Disclosures: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures.
December 16, 2020
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FDA advisory panel endorses spironolactone for HF hospitalization reduction in HFpEF

Disclosures: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures.
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The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4 with one abstention in favor of an indication of spironolactone for the reduction of HF hospitalization in certain patients with HF with preserved ejection fraction.

The committee suggested spironolactone be indicated for HF with mid-range or mildly reduced EF, a range starting at 40% to 45% and ending at 55% to 57%.

Sign outside FDA HQ in Washington, DC.
Source: Adobe Stock

Spironolactone is a mineralocorticoid receptor antagonist currently indicated for the treatment of HFrEF. There are currently no approved therapies for the treatment of HFpEF in the U.S., though on Dec. 15, the committee recommended expanding the indication of sacubitril/valsartan (Entresto, Novartis) to include patients with HFpEF at the lower range of EF, similar to the range suggested for spironolactone.

‘There is enough evidence’

“It was not an altogether easy decision for me because of questions about the data,” Jacqueline D. Alikhaani, BA, consumer representative to the panel who is a volunteer and advocate for the American Heart Association, said during the meeting. “I wish that there had been more ethnic diversity in the trial, but keeping my sights on helping patients who are living with this terrible disease and the quality-of-life issues that exist for patients like that, I felt that overall, there is enough evidence that is positive enough to help patients with HFpEF.”

C. Noel Bairey Merz

Cardiology Today Editorial Board Member C. Noel Bairey Merz, MD, FACC, FAHA, professor of medicine and director of the Barbra Streisand Women's Heart Center, the Preventive and Rehabilitative Cardiac Center, the Cedars-Sinai Clinical Scholars Program and the Linda Joy Pollin Women's Heart Health Program at Cedars-Sinai, who voted in favor of the indication of spironolactone, said the expanded indication should be granted despite concerns about the conduct of the TOPCAT trial. Vastly different results between patients from North America and South America and patients from Eastern Europe and Asia prompted questions about how the trial was designed and implemented; the arguments in favor of an expanded indication discarded the results from Eastern Europe and Asia.

“While it establishes a precedent that I think has made our colleagues concerned, I am equally concerned about establishing a precedent that we cannot do generic trials on a reasonable budget, that our federal government would do in order to buy errant cheap medication for the large population that we serve,” she said. “We always have to balance risk and benefits and I am weighing in support of these types of trials and trying to make them better.”

Spironolactone is a generic drug and the TOPCAT trial was funded by the NHLBI.

Against the new indication

Steven E. Nissen

Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, who voted against the new indication, said “I do think that when we make decisions, it sets precedence. If the pharmaceutical industry came to us with a study like this and said, 'we did this study and the P value was 0.14, but we think a bunch of our sites weren't very good, so we're going to throw those sites out and just look at the data from the sites that we like,' the FDA would not have even brought that before us. I cannot hold other sponsors, including our own government, to a different standard than I would have had over the last 20 years on FDA panels for industry-sponsored studies.”

The primary endpoint here failed by a significant margin,” Nissen said during the panel. “The study was marginally powered in the first place. The large amount of missing [data] is very troubling, particularly when it is different in the two regions that we're trying to consider differently. Then there is the rather ominous question of informative censoring, which I don't think we have ruled out.”

The initial indication for spironolactone was based on the findings of the RALES trial (Pitt P, et al. N Engl J Med. 1999; doi:10.1056/NEJM199909023411001) which found that patients with HFrEF treated with spironolactone experienced lower relative risk for death, (RR = 0.7; 95% CI, 0.6-0.82; P < .001) and HF hospitalization (RR = 0.65; 95% CI, 0.54-0.77; P < .001) compared with placebo.

The randomized, double-blind, placebo-controlled TOPCAT trial sought to assess similar outcomes in a population of patients with HFpEF.

As Healio previously reported, in TOPCAT, treatment with spironolactone did not significantly improve CV mortality, aborted cardiac arrest or HF hospitalization among patients with HFpEF.

According to the presentation, over a mean follow-up of 3.3 years, CV death, HF hospitalization or aborted cardiac arrest occurred in 18.6% of participants in the spironolactone group and 20.4% of the placebo group (HR = 0.89; 95% CI, 0.77-1.04), but the finding was not statistically significant.

However, a post hoc analysis that evaluated the effects of spironolactone by geographic region found that patients from the U.S., Argentina, Brazil and Canada experienced better outcomes (time to CV death, aborted cardiac arrest or HF hospitalization) from spironolactone compared with those from the Republic of Georgia and Russia. Moreover, 31% of participants in the Americas experienced the primary outcome (12.6 events per 100 patient-years) compared with 8.4% of participants in Russia and Georgia (2.3 events per 100 patient-years).

“These observations support the view that the study data from the Americas are much more likely to be predictive of the true effects of spironolactone on outcomes of U.S. patients with HFpEF than the data from the TOPCAT study as a whole,” according to the FDA briefing document. “There are, however, good reasons to be skeptical about accepting the Americas results of TOPCAT. While it is not uncommon to exclude the results of a problematic study site, we know of no precedent for exclusions of a whole region that constitutes almost half of the study population. The best estimate of the effect of a study intervention is usually the prespecified.”