Spironolactone results underwhelming, but were the wrong HF patients studied?

Spironolactone, a mineralocorticoid receptor antagonist (MRA), showed some clinical efficacy as a treatment for heart failure (HF) patients with preserved ejection fraction (EF) but offered no improvements in symptoms after one year. But an accompanying editorial questioned whether the study population truly was experiencing HF. The study and the editorial were published online Feb. 27 in the Journal of the American Medical Association.  

Mineralocorticoid receptor activation leads to sodium retention, potassium loss, endothelial dysfunction, vascular inflammation and other contributors to HF. MRAs reduce cardiovascular mortality in MI patients with left ventricular dysfunction and HF, and in HF patients with reduced EF, but to date there had been no studies of the long-term effect of MRAs on HF with preserved EF.

The Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial was a multicenter, randomized, placebo-controlled, double-blind two-armed trial designed to measure the impact of spironolactone on the diastolic function and exercise capacity of HF patients with preserved EF.

Frank Edelmann, MD, of the Heart Center at the University of Gӧttingen in Germany, and colleagues enrolled patients 50 years of age and older from 10 sites in Germany and Austria. Eligible patients had symptoms of HF consistent with New York Heart Association (NYHA) Class II or III, left ventricular EF of 50 percent or greater, echocardiographic evidence of diastolic dysfunction or atrial fibrillation, and maximum exercise capacity (peak exercise oxygen consumption) of 25mL/kg/min or less.

Between March 2007 and April 2001, the researchers randomized 22 patients (1:1) to receive spironolactone (mean dose 21.6 mg daily) or placebo. The patients had a mean age of 67 years and 52 percent were female; baseline characteristics were similar between the two groups. They were followed for a mean of 11.6 months.

The researchers found that spironolactone treatment improved diastolic function, but that both groups experienced similar increases in exercise capacity as measured by peak exercise oxygen consumption (from 16.3 to 16.8mL/min/kg in the spironolactone group and from 16.4 to 16.9mL/min/kg in the placebo group). The systolic blood pressure of patients taking spironolactone decreased by 3 mm/Hg to a mean of 77, but otherwise there were no differences in NYHA class, quality of life or depressive symptoms between the two groups after treatment. Patients in the spironolactone group experienced a slight decrease in their six-minute walking distance.

Patients randomized to spironolactone experienced elevated potassium levels at higher rates (21 percent) than those randomized to placebo (11 percent), but rates of serious hyperkalemia were similar. There was a decline in hemoglobin concentration and glomular filtration rate in the spirolactone group.

The researchers concluded that “left ventricular end-diastolic filling, left ventricular remodeling and neurohumeral activation were improved with spironolactone, whereas maximal exercise capacity and quality-of-life measures remained unchanged. …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.”

In an accompanying editorial, John G. F. Cleland, MD, and Pierpaolo Pellicori, MD, of Castle Hill Hospital at Hull York Medical School in Kingston-upon-Hull, England, suggested that the greater problem may be the diagnosis of HF in patients with preserved EF. They asserted that the patients enrolled in Aldo-DHF experienced borderline symptoms of HF, and “cardiac dysfunction may not have been severe enough to account for impaired exercise capacity, which could account for the lack of effect of spironolactone,” they wrote.

Although the trial provides “valuable new information,” Cleland and Pellicori concluded that it “is not particularly reassuring in terms of either the efficacy or safety of MRAs for patients with HF and preserved EF.” The editorialists pointed out that the TOPCAT trial is testing spironolactone in a large cohort of patients with more advanced disease, and suggested that the results of this trial may provide more clarity about the effectiveness of MRAs on HF with preserved EF.