Cardiovascular outcomes and mortality associated with proton pump inhibitors versus histamine-2 receptor antagonists in patients with heart failure: a target trial emulation study

Background Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are increasingly prescribed and have been linked to adverse cardiovascular events and mortality. Their impacts in patients with heart failure (HF) remain uncertain. Objective To evaluate the individual and comparative effects of PPIs and H2RAs on cardiovascular disease (CVD) and mortality in patients with HF. Method We conducted a target trial emulation study with the cloning-censoring-weighting design to avoid immortal time, lead time, and survivor biases. Patients with incident HF between Jan 1, 2003, and Dec 31, 2019, were included and followed until Dec 31, 2024. We compared three treatment strategies: PPIs versus non-initiator, H2RAs versus non-initiator, and PPIs versus H2RAs. Marginal structural models were fitted to estimate five-year absolute risks, risk differences, and hazard ratios (HRs) with 95% confidence intervals (CIs) for CVD outcome (composite of non-fatal myocardial infarction, stroke, and HF rehospitalization) and mortality. Sensitivity analyses included the use of gastrointestinal diseases as positive outcome controls. Result Of 66,834 patients with incident HF (median age 75.8 years [SD13.0]; 47.3% male), 27,866 initiated acid-suppressant therapy (PPIs, n=12,246; H2RAs, n=15,620), whereas 38,968 did not; 38,237 had CVD events, and 30,809 died. Compared to non-initiators, initiation of PPIs was associated with 6.66 excess CVD events (HR 1.24, 95% CI 1.19-1.30) and 5.74 more deaths (HR 1.23, 95% CI 1.19-1.27) per 100 patients; H2RA use was linked to 9.17 fewer CVD events (HR 0.93, 95% CI 0.90-0.97) and 0.78 fewer cardiovascular deaths (HR 0.96, 95% CI 0.91-0.99), but a modest increase in all-cause mortality (2.99 more deaths per 100 patients; HR 1.11, 95% CI 1.07-1.14). Compared directly, PPIs were associated with higher risks of CVD (HR 1.30, 95% CI 1.23-1.27) and mortality (HR 1.11, 95% CI 1.07-1.15) than H2RAs. Both PPI and H2RA use were associated with lower risks of gastrointestinal hemorrhage and peptic ulcer (as positive controls), supporting the validity of our primary findings. Results were consistent across subgroup and sensitivity analyses. Conclusion In patients with HF, PPI initiation was associated with increased risks of cardiovascular events and all-cause mortality compared to both H2RA users and non-initiators, while H2RA use was linked to reduced risks of cardiovascular events and cardiac mortality, making H2RAs a potentially preferable alternative to PPIs for acid suppression in patients with HF.cumulative incidence