P: population, I: intervention, C: comparator, O: outcome, n: number, PPI; proton pump inhibitor, H2RA: histamin-2 receptor antagonist, CV: cardiovascular, RCT: randomized controlled trial, ASA: acetylsalicylic acid.
The Shiraev 2018 SR pooled all-cause mortality data from 3 published observational studies 17. Eighty-nine percent of the data was from Charlot et al, 2011, a study of Danish patients following their first myocardial infarction (19,925 of the 22,427 patients in Shiraev 2018 20. The pooled mortality rate was higher among PPI users compared with non-PPI users (OR = 1.68; 95% CI: 1.53 to 1.84) (Table 2). In Charlot et al, 2011 mortality was increased during 1-year follow-up in people taking PPIs (HR = 2.38; 95% CI: 2.12-2.67).
Xie et al, 2019 conducted a longitudinal cohort study emulating a clinical trial using administrative data from the United States’ Veterans Affairs (VA) national database 18. New users of acid suppressing medication were identified between July 2002 and June 2004 and followed via from their medical records for 10 years. The cohort included 214,467 US veterans (mean age of 65), who newly started taking PPIs (n=157,625) or H2RAs (n=56,842). The risk of death was higher with PPI versus H2RA users (HR = 1.17; 95% CI: 1.10 to 1.24). Event rates were 59,771 per 157,625 (37.9%) for PPIs vs 20,287 per 56,842 (35.7%) for H2RAs (Table 2).
A RCT, COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) Moayyedi et al, 2019, conducted a second randomization of participants with heart and peripheral artery disease who were first randomized to rivaroxaban plus ASA or ASA alone. A subgroup without an indication for PPI use or PPI use on entry into the trial was secondarily randomized to receive pantoprazole 40 mg daily vs. placebo. A total of 17,598 participants had no approved indication for PPI treatment; data on adverse events were collected in interviews every 6 months from 580 centers in 33 countries without further verification. The death rates were 630 per 8791 (7.2%) for pantoprazole vs 614 per 8807 (7.0%) for placebo (HR = 1.03; CI: 0.92 to 1.15) (Table 2)19.