Conference Coverage

Spironolactone’s HFpEF benefit happens mostly in women



– Just when the aldosterone receptor antagonists spironolactone and eplerenone received official recognition in the 2017 U.S. heart failure guidelines as the only drug class that benefits patients with heart failure with preserved ejection fraction (HFpEF), a new post-hoc analysis of the pivotal evidence suggests the benefit is mostly in women, with little benefit to men.

The new analysis used data collected from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), which randomized patients with HFpEF to treatment with spironolactone or placebo. Results from the overall study were neutral for the primary outcome of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization (N Engl J Med. 2014 April 10;370[15]:1383-92). However, a series of post-hoc analyses showed that a high percentage of patients enrolled at centers in Russia or Georgia did not match the expected HFpEF profile, and these patients had poor responses to spironolactone. In contrast, patients enrolled at centers in the Americas more frequently matched the study’s target HFpEF profile, and they showed significant improvement for the primary endpoint (Circulation. 2015 Jan 6;131[1]:34-42).

Dr. David Kao, a cardiologist at the University if Colorado at Denver, Aurora. Mitchel L. Zoler/Frontline Medical News

Dr. David Kao

The new analysis, focused on those patients from the Americas, shows that the primary efficacy outcome from the TOPCAT trial was a statistically significant 18% lower in women than in men, David Kao, MD, reported at a meeting of the Heart Failure Association of the ESC.

“The observation that most of the benefit [from spironolactone treatment] may have been in women is interesting, but I don’t think that it would stop me from using [an aldosterone receptor antagonist] in men,” said Dr. Kao while presenting his report. The outcomes in both men and women “head in the same direction. It’s just that the mortality benefit is much clearer in women,” said Dr. Kao, a cardiologist at the University of Colorado at Denver, Aurora.

Among the patients enrolled at centers in North and South America, 882 were women, and 885 were men. Dr. Kao used the data collected in TOPCAT to calculate the impact of spironolactone treatment relative to placebo on outcomes just among women in the Americas and just among men.

The difference in all-cause mortality associated with spironolactone treatment had an even sharper sex disparity that in the primary outcome. Overall, all-cause mortality was 28% less common among women, compared with men, in the Americas. Among women, spironolactone treatment linked with a 30% reduced all-cause mortality rate, compared with placebo. Among men, the survival curves of those on spironolactone or placebo superimposed.

Dr. Kao said that published study results in rats had suggested that eplerenone (Inspra), an aldosterone receptor antagonist like spironolactone, had a more potent effect in females rats, compared with male rats, for preserving left ventricular function and size following myocardial damage. In addition, women with HFpEF often have more left ventricular hypertrophy, while men often have more diastolic dysfunction, and prior findings had suggested that aldosterone plays a role in left ventricular hypertrophy.

TOPCAT received no commercial funding. Dr. Kao had no disclosures.

On Twitter @mitchelzoler

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