NCHR’s Comments Regarding Spironolactone for Heart Failure with Preserved Ejection Fraction

December 16, 2020

Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Meg Seymour, a senior fellow at the center. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.

Today, the committee is asked to consider a new indication of spironolactone for heart failure with preserved ejection fraction (HFpEF). If approved, spironolactone may be the first product with an indication to improve outcomes in patients with HFpEF.  However, as we have all read in the briefing materials, the trial failed to reach the prespecified primary endpoints. While the consideration for approval is not unprecedented in such cases, as FDA pointed out, it is unusual.

That is not the only thing that is unusual about these data.  The results varied widely between the two regions where the study was conducted. For example, the rate of the primary endpoint (cardiovascular death or hospitalization for HF) was 5.4-fold higher in the Americas. FDA stated that there are good reasons to be skeptical of accepting the TOPCAT results from the Americas. There is no precedent for excluding an entire region, rather than a single study site, especially when that region constitutes half of the study sample. Further, the lack of interaction by region means that it is not possible to conclude that the two regions are different enough to exclude half of the results.

The demographics of the study lead to further questions about the data. The sample populations from the two regions varied on numerous, crucial demographics, which complicates interpretation of the data and the question of data exclusion.

The bottom line:  What is the risk of approving this indication if it might not work?  What can be done to improve the quality of the data prior to FDA making a decision about whether or not to approve this indication?


The Cardiovascular and Renal Drugs Advisory Committee voted with 8 yes, 4 no, and 1 abstain on the question “Does the TOPCAT trial provide sufficient evidence to support ANY indication?”