TOPCAT in Print, With All Its Quirks: Spironolactone Misses in HF With Preserved EF

April 10, 2014

BOSTON, MA — It was the trial heart-failure physicians had hoped would come out as a solid win for the aldosterone-blocker spironolactone in the setting of heart failure with preserved ejection fraction (HFPEF). But when it instead turned out "negative," there was still optimism and even glimmers of delight.

In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, now published in the New England Journal of Medicine [1] with lead author Dr Bertram Pitt (University of Michigan, Ann Arbor), treatment with spironolactone failed to improve a composite primary end point of CV death, aborted cardiac arrest, or HF hospitalization in patients with HFPEF over a mean of 3.3 years, compared with placebo. Active therapy also raised serum creatinine levels and risk of hyperkalemia. The >3000-patient trial was conducted at 233 centers in North and South America and in Russia and the Republic of Georgia.

There were eccentricities about some of TOPCAT's prospectively defined outcomes, however, including an imbalance of clinical events based on how patients met the trial's eligibility criteria and a possibly related geographic divide in spironolactone's apparent effects.

A Clinical Message

On the other hand, TOPCAT trialists and some eminent observers have taken heart in a 17% reduction in risk of hospitalization for heart failure (p=0.04) among spironolactone-treated patients. The finding for the trial's most common primary-end-point component, they hold, bodes well for spironolactone's prospects as a treatment for HFPEF, a perplexing disorder for which no solid, truly evidence-based drug therapy has yet been defined.

On presentation of the primary TOPCAT results at the American Heart Association (AHA) 2013 Scientific Sessions , Dr Clyde Yancy (Northwestern University, Chicago, IL) told heartwire that the trial was indeed negative but still conveyed a message that "for the first time, we can modify the natural history of heart failure with preserved ejection fraction." Yancy, who was not part of the trial, said he would indeed use spironolactone for HFPEF but also emphasized the importance of good safety monitoring, "especially for renal function."

A TOPCAT lead investigator, Dr Marc A Pfeffer (Brigham and Women's Hospital, Boston, MA), said at a briefing for the media at the AHA sessions, as previously noted by heartwire , "We're very confident that we've reduced hospitalizations for heart failure." And Dr Margaret M Redfield (Mayo Clinic, Rochester, MN), not with the trial, agreed that it showed a "signal of benefit" but cautioned that safety monitoring in clinical practice might not be as judicious as it was in TOPCAT.

Editorial Questions TOPCAT Entry Criteria

Despite the forward momentum for HFPEF therapy claimed for TOPCAT, however modest or in the eye of the beholder, neither the trial's publication nor an accompanying editorial[2] point to the HF-hospitalization result as a basis for treatment recommendations. "In the context of a neutral primary finding, all other secondary analyses should be considered as provisional," Pitt et al observe. The editorial, from Dr John JV McMurray (University of Glasgow, UK) and Dr Christopher O'Connor (Duke University, Durham, NC), barely mentions the "nominally significant reduction" in HF hospitalizations with spironolactone, instead focusing on the trial's "most anomalous finding," a low event rate in some patients that "reduced the potential for a benefit of spironolactone therapy in this subgroup."

Eligibility had required "a history of hospitalization within the previous 12 months, with management of heart failure a major component of the care provided, or an elevated natriuretic-peptide level within 60 days before randomization." And TOPCAT prospectively stratified patients according to which of those two criteria they used to qualify for the trial. As it turned out, McMurray and O'Connor note and Pitt et al discuss in detail, spironolactone significantly cut the primary end point among patients who entered on the basis of natriuretic-peptide levels (HR 0.65, 95% CI 0.49–0.87; p=0.003), but not at all in those using the HF hospitalization criterion.

Based on that, the editorialists propose that the hospitalization stratum's low event rate may stem from the entry criterion's novel description as hospitalization in which HF management was "a major component of the care provided." In part because of the complexity of making a HFPEF diagnosis, they write, "we wonder whether some of the patients in the hospitalization stratum actually had heart failure with a preserved ejection fraction."

They continue, "These observations suggest that investigators in future trials should specify more precisely what they mean by hospitalization for heart failure and may wish to verify the details of such admissions, at least in a proportion of cases. . . . The TOPCAT trial also underscores the importance of natriuretic-peptide levels as a predictor of adverse outcomes in heart failure and their value as an inclusion and quality criterion in clinical trials, nowhere more so than in heart failure with a preserved ejection fraction, which remains difficult to define."

Outcomes and Concluding Conundrum

TOPCAT had randomized 3445 patients with heart failure and an LVEF >45% to receive the aldosterone antagonist at 15 to 45 mg/day or placebo; patients with severe renal dysfunction had been excluded.

Hazard Ratio (95% CI) for Clinical Outcomes in TOPCAT Over a Mean 3.3 Years

End points HR (95% CI)
CV mortality, aborted cardiac arrest, or HF hospitalization* 0.89 (0.77–1.04)
CV mortality 0.90 (0.73–1.12)
Aborted cardiac arrest 0.60 (0.14–2.50)
HF hospitalization 0.83 (0.69–0.99)
*Primary end point

There were no significant spironolactone effects on the secondary end points of death from any cause, hospitalization for any cause, MI, and stroke. Those receiving spironolactone showed twice the rate of hyperkalemia but about 30% less hypokalemia. The risks of elevated serum creatinine (specifically to two or more times baseline and greater than the upper limit of normal) were 10.2% and 7.0% for spironolactone and placebo, respectively.

Post hoc analyses after noting the outcome difference by entry criteria, Pitt et al note, showed "marked regional variation in event rates," especially much lower rates of the primary end point in Russia and Georgia compared with the remaining participating countries, the US, Canada, Brazil, and Argentina, regardless of randomization group. And "the great majority of patients from Russia and Georgia were enrolled in the hospitalization stratum, whereas patients from the Americas were more evenly balanced between the two strata."

So low event rates in Russia and Georgia, Pitt et al reason—acknowledging the statistical frailties of post hoc analyses—may help explain why spironolactone didn't show a benefit in those countries but may have in the four North and South American countries. They also might have contributed, they write, to the apparent benefit in the patient stratum based on natriuretic-peptide levels vs HF hospitalization.

TOPCAT was sponsored by the National Heart, Lung, and Blood Institute. Pitt discloses receiving consulting fees and holding stock or stock options in AuraSense Therapeutics, Relypsa, and BG Medicine; receiving consulting fees from Pfizer, Bayer, AstraZeneca, Amorcyte, Mesoblast, Takeda Pharmaceutical, and Gambro; receiving fees for serving on data and safety monitoring boards from Novartis and Johnson & Johnson; receiving fees for serving on a clinical-events committee from Juventas Therapeutics; receiving grant support from Forest Laboratories; and "holding a pending patent related to site-specific delivery of eplerenone to the myocardium." Pfeffer reports receiving consulting fees or grant support from Aastrom Biosciences, Abbott Vascular, Amgen, Cerenis Therapeutics, Concert Pharmaceuticals, FibroGen, GlaxoSmithKline, Medtronic, Merck, Roche, Servier, Teva Pharmaceuticals, Celladon, Novartis, and Sanofi and "being a coinventor on patents related to the use of inhibitors of the renin- angiotensin system in selected survivors of myocardial infarction, which are licensed to Novartis and Boehringer Ingelheim." Disclosures for the other coauthors are listed in the article. Yancy and Redfield have previously said they have no disclosures. McMurray discloses that his center is paid by Novartis and Pfizer for his involvement in some of the companies' sponsored clinical trials and that he receives travel reimbursement from those companies related to his involvement in some of those trials. O'Connor discloses that he has received grant support from Roche Diagnostics, GE Healthcare, Johnson & Johnson, Gilead, Otsuka, Amgen, and Astellas and that he has received fees for consulting from Actelion.


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