Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin

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Moayyedi P, et al. "Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial". Gastroenterology. 2019. 157(2):403-412.
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Clinical Question

Can proton pump inhibitor therapy reduce the risk of upper gastrointestinal bleeding in patients receiving antiplatelets and anticoagulants?

Bottom Line

Routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions.

Major Points

Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. Epidemiologic data suggest that patients taking cardio-protective aspirin have a 2-fold increased risk of upper GI complications, and patients taking vitamin K antagonists have a similar increased risk. Combining vitamin K antagonists and nonsteroidal anti-inflammatory drugs can increase the risk of upper GI complications further, with 1 study suggesting a 12-fold increase in risk. New oral anticoagulants (NOACs) are also associated with an increased risk of GI bleeding, and some NOACs are associated with a greater risk of GI bleeding than vitamin K antagonists.

Guidelines suggest that patients receiving the combination of anti-platelet and anticoagulant therapy should receive PPIs to reduce the risk of upper GI bleeding. However, there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin. This present study is the largest PPI trial and the first to evaluate whether PPI therapy can prevent clinically significant upper GI events in patients receiving anticoagulation with or without aspirin therapy.

Guidelines

Design

  • 3 × 2 partial factorial, multicenter, double-blind, randomized placebo-controlled trial
  • n = 17598
    • Pantoprazole (n = 8791)
    • Placebo (n = 8807)
  • Setting: 580 centers in 33 countries
  • Enrolment: March 2013 to May 2016
  • Mean follow-up: After randomization, participants were seen at 1 month, 6 months, and then at 6-month intervals until the end of the study.
  • Analysis: Intention-to-treat
  • Primary outcome: Time to first upper GI clinical event (composite of the following)
    • overt bleeding (hematemesis and/or melena) with a gastroduodenal lesion (peptic ulcer or neoplasia confirmed by endoscopy or radiology) that is bleeding at the time of the procedure,
    • overt upper GI bleeding of unknown origin (patient presents with hematemesis with or without melena that was thought by the attending clinician to relate to the upper GI tract),
    • occult bleeding (drop in the hemoglobin of ≥2 g/dL),
    • symptomatic gastroduodenal ulcer with at least 3 days of GI pain, or at least 5 gastroduodenal erosions (confirmed by endoscopy) with at least 3 days of GI pain,
    • upper GI obstruction,
    • perforation

Population

Inclusion Criteria

  • Stable coronary or peripheral arterial disease
  • Patients with coronary artery disease under the age of 65 years were additionally required to have arterial disease involving 2 vascular beds or 2 additional risk factors.

Exclusion Criteria

  • High risk of bleeding from any site
  • Severe heart failure
  • Significant renal impairment
  • Need for dual antiplatelet or anticoagulant therapy
  • Known hypersensitivity to any of the study drugs

Selected Baseline Characteristics

Comparisons are pantoprazole (n = 8791) vs. placebo (n = 8807).

  • Age, y: 67.6 vs 67.7
  • Females: 22 vs 21%
  • Caucasian: 60 vs 60%
  • BMI, kg/m^2: 28.3 vs 28.4
  • Previous MI: 61.5 vs 61%
  • Previous peptic ulcer: 3 vs 2.5%
  • Liver disease: 1 vs 1%
  • NSAIDs: 5 vs 5%

Interventions

  • All participants were randomly assigned to receive low-dose rivaroxaban 2.5 mg twice a day with aspirin 100 mg once daily, rivaroxaban 5 mg twice a day alone, or aspirin 100 mg once daily alone stratified by center and use of PPI.
  • All participants with no clinical need for a PPI (64%) were further randomized 1:1 to receive pantoprazole (40 mg once daily) or matched placebo stratified by center and antithrombotic treatment arm.
  • After randomization, participants were seen at 1 month, 6 months, and then at 6-month intervals until the end of the study.

Outcomes

Comparisons are pantoprazole (n = 8791) vs. placebo (n = 8807).

Primary Outcomes

Upper GI event
1.2% vs. 1.3% (P=0.35)
Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography
0.2% vs. 0.4% (P=0.03)
Overt upper GI bleeding of unknown origin
0.6% vs. 0.6% (P=0.68)
Bleeding of presumed occult upper GI tract origin with documented decrease in Hb ≥2 g/dL
0.1% vs. 0.1% (P=0.99)
Symptomatic gastroduodenal ulcer
<0.1% vs. 0.2% (P=0.07)
GI pain with underlying multiple gastroduodenal erosions
<0.1% vs. <0.1% (P=0.37)
Upper GI obstruction or perforation
0.2% vs. 0.2% (P=0.41)

Post Hoc Outcomes

Overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography with no need for active bleeding at time of investigation
0.3% vs. 0.6% (P=0.001)
Gastroduodenal ulcer without the need for symptoms prior to diagnosis
0.2% vs. 0.4% (P=0.01)
Multiple gastroduodenal erosions without the need for symptoms prior to diagnosis
<0.1% vs. 0.2% (P=0.01)
Combination of all post-hoc gastroduodenal ulcer/erosion outcomes
0.5% vs. 1.1% (P<.0001)

Criticisms

  • Their definition of gastroduodenal bleeding was very stringent, and events were only included if the lesion was bleeding at the time of endoscopy.
  • The present trial enrolled a population at low risk for upper GI complications.

Funding

  • This study was funded by Bayer AG.

Further Reading