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

      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

      Abbreviations used in this paper:

      CI (confidence interval), HR (hazard ratio), OR (odds ratio), PPI (proton pump inhibitor)
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      Linked Article

      • Long-term Renal Effects of Proton Pump Inhibitor Use
        GastroenterologyVol. 158Issue 4
        • Preview
          We applaud the efforts of COMPASS investigators in examining the long-term risks of proton pump inhibitor (PPI) use.1 However, we would like to alert readers to three important limitations, and argue that the results cannot be used to conclude that long-term PPI use is safe, with particular focus on the risk of chronic kidney disease (CKD).
        • Full-Text
        • PDF
      • Safety of Proton Pump Inhibitors Questioned Based on a Large Randomized Trial of Patients Receiving Rivaroxaban or Aspirin
        GastroenterologyVol. 158Issue 4
        • Preview
          We commend Dr Moayyedi et al for the recent randomized clinical trial, in which the authors concluded that proton pump inhibitors (PPIs) are not associated with long-term harm and “that limiting PPI prescriptions, because of concerns for the long-term harm, is not appropriate.”1 We believe this interpretation might unequivocally be misleading for clinicians, and these findings should be interpreted with great caution, in particular because PPI use is known to be inappropriate in 25%–70% of long-term users and discontinuation of treatment is insufficiently considered.
        • Full-Text
        • PDF
      • What Is the Optimal Follow-up Time to Ascertain the Safety of Proton Pump Inhibitors?
        GastroenterologyVol. 158Issue 4
        • Preview
          We read with great interest the original article by Moayyedi et al1 about the safety of proton pump inhibitors (PPIs) in patients with coronary or peripheral arterial disease receiving either aspirin or rivaroxaban. We would like to congratulate them, because this is one of the largest prospective placebo-controlled studies, to the best of our knowledge. The authors followed patients for a median time of 3 years and showed that PPIs increased only the risk of enteric infections. However, a question may arise: what is the best follow-up time to ascertain the safety of PPIs? In a recently published meta-analysis regarding the relationship between PPIs and dementia, most of studies reported a follow-up time of 6–9 years.
        • Full-Text
        • PDF