Results of TOPCAT, one of the most talked about heart failure trials in recent years, have been published. There were no obvious surprises: Spironolactone is no more beneficial than placebo for patients who have heart failure with preserved ejection fraction.
Mineralocorticoid-receptor antagonists like spironolactone are known to reduce overall mortality and hospitalizations for HF in patients who have reduced ejection fraction, but their effect on patients with preserved ejection fraction "has not been rigorously tested" until now.
The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study was a phase III, double-blind trial involving 3,445 patients treated at 233 sites in the United States, Canada, Brazil, Argentina, Russia, and Georgia. Patients were randomly assigned to receive either spironolactone (1,722 participants) or placebo (1,723 participants) and followed for a mean of 3.3 years, said Dr. Bertram Pitt of the University of Michigan, Ann Arbor, and his associates in a report published online April 9 in the New England Journal of Medicine.
The primary outcome measure – a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF – occurred in 18.6% of patients given spironolactone and 20.4% of those given placebo. This corresponds to incidences of 5.9 events per 100 person-years with active treatment and 6.6 events per 100 person-years with placebo. Both differences were nonsignificant.
There also were no significant differences between the two study groups in time to death from any cause, time to hospitalization for any reason, cause of death, frequency of hospitalization for any reason, and rates of myocardial infarction or stroke, the investigators said (N. Engl. J. Med. 2014 April 9 [doi: 10.1056/NEJMoa1313731]).
In contrast, the 17% reduction in the rate of hospitalization for HFpEF in the spironolactone group relative to controls was significant (P = .04). Moreover, the spironolactone-treated patients had a collective 394 HFpEF hospitalizations, markedly fewer than the 475 in controls. This translated to hospitalization for HFpEF occurring at a rate of 3.8 per 100 person-years in patients randomized to spironolactone, compared with 4.6 per 100 person-years in placebo-treated controls.
The mystifyingly neutral results of this large international trial, presented in November at the annual meeting of the American Heart Association, coincided with a rapidly increasing incidence and awareness of heart failure with preserved ejection fraction, or HFpEF.
Speculation has focused on the differences in treatment response in two areas: geographical location and enrollment criteria.
Geographical differences in event rates have led some to conclude that patients in Eastern Europe just weren’t sick enough to be enrolled. Among patients in the placebo group, the primary endpoint of death or heart failure hospitalization during follow-up occurred at a rate of 12.6 events per 100 patient-years among the 881 patients treated in the four Western Hemisphere countries, and at a rate of 2.3 events per 100 patient-years among the 842 patients treated in Russia or Georgia, a greater than fivefold difference between the two subgroups.
"As a whole, the patients in Russia and Georgia had a lower event rate and were certainly less severely ill than the other patients, but they supposedly still had heart failure," Dr. Scott D. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, said in an earlier interview. "Defining this disorder is difficult, and when a patient has signs and symptoms of heart failure and preserved ejection fraction, you may not be certain that heart failure is causing the symptoms. That’s why many people think that we should use another criterion" to define HFpEF in trials, such as elevated serum level of some form of natriuretic peptide, said Dr. Solomon, a TOPCAT coinvestigator.
By design, patients could enter TOPCAT either because of a recent heart failure hospitalization, which is how 72% of patients got in, or by having a threshold level of natriuretic peptide, the way the remaining 28% entered the study. Within the subgroup enrolled by natriuretic peptide level, spironolactone treatment had a statistically significant effect in reducing the primary endpoint, while in the other 72% the drug produced no discernable benefit over placebo.
The neutral results of TOPCAT represent more than another failed treatment trial; they underscore the heterogeneity of patients diagnosed with HFpEF.
TOPCAT was supported by the National Heart, Lung, and Blood Institute. Dr. Pitt reported ties to AuraSense Therapeutics, Relypsa, and other companies. His associates reported ties to numerous industry sources. Dr. Solomon has financial ties to Novartis and more than 10 other drug and device companies.