Sex-Specific Cancer Risks Associated with Spironolactone Therapy in Geriatric Heart Failure: A Propensity-Score Matched Cohort Analysis

Background Spironolactone, an aldosterone receptor antagonist, is integral to heart failure (HF) treatment protocols. However, concerns have been raised about its potential adverse effects, particularly its antiandrogenic properties and implications for cancer risk. This study aimed to delineate the correlation between spironolactone exposure and cancer incidence in an elderly cohort diagnosed with HF, with a focus on sex-specific outcomes. Methods We conducted a retrospective cohort study using the TriNetX database, identifying elderly subjects (≥ 65 years) with a confirmed HF diagnosis. Subjects were classified according to their spironolactone prescription status. Propensity score matching was applied to control for confounding variables, including demographics, comorbidities, laboratory parameters, and concurrent cardiac medications. The primary outcome was the incidence of cancer within one year following spironolactone initiation. Results A total of 479,598 elderly subjects were identified. After propensity score matching, the study sample comprised 90,322 individuals with spironolactone (45,045 women and 50,277 men). The analysis revealed a sex-dependent difference in cancer risk post-spironolactone exposure. Women exhibited a statistically significant increase in the incidence of breast, kidney, and head and neck cancers, whereas men showed a reduced incidence of bladder, head and neck, and kidney cancers. In particular, the incidence of hepatocellular carcinoma was elevated in both sexes, suggesting a potential direct effect of spironolactone on hepatic carcinogenesis. Conclusion This large-scale cohort study provides evidence of a sex-specific association between spironolactone use and cancer risk in elderly HF patients. The observed increase in hepatocellular carcinoma in all sexes implicates a complex mechanism of action that may involve direct liver effects, warranting further mechanistic studies. These findings underscore the need for sex-stratified risk-benefit considerations in clinical decision-making regarding spironolactone prescription.