Conference Coverage

More TOPCAT flaws back spironolactone’s HFpEF efficacy

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Spironolactone challenges guideline writers

This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.

Mitchel L. Zoler/Frontline Medical News

Dr. Barry H. Greenberg

The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.

There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.

Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.




ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.

In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).

Dr. Eileen O'Meara Mitchel L. Zoler/Frontline Medical News

Dr. Eileen O'Meara

But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.

Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.

Dr. Marc A. Pfeffer Mitchel L. Zoler/Frontline Medical News

Dr. Marc A. Pfeffer

“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”

After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.

On Twitter @mitchelzoler

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