April 9th, 2014
TOPCAT Fails to Find Advantage for Spironolactone in HFPEF
Although a significant portion of people with heart failure have preserved ejection fraction, none of the proven heart failure therapies has been shown to be beneficial in this important and growing heart failure subpopulation. Now a new NHLBI-funded study has failed to find a benefit in this group for spironolactone, which is a cornerstone of therapy for heart failure patients with reduced ejection fraction. But trial investigators and heart failure experts believe it is too early to dismiss hope that the drug may eventually be found to work in this population.
TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), published in the New England Journal of Medicine, randomized 3,445 patients with heart failure with preserved ejection fraction (HFPEF) to either spironolactone, an aldosterone antagonist, or placebo. After 3.3 years of followup the primary outcome — a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure — occurred in 18.6% of the spironolactone group and 20.4% of the placebo group. This difference did not achieve statistical significance (hazard ratio 0.89, CI 0.77 – 1.04, p=0.14).
However, there was a statistically significant difference in one component of the composite endpoint. Hospitalization for heart failure was reduced from 14.2% in the placebo group to 12% in the spironolactone group (p=0.04).
The results were consistent across different subgroups, with one important exception. At the time of enrollment patients were stratified according to their eligibility criteria. 71.5% were enrolled because in the past year they had been hospitalized and the management of heart failure had been a major component of their care. 28.5% did not meet the hospitalization criteria but were enrolled because they had elevated BNP levels. The primary endpoint was significantly reduced in the BNP stratification but not in the hospitalization stratification.
Geographic differences may have played an important role in this discrepancy. Nearly half the patients in the trial were enrolled in Russia and George. These patients had lower event rates than subjects elsewhere and were much more likely to be enrolled in the hospitalization stratum. The authors wrote: “The discrepancy in event rates with placebo may have contributed to the observed treatment benefit in the Americas but not in Russia or Georgia (where low event rates would be difficult to reduce further) and the observed treatment benefit among patients enrolled in the BNP stratum but not among those enrolled in the hospitalization stratum (because most of the patients enrolled in Russia and Georgia were in the hospitalization stratum).”
In an accompanying editorial, John McMurray and Christopher O’Connor analyze this issue and end up questioning “whether some of the patients in the hospitalization stratum actually had heart failure with a preserved ejection fraction, not least because this is a diagnosis that is not straightforward and that relies on the ruling out of other potential causes of dyspnea and edema.”
In a discussion of the trial results on CardioExchange, principal investigators Bert Pitt and Marc Pfeffer said that although the trial as a whole was not underpowered, the low event rates in Russia and Georgia suggest that “we were certainly underpowered in these countries.” Furthermore, “if you look at the results in the Americas (Canada, US, Argentina, Brazil) where the placebo event rate is compatible with prior HFPEF studies, spironolactone significantly reduced the primary outcome and its two major components.” They warned, however, that this is “a post hoc analysis and therefore is open to debate.”
Clyde Yancy, who was not involved with the trial, also discussed the results on CardioExchange. Because of the absence of available treatments for HFPEF, Yancy said that TOPCAT should not be viewed as a “positive” or “negative” trial: “A much better approach to the TOPCAT data is to declare that this was an informative trial that adds to our understanding of HFPEF.”
Ultimately, the topline signal here was simply not robust enough. But it was not absent; the HF hospitalization data are reasonable and even more so when considered both in the North America cohort and again in the group stratified according to an elevated BNP. Moreover, the significant geographic variation, i.e., the Russian and Georgian cohorts, really speaks to a potential clinically important but not statistically significant advantage. Reducing heart failure hospitalizations, especially in HFPEF, is a good thing.
TOPCAT, said Yancy, is “not the home run we sought, and won’t make the guidelines for heart failure today, but perhaps it’s good enough—at least for now.” Yancy said that in his own practice “I have and will continue to use” aldosterone antagonists in HFPEF.