COGENT

Published

Bhatt DL, et al. "Clopidogrel with or without omeprazole in coronary artery disease". The New England Journal of Medicine. 2010. 363(20):1909-17.
PubMed • Full text • PDF

Clinical Question

In patients with CAD requiring aspirin and clopidogrel, what is the effect of omeprazole on GI and CV outcomes?

Bottom Line

Among patients with CAD requiring aspirin and clopidogrel, there was no significantly increased risk in CV events when omeprazole was added. However, there was a significant reduction in GI events, particularly an 87% reduction in overt upper GI bleed.

Major Points

The 2010 Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) randomized 3761 high-risk patients with ACS or undergoing PCI to omeprazole or placebo. The trial was stopped early because of cessation of sponsor funding. It demonstrated a 66% reduction in the primary GI endpoint which was a composite of overt and occult GI bleed, symptomatic gastroduodenal ulcers, or erosive disease at 180 days. In particular, there was an 87% reduction in overt upper GI bleeding. The NNT to prevent one overt GI bleed was 90. Despite previous observational studies raising concerns that PPIs may inhibit the antiplatelet effect of clopidogrel, COGENT demonstrated no such impact of omeprazole on cardiovascular outcomes or cardiovascular mortality, reassuring the safety of omeprazole in combination with clopidogrel.

A 2012 systematic review reached similar conclusions in its meta-analysis, which was only included two trials (including COGENT). They also found evidence of attenuation of the antiplatelet effect of clopidogrel with co-administration with PPIs, but this doesn't appear to result in worse clinical outcomes.

Guidelines

As of June 2015, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
• N=3761
  • Clopidogrel and omeprazole (n=1876)
  • Clopidogrel alone (n=1885)
• Setting: 393 sites in 15 countries
• Enrollment: 2008
• Median follow-up: 106 days

Population

Inclusion Criteria

• Age ≥21 years
• Use of clopidogrel with aspirin anticipated for at least next 12 months, including patients presenting with ACS or undergoing PCI

Exclusion Criteria

• Hospitalized patients for whom discharge within 48 hours after randomization was not anticipated
• Need for short-term or long-term use of PPI, H2-receptor antagonist, sucralfate, or misoprostol
• Preexisting erosive esophagitis or esophageal or gastric variceal disease or previous non-endoscopic gasric surgery
• Received clopidogrel or another thienopyridine for >21 days before randomization
• Received oral anticoagulation therapy that could not be safely discontinued for duration of study
• Recent fibrinolytic therapy

Baseline Characteristics

• Demographics: Age 69 years, male sex 68%, White race 94%
• Median BMI: 28.4 kg/m²
• Negative for Helicobacter pylori: 9%
• CV history: PCI 72%, ACS 42%, MI 30%, PAD 12%, CVA 8%
• CV risk factors: HTN 81%, DM 30%, HLD 78%, current smoking 13%
• Current alcohol use: 52%
• History of GIB or ulcer: 4.2%
• NSAID use: 89%

Baseline Medications

• Aspirin: 59.3%
• Statin: 67.2%
• Clopidogrel: 69.2%

Interventions

• Fixed-dose combination pill containing clopidogrel 75mg and omeprazole 20mg vs. clopidogrel 75mg alone
• Stratification based on two baseline factors: Helicobacter pylori serologies and use of NSAIDs
• All patients received enteric-coated aspirin at a dose of 75 to 325mg daily.

Outcomes

Comparisons are omeprazole vs. placebo expressed as event rate at 180 days.

Primary Outcomes

Composite of GI events

1.1% vs. 2.9% (HR 0.34; 95% CI 0.18-0.63; P<0.001)

Composite of CV events

4.9% vs. 5.7% (HR 0.99; 95% CI 0.68-1.44; P=0.96)

Secondary Outcomes

Composite of overt and occult GIB

0.8% vs. 2.0% (HR 0.30; 95% CI 0.13-0.66; P=0.001)

Composite of overt GIB

0.2% vs. 1.2% (HR 0.13; 95% CI 0.03-0.56; P=0.001)

Overt gastroduodenal bleeding

0.1% vs. 0.6% (HR 0.12; P=0.03)

Overt upper GIB

0.1% vs. 0.6% (HR 0.13; P=0.03)

Occult bleeding

0.6% vs. 0.8% (P=0.21)

GI pain with underlying multiple erosive diseases

0.2% vs. 0.7% (P=0.05)

Symptomatic gastroduodenal ulcer

0.1% vs. 0.2% (P=0.27)

Symptomatic GERD

0.2% vs. 1.2% (HR 0.22; 95% CI 0.06-0.79; P=0.01)

MI

1.2% vs. 1.5% (HR 0.92; 95% CI 0.44-1.90; P=0.81)

Revascularization

4.0% vs. 4.6% (HR 0.91; 95% CI 0.59-1.38; P=0.64)

Stroke

0.2% vs. 0.3% (P=0.43)

CV mortality

0.4% vs. 0.3% (P=0.49)

All-cause mortality

0.4% vs. 0.5% (P=1.00)

Subgroup Analysis

No significant interactions among sub-groups or according to stratification variables

Composite of GI events

Presence vs. absence of H. pylori (P=0.47)

Use vs. non-use of NSAIDs (P=0.97)

Borderline significant interaction on basis of sex (P=0.05)

Composite of CV events

Presence vs. absence of H. pylori (P=0.42)

Use vs. non-use of NSAIDs (P=0.68)

Adverse Events

Overall adverse events

41.3% vs. 42.8% (P=0.33)

Serious adverse events

10.1% vs. 9.4% (P=0.48)

Diarrhea

3.0% vs. 1.8% (P=0.01)

Criticisms

• Limited power: trial was terminated prematurely resulting in a smaller number of events than anticipated as the sponsor became bankrupt.
• Confidence interval around the hazard ratio for CV events was wide. The absence of interaction between clopidogrel and omeprazole cannot be definitively ruled out, especially in the 2-3% of the white population with homozygosity for the loss-of-function CYP2C19. In homozygous patients, PPIs may indeed reduce the level of active metabolite and blunt the clinical effectiveness of clopidogrel.
• The single-pill formulation used in this study differs from generic omeprazole in regards to its release kinetics.
• Not designed to detect differences among other PPIs, although omeprazole has been most commonly implicated.
• The follow-up may not be of sufficient duration.

Funding

• Supported by Cogentus Pharmaceuticals
• Blinded and open-label enteric-coated aspirin supplied by Paraxel