Gastroenterology

Gastroenterology

Volume 157, Issue 2, August 2019, Pages 403-412.e5
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

https://doi.org/10.1053/j.gastro.2019.04.041Get rights and content

Background & Aims

Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk.

Methods

We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation.

Results

There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67–1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28–0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27–0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609–2528).

Conclusions

In a randomized placebo-controlled trial, we found that 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. ClinicalTrials.gov ID: NCT01776424.

Section snippets

Trial Design

The design of the COMPASS trial has been published previously.11 This is a 3 × 2 partial factorial, multicenter, double-blind, randomized placebo-controlled trial, evaluating patients with stable atherosclerotic vascular disease.10 Participants were randomized to rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg once daily alone to compare the primary outcomes of cardiovascular death, stroke, or myocardial infarction in these 3

Results

There were 17,598 participants recruited between March 2013 and May 2016 and randomized to pantoprazole 40 mg or placebo. The flow of participants through the trial is described in Supplementary Figure 1. The main reason for exclusion from the PPI arm of the trial was that patients were considered to have a clinical need for PPI based on their physicians’ judgment at the time of enrollment (Supplementary Figure 1). Mean age of participants was 67.6 years, 13,792 (78%) were male, 4074 (23%) were

Discussion

This 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. The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact

Acknowledgments

Author contributions: All authors were involved in data acquisition, general design of the trial, interpretation of the data and critical revision of the manuscript. L. Dyal and O. Shestakovska were involved with the primary analysis of the data. P. Moayyedi, J.W. Eikelboom, J. Bosch, S.J. Connolly, and S. Yusuf were involved in the initial draft of the manuscript. P. Moayyedi, J.W. Eikelboom, J. Bosch, S.J. Connolly, N. Cook Bruns, E. Muehlhofer and S. Yusuf were involved with the design of

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    Conflicts of interest These authors disclose the following: Dr Moayyedi has received funding for research (related to inflammatory bowel disease and irritable bowel syndrome) from Allergan and Takeda. Dr Eikelboom reports receiving grant support and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis. Dr Connolly is receiving lecture fees and consulting fees from Bristol-Myers Squibb, Pfizer, Portola Pharmaceuticals, Boehringer Ingelheim, Servier, Daiichi Sankyo, and Medtronic. Dr Hart is receiving grant support, fees for serving as principal investigator of the Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial, and advisory board fees from Bayer. Dr Diaz is receiving grant support from the Population Health Research Institute. Dr Alings is receiving consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi-Aventis. Dr Lonn is receiving consulting fees from Bayer, Amgen, Sanofi, Novartis, and Servier. Dr Anand is receiving consulting fees and lecture fees from Bayer and Novartis. Dr Avezum is receiving consulting fees from Boehringer Ingelheim. Dr Branch is receiving grant support from Astellas and serving on an advisory board for Janssen. Dr Bhatt is receiving grant support from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, the Medicines Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, and Ironwood Pharmaceuticals, collaborating on research (uncompensated) with FlowCo, PLx Pharma, Takeda, and Merck, receiving fees for serving on data monitoring committees, an operations committee, a publications committee (US co-national leader), and a steering committee from the Population Health Research Institute, serving as editor-in-chief of the Harvard Heart Letter for Belvoir Publications, serving as chief medical editor of Cardiology Today’s Intervention for Slack Publications, receiving fees for serving on continuing medical education steering committees from WebMD, receiving advisory board fees from Elsevier, serving on uncompensated advisory boards for Medscape Cardiology and Regado Biosciences, serving as editor-in-chief of the Journal of Invasive Cardiology for HMP Communications, serving as deputy editor for Clinical Cardiology, serving as guest editor and associate editor for the Journal of the American College of Cardiology, serving as chair of the research and publications committee of the Veterans Affairs Cardiovascular Assessment, Reporting, and Tracking system for the Department of Veterans Affairs, serving as site co-investigator for Biotronik and Boston Scientific, serving on an uncompensated advisory board for Cardax, and receiving fees for serving on data monitoring committees from the Cleveland Clinic, Duke University, and Mount Sinai School of Medicine. Dr Zhu is receiving lecture fees from Bayer, Boehringer Ingelheim, and Sanofi. Dr Liang is receiving lecture fees from Bayer, Boehringer Ingelheim, and Sanofi. Dr Maggioni is receiving fees for serving as a study committee member from Novartis, Bayer, Fresenius Medical Care, and Cardiorentis. Dr Kakkar is receiving grant support and fees for serving as steering committee chairman from Bayer, and consulting fees from Boehringer Ingelheim, Daiichi Sankyo Europe, Janssen, Sanofi, and Armetheon. Dr Fox is receiving grant support and honoraria from AstraZeneca and honoraria from Sanofi/Regeneron Pharmaceuticals. Dr Parkhomenko is receiving grant support and honoraria from Pfizer, Bayer, Janssen, AstraZeneca, Sanofi, and Merck Sharp & Dohme. Dr Störk is receiving grant support from Servier and Boehringer Ingelheim, grant support and lecture fees from Novartis and Thermo Fisher Scientific, and lecture fees from Pfizer. Dr Dans is receiving lecture fees from Pfizer and Boehringer Ingelheim. Dr Torp-Pedersen is receiving grant support from Biotronik. Dr Verhamme is receiving grant support, lecture fees, and consulting fees from Bayer HealthCare, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, and Brisol-Myers Squibb, grant support from Sanofi and Leo Pharma, and consulting fees from Portola Pharmaceuticals. Dr Vinereanu is receiving grant support, lecture fees, and consulting fees from Boehringer Ingelheim, Pfizer, and Novartis and grant support and lecture fees from Servier. Dr Lewis is receiving lecture fees and honoraria from Pfizer/Bristol-Myers Squibb. Dr Steg is receiving fees for serving on a steering committee from Amarin, Janssen, and CSL Behring, fees for serving on a steering committee and lecture fees from AstraZeneca, lecture fees and consulting fees from Bayer and Bristol-Myers Squibb, fees for preparation of educational material from Boehringer Ingelheim, consulting fees and fees for serving on a data and safety monitoring board from Eli Lilly and Merck Sharp & Dohme, consulting fees from Novartis and Regeneron Pharmaceuticals, fees for serving on a critical-event committee from Pfizer, fees for serving on a steering committee and consulting fees from Sanofi, and fees for serving on a steering committee, consulting fees, and fees for serving on a data and safety monitoring board from Servier. Dr Cook Bruns and Dr Muehlhofer are employed by Bayer. Dr Yusuf is receiving grant support and honoraria from Bayer, Boehringer Ingelheim, Astra-Zeneca, Bristol-Myers Squibb, and Cadila Pharmaceuticals. The remaining authors disclose no conflicts.

    Funding This study was funded by Bayer AG.

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