Efficacy of spironolactone in reducing the risk of cardiovascular events and long-term mortality in those with resistant hypertension: findings from the Anglo-Scandinavian Cardiac Outcomes Trial

Abstract Background Spironolactone is a mineralocorticoid receptor antagonist widely used to treat resistant hypertension (RH). It is known to be effective in reducing blood pressure; however, amongst RH patients, there is little evidence for its efficacy in reducing cardiovascular (CV) morbidity and/or long-term mortality. Purpose To establish whether the use of spironolactone in RH is associated with CV or mortality benefits. Methods Using the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) cohort, we identified 8,776 participants with RH (median in-trial follow-up: 3.7 years), and amongst them, as a part of the ASCOT Legacy cohort, 4,196 participants had long-term-follow-up (median follow-up: 13.5 years). After RH diagnosis, those with continuous use of spironolactone (of 6 weeks) were defined as users, and others were non-users. All patients were given algorithm-based treatment to a target BP of below 140/90 mm Hg. The primary outcome of the in-trial analysis was a composite 3-point MACE (non-fatal NF stroke, NF-myocardial infarction, and all-cause mortality), and for the Legacy cohort, all-cause- and CV mortality. Covariate-adjusted, marginal structural survival models were used using an ‘at-risk’ design, accounting for the probability of treatment assignment at each time point. We adjusted for other confounding variables, such as cumulative systolic BP (SBP) before RH diagnosis, treatment allocation etc. Results 13.4% of 8776 RH patients (mean age 65.0 years, 20.4% female) were subsequent spironolactone users. Compared to non-users, spironolactone users experienced a greater drop in SBP from RH diagnosis to censoring (23.34mmHg vs 13.62mmHg). The incidence of the primary outcome was numerically similar in spironolactone users (78 events; 29.3 events per 1000 person-years) than in non-spironolactone users (818 events, 30.2 events per 1000 person-years). After adjustment for confounders, spironolactone users had a significantly lower risk of the 3-point MACE than non-users (HR 0.90 (95% CI, 0.81-0.99, p=0.04)) and all-cause mortality (HR 0.85 (95% CI, 0.75 to 0.96, p=0.01)) but no difference in CV mortality (HR 0.83 (95% CI, 0.68-1.01, p=0.07). These findings were unchanged after adjustment for the subsequent reduction in SBP. In the Legacy cohort, spironolactone users had a significantly lower risk of all-cause mortality (HR 0.92 (95% CI, 0.86-0.99, p=0.03) but with no significant effect on long-term CV mortality (HR 0.97 (95% CI, 0.86-1.95, p=0.56). Conclusion In this analysis, amongst those with RH, the use of spironolactone was independently associated with a significant reduction in CV morbidity and mortality in the medium term, with long-term reduction in all-cause mortality. These observational non-randomised findings need further evaluation, but do provide some evidence supporting the use of spironolactone in those with RH.