Clopidogrel and the Optimization of Gastrointestinal Events Trial - COGENT

Oct 06, 2010
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Peter C. Block, MD, FACC
Trial Sponsor:
Cogentus Pharmaceuticals
Date Presented:
01/01/2009
Date Published:
01/01/2010
Date Updated:
10/06/2010
Original Posted Date:
10/06/2010
References

Description:

A few platelet studies have indicated that proton pump inhibitors (PPIs), specifically omeprazole, are associated with reduced antiplatelet efficacy of clopidogrel, when used together. In addition, the use of dual antiplatelet therapy is often fraught with problems of gastrointestinal (GI) bleeding in patients at higher risk for bleeding. The current trial sought to study clinical GI and cardiovascular (CV) outcomes in patients on dual antiplatelet therapy with aspirin and clopidogrel, who had no indication for a PPI.

Hypothesis:

PPIs would be associated with a lower risk of bleeding as compared with placebo in patients at average risk for bleeding from antiplatelet therapy. This would be achieved without a significant increase in adverse clinical outcomes resulting from possible reduced antiplatelet efficacy of clopidogrel.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patients Screened: 4,444
Patients Enrolled: 3,761
Mean Follow Up: 180 days
Mean Patient Age: Median: 68.6 years
Female: 32%

Patient Populations:

  • Age ≥21 years
  • Clopidogrel therapy with concomitant aspirin was anticipated for at least the next 12 months
    o Acute coronary syndrome
    o Undergoing placement of a coronary stent

Exclusions:

  • Hospitalized patients for whom discharge was not anticipated within 48 hours of randomization
  • Requirement for current or chronic use of a PPI, 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

Primary Endpoints:

  • Composite GI events, defined as 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
  • Composite of CV death, nonfatal MI, coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), or ischemic stroke

Secondary Endpoints:

  • Occurrence of gastroesophageal reflux disease, as evidenced by symptomatic, endoscopically confirmed erosive esophagitis

Drug/Procedures Used:

Patients were randomized to receive either a fixed dose of clopidogrel 75 mg along with omeprazole 20 mg (CGT-2168), or clopidogrel with placebo.

Concomitant Medications:

All patients received enteric coated aspirin at a dose of 75-325 mg daily; statins (68%); nonsteroidal anti-inflammatory drugs (NSAIDs; 9%)

Principal Findings:

A total of 3,761 patients were randomized, 1,876 to clopidogrel + omeprazole, and 1,885 to clopidogrel alone. The trial was terminated early when the sponsor lost financing. Baseline characteristics were fairly similar between the two groups. About 49% of the patients were H. pylori positive, and 9% had used NSAIDs. History of myocardial infarction (MI) or stroke was noted in 30% and 8% of the patients, respectively. About 13% were current smokers, 52% consumed alcohol, and 4% had a history of GI bleeding or an ulcer in the past.

The primary endpoint of GI events at 180 days was significantly lower in the clopidogrel + omeprazole arm, as compared with the clopidogrel alone arm (1.1% vs. 2.9%, hazard ratio 0.34, 95% confidence interval 0.18-0.63, p < 0.001). There was no interaction when stratified by H. pylori or NSAID use status. Of the individual components of the primary endpoint, overt gastroduodenal bleeding (0.1% vs. 0.6%, p = 0.03) and overt upper GI bleeding of unknown origin (0.1% vs. 0.6%, p = 0.03) were both significantly reduced in the combination arm, as compared with the placebo arm.

CV events, including any CV event (4.9% vs. 5.7%, p = 0.98), MI (1.2% vs. 1.5%, p = 0.83), revascularization (4.0% vs. 4.6%, p = 0.70), stroke (0.2% vs. 0.3%, p = 0.43), CV mortality (0.4% vs. 0.3%, p = 0.49), and all-cause mortality (0.4% vs. 0.5%, p = 1.0) were similar between the combination and placebo arms, respectively. In addition, there were no cases of stent thrombosis in the clopidogrel + omeprazole arm, as compared with two in the clopidogrel + placebo arm.

Serious adverse events were similar (10.1% vs. 9.4%, p = 0.48). Diarrhea was more frequent in patients receiving omeprazole (3.0% vs. 1.8%, p = 0.01).

Interpretation:

The results of this landmark trial indicate that the concomitant use of clopidogrel with omeprazole is associated with a reduction in composite GI events when used in patients who were not at high risk for GI bleeding, including overt upper GI bleeding. This is achieved without an increase in adverse CV events, contrary to what has been suggested by ex vivo platelet assays, and a few observational studies.

Similar concerns from ex vivo platelet assays had been raised for atorvastatin when used with clopidogrel, but had not borne out when tested for clinical outcomes in randomized controlled trial data sets. This highlights the importance of clinical outcomes over surrogate measures, such as platelet assays, and also the importance of well-conducted randomized controlled trials over observational studies.

One issue is that it is unknown if clopidogrel and omeprazole taken together would have the same lack of interaction as the fixed dose combination tested in this trial. This will need to be tested in future trials, since the company making this fixed dose combination is now defunct. Also, since homozygosity for loss of function of the CYP2C19 gene has been shown to be associated with reduced transformation of clopidogrel to active metabolite, future studies will also need to focus on the effect of PPIs in this subgroup of patients.

References:

Bhatt DL, Cryer BL, Contant CF, et al., on behalf of the COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;Oct 6:[Epub ahead of print].

Presented by Dr. Deepak Bhatt at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2009), San Francisco, CA, September 24, 2009.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Platelet Aggregation Inhibitors, Diarrhea, Coronary Disease, Ticlopidine, Blood Platelets, Heptanoic Acids, Proton Pump Inhibitors, Stents, Pyrroles, Ulcer, Thrombosis, Omeprazole


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