Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin

Gastroenterology. 2019 Sep;157(3):682-691.e2. doi: 10.1053/j.gastro.2019.05.056. Epub 2019 May 29.

Abstract

Background & aims: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.

Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.

Results: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.

Conclusions: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

Keywords: Bacteria; CVD; Reflux; Thrombosis.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aspirin / administration & dosage*
  • Aspirin / adverse effects
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / drug therapy*
  • Double-Blind Method
  • Drug Administration Schedule
  • Enterocolitis, Pseudomembranous / chemically induced
  • Enterocolitis, Pseudomembranous / microbiology
  • Factor Xa Inhibitors / administration & dosage*
  • Factor Xa Inhibitors / adverse effects
  • Female
  • Gastrointestinal Hemorrhage / chemically induced
  • Gastrointestinal Hemorrhage / prevention & control*
  • Humans
  • Male
  • Middle Aged
  • Pantoprazole / administration & dosage*
  • Pantoprazole / adverse effects
  • Peripheral Arterial Disease / diagnosis
  • Peripheral Arterial Disease / drug therapy*
  • Platelet Aggregation Inhibitors / administration & dosage*
  • Platelet Aggregation Inhibitors / adverse effects
  • Prospective Studies
  • Proton Pump Inhibitors / administration & dosage*
  • Proton Pump Inhibitors / adverse effects
  • Risk Assessment
  • Risk Factors
  • Rivaroxaban / administration & dosage*
  • Rivaroxaban / adverse effects
  • Time Factors
  • Treatment Outcome

Substances

  • Factor Xa Inhibitors
  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors
  • Rivaroxaban
  • Pantoprazole
  • Aspirin

Associated data

  • ClinicalTrials.gov/NCT01776424