The COGENT Trial

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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
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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.
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Algorithm to Assess GI Risk With Antiplatelet
Therapy
Need for antiplatelet therapy
Yes
Assess GI risk factors
GI bleedingDual antiplatelet
therapyConcomitant anticoagulant
Yes
History of ulcer complication History of ulcer
disease (nonbleeding)
Test for H pylori treat if infected
Yes
No
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
200852150217. Circulation 2008. AJG 2008.
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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)
plt0.0001
Gilard et al. J Am Coll Cardiol 200851256-60.
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Risk of All-Cause Mortality and Recurrent ACS in
Patients Taking Clopidogrel and 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.
2009301(9)937-944.
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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
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, 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.

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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 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.

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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 gt 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 (lt 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
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
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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
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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
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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
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Composite Cardiovascular Event Hazard Ratios for
Baseline Variables
Vertical Line is Overall Hazard
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Composite Cardiovascular Event Hazard Ratios for
Medical History Variables
Vertical Line is Overall Hazard
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HR 0.5595 CI 0.36 0.85 p0.007 (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