Aldosterone Antagonism Revisited: But anomalous findings leave treatment for HFpEF in limbo

ACCEL | Some patients with heart failure (HF) have a normal or near-normal left ventricular ejection fraction—so-called heart failure with preserved ejection fraction (HFpEF). To date, no treatment has been shown to improve outcomes in HFpEF. Consequently, care of these patients can be difficult and is typically limited to efforts to relieve symptoms.


  • Increased aldosterone levels and/or activation of the mineralocorticoid receptor result in a vicious cycle that leads to up-regulation of the renin angiotensin-aldosterone system, an increase in reactive oxygen species, and target organ damage.
  • In a recent trial, aldosterone blockers failed to show benefit in patients with HFpEF.
  • Investigators reported marked regional differences in outcomes in this study and unusually low event rates in the placebo arm of the trial, as well as some question as to whether trial participants indeed had HFpEF.
Given the beneficial effects of mineralocorticoid-receptor antagonists (MRAs) in HF with reduced ejection fraction (HFrEF), Bertram Pitt, MD, and colleagues conducted a trial comparing spironolactone with placebo in patients with HFpEF. The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) was funded by the National Heart, Lung, and Blood Institute (NHLBI). It was an international trial comparing spironolactone treatment (n = 1,722) to placebo (n = 1,723) in patients with at least one symptom and one sign of HF and an EF ≥45%.1

According to Marc A. Pfeffer, MD, PhD, who presented the TOPCAT data at AHA.13, “In the overall population, we did not show a significant difference in the primary [composite] outcome of cardiovascular mortality, aborted cardiac arrest, or hospitalization for heart failure between those who received spironolactone and those who did not.” This primary outcome occurred in 20.4% of those in the placebo arm versus 18.6% in the spironolactone arm (p = 0.138)

“On the other hand,” Dr. Pfeffer said, “we did show a reduction in hospitalizations for heart failure in the spironolactone group, but if physicians use spironolactone for this purpose, they have to carefully monitor potassium and creatinine.”

Surprising (To Say the Least)

The hypothesis studied was sound, trial design and oversight were impeccable, conduct of the trial was exceptional, and the consistency of the efficacy of MRAs was unwavering. The lead investigators do not think the problem was overall lack of power, but there was a major issue: about half of the patients (those from Russia and the Republic of Georgia) had a placebo event rate that was not compatible with what has been seen in prior trials of HFpEF, but was actually comparable to that of a group with a single risk factor (such as hypertension without HF).

In a post-hoc analysis, in the Americas, spironolactone significantly reduced the primary outcome and its two major components: cardiovascular mortality and HF hospitalization. Specifically, the primary outcome occurred in 242 patients in the spironolactone group (27.3%) and 280 patients in the placebo group (31.8%, which is comparable to the placebo arm of other clinical trials of HFpEF). Compare that to Russia and Georgia, where the primary outcome occurred in 78 patients in the spironolactone group (9.3%) and 71 patients in the placebo group (8.4%). That event rate is much lower than expected.

Given the low event rate in Russia and Georgia, the investigators admit the trial was certainly underpowered in these countries.

In a commentary accompanying the TOPCAT results, John J.V. McMurray, MD, and Christopher O’Connor, MD, wrote that geographic differences in outcome have been a focus of concern in some previous trials involving HF patients.2 The most anomalous finding in TOPCAT, they noted, was the low event rate in the hospitalization stratum. In previous trials, a history of hospitalization for HF has been predictive of high event rates, even in HFpEF. In the subset of patients randomized on the basis of elevated BNP, rather than a history of hospitalization (a major component of which was thought to be HF), spironolactone resulted in a significant reduction in the primary endpoint.

In their commentary, they wondered whether some of the patients in the hospitalization stratum of TOPCAT actually had HFpEF—mainly because this is a diagnosis that relies on ruling out other potential causes of dyspnea and edema. Drs. McMurray and O’Connor wrote, “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, as well as monitor event rates according to inclusion stratum and region during follow-up.”


  1. Pitt B, Pfeffer MA, Assmann SF, et al. N Engl J Med. 2014;370:1383-92.
  2. McMurray JJV, O’Connor C. N Engl J Med. 2014;370:1453-54.
To listen to an interview with Bertram Pitt, MD, about aldosterone antagonism, visit The interview was conducted by Carl J. Pepine, MD.

Keywords: CardioSource WorldNews Interventions

< Back to Listings