Drug Has Mixed Results in Diastolic HF

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By Todd Neale, Senior Staff Writer, MedPage Today

Published: February 26, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • This randomized, controlled trial demonstrated echocardiographic, but not clinical improvements in patients with diastolic dysfunction who received spironolactone.
  • Not that the study was underpowered to detect mortality differences.

In patients with heart failure with preserved ejection fraction, spironolactone improved left ventricular diastolic function but did not affect clinical status, the Aldo-DHF trial showed.

One of the two primary endpoints — an echocardiographic measure of diastolic function (E/e’) — showed a significant improvement with spironolactone versus placebo through 1 year of treatment (P<0.001), according to Burkert Pieske, MD, of the Medical University of Graz in Austria, and colleagues.

However, there was no difference between the groups on the other primary endpoint, maximal exercise capacity on cardiopulmonary exercise testing (peak VO2) at 1 year (P=0.81), the researchers reported in the Feb 27. issue of the Journal of the American Medical Association. The findings were reported last year at the European Society of Cardiology meeting.

In addition, spironolactone did not have any effect on heart failure symptoms, quality of life, depressive symptoms, or hospitalizations, and slightly reduced the average 6-minute walking distance (517 versus 536 meters, P=0.02).

“Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations,” Pieske and colleagues wrote.

Heart failure with preserved ejection fraction, or diastolic heart failure, accounts for more than half of all heart failure causes, but there are no proven therapies.

“This is the first trial to show … that therapy with a drug for diastolic heart failure results in improvement in diastolic abnormalities of the left ventricle,” Jeffrey Teuteberg, MD, medical director of the UPMC Artificial Heart Program in Pittsburgh, said in an interview. “Unfortunately, it didn’t show improvements in quality of life or exercise capacity, so I think this lays the groundwork to some degree [for] further trials for diastolic heart failure.”

In the Aldo-DHF trial, which took place at 10 sites in Germany and Austria between 2007 and 2012, the authors evaluated aldosterone receptor blocker therapy with spironolactone in 422 ambulatory patients ages 50 and older (mean age 67) who had the following:

  • Chronic New York Heart Association class II or III heart failure (86% had class II symptoms)
  • A left ventricular ejection fraction of at least 50%
  • Echocardiographic evidence of diastolic dysfunction or atrial fibrillation at presentation
  • A peak VO2 no greater than 25 mL/min/kg

On a background of standard risk factor control, the patients were randomized to spironolactone 25 mg/day or placebo. The study lasted 12 months.

The improvement seen on the coprimary endpoint of E/e’ with spironolactone became apparent as early as 6 months and was sustained through 1 year. There was no difference between the groups in peak VO2 at any time point.

Aside from the measure of diastolic function, there were some other indicators of benefit, including a reduction in the left ventricular mass index by 6 g/m2 (P=0.009) and significantly lower levels of N-terminal pro-brain-type natriuretic peptide (median 152 versus 165 ng/L, P=0.03). Also, left ventricular ejection fraction at the end of the study was slightly higher in the spironolactone group (67.2% versus 65.9%, P=0.04).

But those changes were not associated with an improvement in the clinical status of the patients.

“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,” Pieske and colleagues wrote.

In terms of safety, spironolactone increased serum potassium levels by 0.2 mmol/L (P<0.001) and decreased estimated glomerular filtration rate by 5 mL/min/1.73 m2 (P<0.001). There was no difference between the groups in the rate of serious hyperkalemia, but the proportion of patients who had worsening renal function was greater in the spironolactone group (36% versus 21%, P<0.001).

The researchers acknowledged that the study may have been limited by the inclusion of stable patients with moderate heart failure; thus, the findings may not apply to a sicker population. In addition, the study was not powered to evaluate differences in heart failure hospitalizations or mortality.

In an accompanying editorial, John Cleland, MD, PhD, and Pierpaolo Pellicori, MD, of the University of Hull in Kingston-upon-Hull in England, questioned whether the patients in the trial actually had heart failure, noting that various indicators were better in the current trial than in other studies of diastolic heart failure.

“In Aldo-DHF, 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.

“Ultimately, the Aldo-DHF trial provides valuable new information but is not particularly reassuring in terms of either the efficacy or safety of mineralocorticoid antagonists for patients with [heart failure with preserved ejection fraction],” they wrote. “A large trial, TOPCAT, is expected to report the effects of spironolactone on morbidity and mortality in a similar population but with more advanced disease.”

The study was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Aldo-DHF was funded by the Federal Ministry of Education and Research. The University of Göttingen was the formal sponsor.

Pieske reported receiving speaker honoraria from Bayer Healthcare, Boehringer Ingelheim, Servier, Medtronic, Bristol-Myers Squibb (BMS), and Menarini and serving as a consultant and/or steering committee member for Bayer Healthcare, Menarini, and Novartis. He participated in research cooperations (institutional) with Bayer Healthcare and Medtronic. His co-authors reported relationships with Berlin Chemie, Novartis, Pfizer, Servier, Bayer, Gilead, CVRx, Relypsa, Sanofi, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Johnson & Johnson, Medtronic, Verlag Hans Huber, Deutscher Ärzteverlag, KKH-Allianz, Merck Sharpe & Dohme, BMS, sanofi-aventis, Health Insurance Company, BMW, Impulse Dynamics, and Robert Bosch Health Care.

The editorialists reported that they had no conflicts of interest.

Primary source: Journal of the American Medical Association
Source reference:
Edelmann F, et al “Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial” JAMA 2013; 781-791.

Additional source: Journal of the American Medical Association
Source reference:
Cleland J, Pellicori P “Defining diastolic heart failure and identifying effective therapies” JAMA 2013; 309: 825-826.

Related Article(s):

  • ESC: Drug Shows Some Benefit for Diastolic HF

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