Use of histamine H2 receptor antagonists and outcomes in patients with heart failure: a nationwide population-based cohort study

Abstract

Background: Histamine H₂ receptor activation promotes cardiac fibrosis and apoptosis in mice. However, the potential effectiveness of histamine H₂ receptor antagonists (H2RAs) in humans with heart failure is largely unknown. We examined the association between H2RA initiation and all-cause mortality among patients with heart failure.

Methods: Using Danish medical registries, we conducted a nationwide population-based active-comparator cohort study of new users of H2RAs and proton pump inhibitors (PPIs) after first-time hospitalization for heart failure during the period 1995-2014. Hazard ratios (HRs) for all-cause mortality and hospitalization due to worsening of heart failure, adjusting for age, sex, and time between heart failure diagnosis and initiation of PPI or H2RA therapy, index year, comorbidity, cardiac surgery, comedications, and socioeconomic status were computed based on Cox regression analysis.

Results: Our analysis included 42,902 PPI initiators (median age 78 years, 46% female) and 3,296 H2RA initiators (median age 76 years, 48% female). Mortality risk was lower among H2RA initiators than PPI initiators after 1 year (26% vs 31%) and 5 years (60% vs 66%). In multivariable analyses, the 1-year HR was 0.80 (95% CI, 0.74-0.86) and the 5-year HR was 0.85 (95% CI, 0.80-0.89). These findings were consistent after propensity score matching and for ischemic and nonischemic heart failure, as for sex and age groups. The rate of hospitalization due to worsening of heart failure was lower among H2RA initiators than PPI initiators.

Conclusion: In patients with heart failure, H2RA initiation was associated with 15%-20% lower mortality than PPI initiation.

Keywords: epidemiology; heart failure; histamine H2 receptor; mortality.

Figure 1

Kaplan–Meier survival curve for initiators of proton pump inhibitors and histamine H₂ receptor antagonists. Abbreviations: H2RA, histamine H₂ receptor antagonist; PPI, proton pump inhibitor.

Figure 2

One-year all-cause mortality in subgroups of heart failure patients, comparing new users of H2RA and new users of PPIs. Notes: Adjusted by age group, sex, index-year categories, time from heart failure diagnosis until first prescription for PPI or H2RA, coronary artery disease, valvular heart disease, hypertension, atrial fibrillation or atrial flutter, venous thromboembolism, stroke, intermittent claudication, diabetes mellitus, obesity, cancer within 1 year, chronic pulmonary disease, chronic kidney disease, dementia, depression, illicit drug abuse/alcohol abuse/smoking, peptic ulcer disease, gastroesophageal reflux disease, anemia, chronic liver disease, alcoholism-related disorders, musculoskeletal disorders, inflammatory bowel disease, cardiac surgery within past 90 days (coronary artery bypass graft surgery and percutaneous coronary intervention), comedication within past 90 days (beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor II blockers, diuretics, statins, NSAIDs, antithrombotics, benzodiazepines, and opioids), income, and employment (except the stratifying variable). Abbreviations: ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor II blocker; H2RA, histamine H₂ receptor antagonist; PPI, proton pump inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs.