMI

0.98467.2 years (11.1)68.6 years

67.2 years (10.8)68.7 years

Age

Mean (SD)Median

Mean (SD)Median

0.757114 (6.1)208 (5.8)History of Stroke

0.426158 (8.5)172 (9.3)History of PAD

0.468466 (25.0)484 (26.1)History of MI

0.382699 (37.5)669 (36.1)History of ACS0.8081769/63/561756/68/51White/Black/Other

0.456105 (5.6)116 (6.2)Used NSAIDs

0.938926 (49.0)923 (49.2)H. Pylori Positive

p-value for differencePlacebon (%)Treatedn (%)Variable


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Days

S u r v

i v a

l P r o

b a

b i l i t y

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

0 . 9

0

0 . 9

2

0 . 9

4

0 . 9

6

0 . 9

8

1 . 0

0

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite Cardiovascular Events

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


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Days

S u r v

i v a

l P r o

b a

b i l i t y

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

0 . 9

0

0 . 9

2

0 . 9

4

0 . 9

6

0 . 9

8

1 . 0

0

PlaceboTreated

Survival Curves for PPI Treated vs PlaceboMI Events


HR = 0.9695% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk

Treated: 36 events, 1839 at risk


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Days

S u r v

i v a

l P r o

b a

b i l i t y

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

0 . 9

0

0 . 9

2

0 . 9

4

0 . 9

6

0 . 9

8

1 . 0

0

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboRevascularization


HR = 0.9595% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk

Treated: 69 events, 1806 at risk


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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

BMI 30

Overall

Composite Cardiovascular Event HazardRatios for Baseline Variables

Vertical Line is Overall Hazard


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Composite Cardiovascular Event HazardRatios 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

Vertical Line is Overall Hazard


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Days

S u r v

i v a

l P r o

b a

b i l i t y

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

0 . 9

0

0 . 9

2

0 . 9

4

0 . 9

6

0 . 9

8

1 . 0

0

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


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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


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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

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