Spironolactone not beneficial in heart failure with preserved ejection fraction [TOPCAT trial]

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1. There was no significant difference in the primary composite outcome (death from cardiovascular causes, aborted cardiac arrest, and hospitalization for heart failure) between the spironolactone and placebo groups. 

2. Post hoc analyses showed that spironolactone benefited patients in the Americas but not Russia or Georgia, where event rates were lower. 

Evidence Rating Level: 1 (Excellent)     

Study Rundown: Mineralocorticoid-receptor antagonists such as spironolactone have been shown to reduce mortality and hospitalizations in patients with heart failure with reduced ejection fraction. The multicenter, international Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial was designed to test whether spironolactone also improves outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Patients were enrolled if they had a history of hospitalization with management of heart failure or if they met brain natriuretic peptide (BNP) criteria. The study found that spironolactone did not significantly reduce the incidence of the primary outcome, which was a composite of death from cardiovascular causes, aborted cardiac arrest, and hospitalization for heart failure. When the components of the primary outcome were considered individually, only hospitalization for heart failure was significantly reduced in the spironolactone group compared to the placebo group.

Because the primary endpoint was not met, all other analyses must be interpreted with caution. However, there is currently no medical therapy that has been shown to improve outcomes in HFpEF; it is therefore especially important to consider which subgroups of patients with HFpEF might benefit from spironolactone. Post hoc analyses revealed that patients in Russia and Georgia did not benefit from spironolactone; these patients had lower event rates and were more likely to be enrolled according to the hospitalization criterion than the BNP criterion. It is also possible that some enrolled participants did not have HFpEF, which causes non-specific symptoms and is difficult to diagnose. In contrast, patients enrolled in the Americas benefited from spironolactone and had higher event rates. Further research is needed to clarify which, if any, subgroups of patients with HFpEF could benefit from spironolactone.

Click to read the study, published today in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure

In-Depth [randomized controlled trial]: This multicenter, international study randomized 3,445 patients with HFpEF to receive either spironolactone or placebo. In order to be eligible, patients had to either have a history of hospitalization within the previous 12 months for management of heart failure (hospitalization stratum) or have an elevated BNP level within 60 days before randomization (BNP stratum). Randomization was stratified according to whether the patient met the hospitalization or BNP criterion. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest and hospitalization for management of heart failure.

After a mean follow-up period of 3.3 years, the incidence rate of the primary outcome was 5.9 events per person-years in the spironolactone group and 6.6 events per 100 person-years in the placebo group (HR 0.89; 95% CI, 0.77 to 1.04). When the components of the primary outcome were considered individually, only hospitalization for heart failure was significantly more common in the placebo group (12% of spironolactone vs. 14.2% of placebo group; HR 0.83; 95% CI, 0.69 to 0.99). Exploratory post hoc analyses demonstrated that patients from Russia and Georgia did not benefit from spironolactone; event rates in this population were low and the majority of patients were enrolled in the hospitalization stratum. In contrast, patients in the Americas did benefit significantly from spironolactone; these participants were more evenly distributed between the two strata and had higher event rates.

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