February 26th, 2013

Mixed Results for Spironolactone in Heart Failure with Preserved Ejection Fraction

Although the mineralocorticoid receptor antagonists spironolactone and eplerenone have been shown to be beneficial in patients with heart failure (HF) with reduced ejection fraction (EF), their role in  HF patients with preserved EF has not been tested until now. Now the results of the Aldo-DHF study (Aldosterone Receptor Blockade in Diastolic Heart Failure), published in the Journal of the American Medical Association, demonstrate that although the treatment works as expected to improve diastolic function in this patient population, no clinical benefits were observed in association with these changes.

Patients (n=422) in Germany and Austria with NYHA class II or III HF with preserved left ventricular (LV) EF were randomized to spironolactone or placebo for one year.  Compared with placebo, spironolactone was associated with improvements in LV end-diastolic filling, LV remodeling, and neurohumoral activation. However, there were no significant differences in maximal exercise capacity or quality of life between the groups.

The investigators point out that similar findings occurred in studies of HF patients with reduced EF. Although the trials showed reductions in all-cause mortality and HF hospitalizations, there were no differences in exercise capacity or quality-of-life measurements. They also note that previous trials with other drug classes have not resulted in improvement in diastolic function. Thus, “spironolactone is the first drug to show an improvement in diastolic function among patients with HF with preserved EF in a randomized, double-blind, placebo-controlled clinical trial.”

The authors speculate that their discordant results may be explained by “mild symptoms and only mildly dilated left atria as well as by the low prevalence of atrial fibrillation” among patients in their study. It is also possible that clinical benefits of spironolactone might have needed more than one year to become apparent.

Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit. The low event rate in the Aldo-DHF trial may indicate that the study population likely represented early-stage HF with preserved EF, and longer follow-up may have been needed to fully evaluate the potential effects of spironolactone on symptomatic or clinical outcome end points.

In an accompanying editorial, John Cleland and Pierpaolo Pellicori write that cardiac dysfunction of patients in the trial “may not have been severe enough to account for impaired exercise capacity, which could account for the lack of effect of spironolactone.” Cleland and Pellicori don’t think the results show that spironolactone lacks benefit in patients with preserved EF. “…absence of evidence cannot be construed as evidence of absence of an effect,” they write. However, the current lack of evidence for any clinical benefit in this population is still troubling: Although the trial provides important new information, it “is not particularly reassuring in terms of either the efficacy or safety of MRAs” in this patient population.

5 Responses to “Mixed Results for Spironolactone in Heart Failure with Preserved Ejection Fraction”

  1. Not sure these are mixed results for patients. Patient outcomes are not mixed.

  2. David Powell , MD, FACC says:

    TOPCAT (about 3500 patients) should provide the clinical answer.

  3. Carlos Cuneo, MD says:

    TOPCAT is the first study looking for this intervention in patients with heart failure with no systolic failure. It will be so difficult to perform other similar study, because spironolactone has no marketing interest. We are anxious waiting for the results

  4. Judith Andersen, AB, MD says:

    Don’t know how to interpret either the “outcomes” of this study or the opinions above.”Natural history” of diastolic dysfunction is a moving target, conditioned by so many modulators that it is difficult to define. But the results of one year of specific pharmacologic treatment with definite improvement in cardiac function but no documented increase in exercise capacity and quality of life as end-points, in the lifetime of patients with diastolic dysfunction– where is the disconnect ? Forgive my ignorance, I haven’t read all the data but please — in the absence of a focused rehabilitation program, neither improvement in exercise tolerance nor an improvement in quality of life is reasonable to expect in this population. A heart that has recovered its ability to tolerate increased work, but is not tasked to provide it, cannot be regarded as a failure.

  5. The study is neagtive. Any other conclusion is disingeneous at best.