Troubled NHLBI TOPCAT Trial Disappoints

Though a important portion of folks with heart failure have preserved ejection fraction, none of the confirmed heart failure therapies has been proven to be advantageous in this critical and expanding heart failure subpopulation. Now a new NHLBI-funded review has failed to uncover a advantage in this group for spironolactone, which is a cornerstone of therapy for heart failure sufferers with decreased ejection fraction. But trial investigators and heart failure specialists think it is too early to dismiss hope that spironolactone and other aldosterone antagonists– like Pfizer’s Inspra (eplerenone)– may possibly eventually be found to operate in this population.

TOPCAT (Treatment method of Preserved Cardiac Perform Heart Failure with an Aldosterone Antagonist), published in the New England Journal of Medicine, randomized 3,445 individuals with heart failure with preserved ejection fraction (HFPEF) to either spironolactone or placebo. Following 3.three years of followup the major outcome– a composite of death from cardiovascular leads to, aborted cardiac arrest, or hospitalization for the management of heart failure– occurred in 18.6% of the spironolactone group and twenty.4% of the placebo group. This distinction did not attain statistical significance (hazard ratio .89, CI .77 – 1.04, p=.14).

However, there was a statistically significant difference in 1 component of the composite endpoint. Hospitalization for heart failure was diminished from 14.two% in the placebo group to 12% in the spironolactone group (p=.04).

The benefits have been consistent across various subgroups, with a single essential exception. At the time of enrollment sufferers had been stratified according to their eligibility criteria. 71.five% were enrolled simply because in the previous 12 months they had been hospitalized and the management of heart failure had been a major part of their care. 28.five% did not meet the hospitalization criteria but had been enrolled due to the fact they had elevated BNP ranges. The primary endpoint was substantially reduced in the BNP stratification but not in the hospitalization stratification.

Geographic variations could have played an critical part in this discrepancy. Almost half the sufferers in the trial had been enrolled in Russia and George. These sufferers had decrease occasion prices than topics elsewhere and have been a lot much more probably to be enrolled in the hospitalization stratum. The authors wrote: “The discrepancy in occasion charges with placebo may possibly have contributed to the observed treatment benefit in the Americas but not in Russia or Georgia (in which lower occasion costs would be tough to reduce even more) and the observed remedy advantage among sufferers enrolled in the BNP stratum but not amongst individuals enrolled in the hospitalization stratum (since most of the individuals enrolled in Russia and Georgia have been in the hospitalization stratum).”

In an accompanying editorial, John McMurray and Christopher O’Connor analyze this situation and end up questioning “whether some of the patients in the hospitalization stratum in fact had heart failure with a preserved ejection fraction, not least simply because this is a diagnosis that is not easy and that relies on the ruling out of other potential leads to of dyspnea and edema.”

In a discussion of the trial benefits on CardioExchange, principal investigators Bert Pitt and Marc Pfeffer stated that even though the trial as a total was not underpowered, the lower event charges in Russia and Georgia suggest that “we were certainly underpowered in these countries.” Additionally, “if you look at the benefits in the Americas (Canada, US, Argentina, Brazil) in which the placebo event rate is compatible with prior HFPEF studies-– spironolactone considerably reduced the main end result and its two key components.” They warned however that this is “a post hoc examination and as a result is open to debate.”

Clyde Yancy, who was not involved with the trial, also discussing the results of the trial on CardioExchange. Since of the absence of obtainable treatment options for HFPEF, Yancy stated that TOPCAT ought to not be viewed as a “positive” or “negative” trial: “A a lot far better method to the TOPCAT information is to declare that this was an informative trial that adds to our comprehending of HFPEF.”

He continued:

In the long run, the topline signal here was just not robust ample. But it was not absent the HF hospitalization data are reasonable and even a lot more so when deemed each in the North America cohort and yet again in the group stratified in accordance to an elevated BNP. Moreover, the substantial geographic variation, i.e., the Russian and Georgian cohorts, really speaks to a possible clinically important but not statistically considerable benefit. Lowering heart failure hospitalizations, particularly in HFPEF, is a great thing.

TOPCAT, stated Yancy, is “not the house run we sought, and won’t make the guidelines for heart failure today, but possibly it’s very good enough—at least for now.” Yancy said that in his very own practice “I have and will carry on to use” aldosterone antagonists in HFPEF.

Troubled NHLBI TOPCAT Trial Disappoints