Does Spironolactone Benefit Patients with HF and Preserved Systolic Function?

April 9, 2014

Does Spironolactone Benefit Patients with HF and Preserved Systolic Function?

  1. Harlan M. Krumholz, MD, SM

In a randomized trial, the drug showed no significant advantage over placebo, but the case may not be closed.

  1. Harlan M. Krumholz, MD, SM

Mineralocorticoid-receptor antagonists such as spironolactone reduce risk for adverse events in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). In small studies, these drugs improved diastolic and myocardial function, even in patients with normal LVEF (NEJM JW Cardiol Mar 13 2013).

To test whether spironolactone improves clinical outcomes in HF patients with preserved systolic function, investigators for the international, NIH-sponsored TOPCAT trial randomized 3445 adults (mean age, 69; approximately 50% women) who had a HF hospitalization within the previous year or an elevated natriuretic peptide level within the previous 60 days to receive spironolactone or placebo in addition to their existing treatments for HF and any comorbidities. All participants had an LVEF of ≥45% (median, 56%), controlled blood pressure, and a potassium level less than 5.0 mmol/L.

The rate of the primary endpoint, a composite of cardiovascular death, aborted cardiac arrest, and HF hospitalization, was 18.6% in the spironolactone group and 20.4% in the placebo group (hazard ratio, 0.89; 95% confidence interval, 0.77–1.04). The HR for cardiovascular death was 0.90 (95% CI, 0.73–1.12). The rate of hospitalization for HF was significantly lower in the spironolactone group (6.8 vs. 8.3 per 100 person-years; P=0.03). Adverse-event rates were similar in the two groups.


The failure of an inexpensive drug to show a significant benefit in patients with a condition for which effective therapies are lacking is disappointing. Nonetheless, I find it hard to dismiss the possibility that this drug is beneficial based on these results. The trial was powered for a number needed to treat (NNT) of about 30. The observed NNT of 56, although nonsignificant, is of a magnitude that could be meaningful for this disorder. However, all we have for now is another negative study for patients with HF and preserved systolic function.

Editor Disclosures at Time of Publication

  • Disclosures for Harlan M. Krumholz, MD, SM at time of publication Consultant / Advisory board United Healthcare Equity ImageCor Speaker's bureau Centrix Grant / research support FDA; NIH-NHLBI; Commonwealth Fund; The Catherine and Patrick Weldon Donaghue Medical Research Foundation; Robert Wood Johnson Foundation; Medtronic Editorial boards; American Journal of Managed Care; American Journal of Medicine; Archives of Medical Science; Central European Journal of Medicine; Congestive Heart Failure; Critical Pathways in Cardiology; Current Cardiovascular Risk Reports; JACC: Cardiovascular Imaging; Journal of Cardiovascular Medicine; Circulation: Cardiovascular Quality and Outcomes Leadership positions in professional societies American Board of Internal Medicine (Chair, Assessment 2020 Task Force); American College of Cardiology (CV Research and Scholarly Activity, and Lifelong Learning Oversight Committee); American College of Physicians (CV Research and Scholarly Activity); American Heart Association (CV Research and Scholarly Activity); Centers for Medicare & Medicaid Services (Heart Care Technical Expert Panel); Oklahoma Foundation for Medical Quality (Heart Care Technical Expert Panel); VHA, Inc. (Center of Applied Healthcare Studies External Advisory Board)


Reader Comments (3)

ANDERS HERNBORG Physician, Family Medicine/General Practice, Hyltebruk, Sweden

Dear Dr Harlan Krumholz! You are my favorite among US cardiologist mostly because of knowledge, common sense and integrity, net least I think you influenzed the latest US guidelines of lipidlowering treatment, even if I think those guideline recommend too much of primary prevention to people with moderate risk.
But in this comment you made me disappointed. As I am sure you know, mentioning a figure of NNT without giving the length (yrs) of treatment hve absolute no meaning as the figure is ten times bigger if it is for one year compared to ten yrs.

Houman Khalili MD

The Eastern European cohort of the study had an inexplicably low mortality, makes one wonder if these patients had a clear diagnosis of HFpEF, if so this would invariably bias the results toward the null. Unfortunately this study does nothing to address utility of spironolactone in this patient population.

javeria sajjad Resident, Internal Medicine

if LVEF is more than 45% its pretty good enough to not allow a state of fluid overload probably thats why spironolactone is not favourable in thic scenario

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