Moayyedi P, Eikelboom JW, Bosch J, et al. 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. (Original study)

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.

Discipline Area Score
Internal Medicine 6 / 7
Cardiology 6 / 7
Hematology 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Hemostasis and Thrombosis 5 / 7
Comments from MORE raters

Cardiology rater

Proton pump inhibitors are commonly prescribed and I often stop them if I see no obvious clinical indication. Part of the motivation for stopping is that I worry about adverse effects of the drug. This large RCT suggests I should be less worried as adverse events were similar between PPI and placebo. There was an increase in enteric infection including Clostridium difficle and this cant be ignored. Despite the size of the study, it may still have been under-powered to definitively exclude a between group difference and I wonder if the data in this healthy cohort are still valid in sick hospital patients. I suspect, I will continue to stop PPI if I think it unnecessary.

Family Medicine (FM)/General Practice (GP) rater

COMPASS enrolled a population with established stable cardiovascular disease randomized to aspirin/rivaroxaban combination. The risk for gastric bleeding was hence substantial and further increased by older age. Most physicians would be confident that the benefits of PPI clearly outweigh the risk for infrequent events such as pneumonia. This would not be considered inappropriate prescribing, which should be a true concern when PPIs are used for simple gastrooesophageal reflux or dyspepsia. The trial duration was relatively short, however, many patients use PPIs for decades.

General Internal Medicine-Primary Care(US) rater

Still need to rule out increased risk for gastric cancer.

Hematology rater

A well-conducted study confirming the safety of long-term use of PPIs, irrespective of the concomitant use of ASA or rivaroxaban.

Internal Medicine rater

This large well-executed RCT of pantoprazole vs placebo over 3 years in patients with CAD/PAD provides clinically important information regarding the safety of pantoprazole. First, it confirms that PPIs do not in and of themselves increase the risk for CV events, indicating that prior observational studies were seriously confounded. Second, pantoprazole increased the risk for enteral infection, although the absolute risk increase was low (+0.4%; NNH 125 over 3 years). Third, in this group of RCT participants with limited non-CV comorbidities, pantoprazole did not meaningfully increase the risk for other adverse effects such as dementia, CKD, or pneumonia that have previously been associated with PPI use. Of note, CV outcomes were systematically defined, collected, and adjudicated in a blinded fashion, whereas other events (infections, dementia, CKD) were collected via patient interview without adjudication, so it is likely these other outcomes were under-reported.
Comments from EvidenceAlerts subscribers

Miss. Valérie Paquet (10/1/2019 8:36 AM)

It's safe (?) but doesn't prevent GI bleeding in a low-risk cohort.

Dr. Mosedi Namane (9/19/2019 11:01 AM)

I'm interested in finding out about the long-term effects of using PPI. The study is however useful for informing us that there is not much to worry about during the first 3 years of taking pantoprazole in this group of patients.