Esomeprazole Compared With Famotidine in the Prevention of Upper Gastrointestinal Bleeding in Patients With Acute Coronary Syndrome or Myocardial Infarction - Esomeprazole vs. Famotidine in Prevention of GI Bleeding in ACS or MI

Dec 12, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Cardiac Research Fund, Ruttonjee Hospital, Hong Kong
Date Published:
01/01/2011
Date Updated:
12/12/2011
Original Posted Date:
12/12/2011
References

Description:

The use of dual antiplatelet therapy and anticoagulants is often fraught with problems of gastrointestinal bleeding (GIB) in patients presenting with acute coronary syndrome (ACS). The current trial sought to study the relative efficacy of esomeprazole, a protein pump inhibitor (PPI), versus famotidine, an H2 receptor antagonist, in ACS patients, most of whom were not at a higher risk for bleeding.

Hypothesis:

Esomeprazole would be superior to famotidine for preventing upper GIB in patients presenting with ACS, who were initiated on dual antiplatelet therapy (DAPT) and anticoagulants.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Admission with ACS, including STEMI
  • Requiring active treatment with aspirin, clopidogrel, and enoxaparin or thrombolytics

    Number of screened applicants: 653
    Number of enrollees: 313
    Duration of follow-up: median 18 weeks
    Mean patient age: 64 years
    Percentage female: 25%

Exclusions:

  • Known active peptic ulcer disease or GIB within 8 weeks
  • Known iron deficiency anemia
  • Mechanical ventilation with endotracheal intubation
  • Active cancer
  • Liver cirrhosis
  • End-stage renal failure
  • Life expectancy <1 year
  • Known allergy to aspirin, clopidogrel, enoxaparin, famotidine, or esomeprazole
  • Pregnancy, lactation, child-bearing potential in the absence of contraception
  • Co-prescription of nonsteroidal anti-inflammatory drugs, corticosteroid, or warfarin
  • Non-oral feeding or impaired GI absorption
  • Already treated with a PPI for >1 day
  • Another clinical trial drug for ulcer disease

Primary Endpoints:

  • Overt bleeding of gastroduodenal origin (confirmed by means of upper endoscopy), overt upper GIB of unknown origin, bleeding of occult GI origin (confirmed by means of upper GI endoscopy), obstruction, or perforation

Secondary Endpoints:

  • Occurrence of a composite of the primary endpoint or occult bleeding of unknown origin

Drug/Procedures Used:

Patients were randomized to receive either oral 20 mg esomeprazole daily or 40 mg famotidine daily, given before bedtime, at least 1 hour after dinner.

Concomitant Medications:

Aspirin 300 mg load/80-160 mg daily, clopidogrel 300 mg load/75 mg daily, enoxaparin (97%), and thrombolytics (9%)

Principal Findings:

A total of 313 patients were enrolled, 164 to esomeprazole and 149 to famotidine. Baseline characteristics were fairly similar between the two arms. Previous peptic ulcer disease was noted in 4.5% of patients, and previous GIB in 0.3%. About 19% were current smokers, and 3% consumed alcohol. About 32% had been on aspirin within the past 7 days, 4.5% on clopidogrel, 4% on famotidine, and 1.5% on a PPI. The index diagnosis was ST-segment elevation myocardial infarction (STEMI) in 18% and non-STEMI in 45%. Percutaneous coronary intervention was undertaken in about 43% of patients. About 21% discontinued the study drug before 28 days, mainly due to minor coronary disease on angiography, where the perceived risk of continuing clopidogrel outweighed its benefit.

Over a median duration of about 18 weeks, the primary composite endpoint of overt bleeding of gastroduodenal origin, overt upper GIB of unknown origin, bleeding of occult GI origin, obstruction, or perforation was lower in the esomeprazole arm as compared with the famotidine arm (0.6% vs. 6.1%, hazard ratio 0.095, 95% confidence interval 0.005-0.504, p = 0.0052). Hemoglobin drop ≥2 g/dl was also lower (1.8% vs. 6.0%). Significant bleeding from other sites was similar (1.8% vs. 2.8%). Major adverse cardiac events were similar (4.3% vs. 3.4%, p = 0.78).

Interpretation:

The results of this trial indicate that esomeprazole, a PPI, is superior to double-dose famotidine, an H2 blocker, in reducing intermediate-term GIB events in patients presenting with ACS and receiving DAPT with other anticoagulants. The majority of these patients were not at a higher risk for bleeding. Cardiovascular outcomes were similar between the two arms over the study duration.

The issue of PPI use with clopidogrel has been vexing. Multiple retrospective studies, including ex vivo platelet studies, have demonstrated an adverse interaction between PPIs, especially omeprazole and esomeprazole, and clopidogrel. In contrast, the landmark COGENT trial compared a fixed-dose combination of clopidogrel and omeprazole versus clopidogrel alone, and demonstrated no negative interaction between clopidogrel and omeprazole for cardiovascular outcomes, but also noted a reduction in bleeding events with the former strategy.

The current trial, though significantly smaller, adds to the results of the COGENT trial by further demonstrating the superiority of a PPI over an H2 blocker for the prevention of bleeding events in patients with coronary artery disease who receive DAPT and anticoagulants. This strategy is also endorsed by the most recent American College of Cardiology/American Heart Association/American College of Gastroenterology guidelines on this topic.

References:

Ng FH, Tunggal P, Chu WM, et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol 2011;Nov 22:[Epub ahead of print].

Keywords: Coronary Artery Disease, Follow-Up Studies, Platelet Aggregation Inhibitors, Receptors, Histamine H2, Blood Platelets, Ticlopidine, Fibrinolytic Agents, Purinergic P2Y Receptor Antagonists, Hemoglobins, Famotidine, Confidence Intervals, Myocardial Infarction, Acute Coronary Syndrome, Proton Pump Inhibitors, Percutaneous Coronary Intervention, Dinucleoside Phosphates, Esomeprazole, Enoxaparin, Omeprazole, Peptic Ulcer


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