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Heart failure with preserved ejection fraction (HFpEF) currently accounts for half of heart failure diagnoses. The incidence of HFpEF is expected to rise and treatments that benefit mortality and morbidity are needed.1 Studies showing benefit of medical treatments in heart failure are limited to those with left ventricular ejection fractions < 40%.2,3 Current guidelines have no specific recommendations for patients with HFpEF other than to manage comorbidities.3 One class of medications, the mineralcorticoid-receptor antagonists (e.g., spironolactone), has been shown to benefit mortality and reduce hospitalizations for heart failure in patients with heart failure with reduced ejection fraction (HFrEF).  Small trials have found some benefit of this class of medication in HFpEF in improving various diastolic function measures, however the effect on long-term outcomes have not been adequately studied.  The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial was designed to evaluate if spironolactone improves clinical outcomes in patients with symptomatic HFpEF.3

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The TOPCAT trial was an international, multicenter, randomized study that evaluated spironolactone or placebo in patients with HFpEF.  Eligible patients had at least one sign and symptom of heart failure, a LVEF ≥ 45%, controlled systolic BP (SBP < 140mmHg or ≤ 160 mmHg if on 3 or more medications), a potassium < 5 mmol/L, and a history of hospitalization within 12 months (with HF being a major component of the care) or an elevated natriuretic peptide level within 60 days of randomization.   Randomization was stratified by enrollment based on hospitalization or elevated natriuretic peptide.  Eligible patients were randomly assigned to spironolactone or matching placebo; spironolactone was initially administered as 15mg daily and was maximized to 45mg daily during the first four months. Other therapies for heart failure were continued.  The primary outcome was a composite of death of cardiovascular nature, aborted cardiac arrest, or hospitalization due to heart failure.3

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A total of 3,445 patients were randomized with 2464 in the hospitalization stratum (71.5%) and 981 in the natriuretic peptide stratum (28.5%) with a mean follow-up of 3.3 years.  Baseline characteristics were similar between the spironolactone (n=1722) and placebo (n=1723) groups.  In regards to the primary outcome, 320 spironolactone patients (18.6%) and 351 placebo patients (20.4%) experienced at least one component of the primary outcome (5.9 events per 100 person-years compared to 6.6 events per 100 person-years, respectively; HR 0.89; 95% CI, 0.77-1.04; p = 0.14). The only marginally significant component of the primary outcome was hospitalization due to heart failure, which occurred in 206 in the spironolactone (12.0%) and 245 in the placebo (14.2%) group (HR 0.83; 95% CI, 0.69-0.99; p=0.04).  The frequency of hospitalizations for heart failure was also lower in the spironolactone group. There was no statistical difference in cardiovascular deaths, total deaths or hospitalizations for any reason.  Differences in the effect of spironolactone were seen between the hospitalization and natriuretic peptide stratums at randomization.  Spironolactone showed no benefit for composite outcome in the hospitalization arm (HR 1.01; 95% CI, 0.84-1.21), but was beneficial in natriuretic peptide arm (HR 0.65; 95% CI, 0.49-0.87; p=0.003). Patients in the natriuretic peptide stratum tended to be older, not currently smoking, had higher serum creatinine levels, lower potassium levels, lower eGFR, and were less likely to be enrolled from the Russia or Georgia sites.  A regional difference in event rates was found in a post hoc analysis with a benefit of spironolactone in the Americas, and no benefit in the Russia and Georgia sites. Spironolactone had a higher rate of hyperkalemia (18.7% vs. 9.1%), and was more likely to double the serum creatinine (10.2% vs. 7%).3

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Spironolactone was not found to reduce ...

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