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

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.

• Authors: Paul Moayyedi, John W Eikelboom, Jackie Bosch, Stuart J Connolly, Leanne Dyal, Olga Shestakovska, Darryl Leong, Sonia S Anand, Stefan Störk, Kelley R H Branch, Deepak L Bhatt, Peter B Verhamme, Martin O'Donnell, Aldo P Maggioni, Eva M Lonn, Leopoldo S Piegas, Georg Ertl, Matyas Keltai, Nancy Cook Bruns, Eva Muehlhofer, Gilles R Dagenais, Jae-Hyung Kim, Masatsugu Hori, P Gabriel Steg, Robert G Hart, Rafael Diaz, Marco Alings, Petr Widimsky, Alvaro Avezum, Jeffrey Probstfield, Jun Zhu, Yan Liang, Patricio Lopez-Jaramillo, Ajay K Kakkar, Alexander N Parkhomenko, Lars Ryden, Nana Pogosova, Antonio L Dans, Fernando Lanas, Patrick J Commerford, Christian Torp-Pedersen, Tomek J Guzik, Dragos Vinereanu, Andrew M Tonkin, Basil S Lewis, Camilo Felix, Khalid Yusoff, Kaj P Metsarinne, Keith A A Fox, Salim Yusuf, COMPASS Investigators
• Journal: Gastroenterology (Gastroenterology) Vol. 157 Issue 3 Pg. 682-691.e2 (09 2019) ISSN: 1528-0012 [Electronic] United States
• PMID: 31152740 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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