Spironolactone Disappoints in Preserved-EF HF: Aldo-DHF in Print

February 26, 2013

CHICAGO — A year of aldosterone blockade failed to improve exercise capacity, symptoms, or quality-of-life measures in a placebo-controlled trial of >400 patients with heart failure and LV ejection fractions >50% [1]. However, spironolactone treatment in the study led to significant gains in echocardiographic measures of diastolic function.

Although the strategy is under exploration in other trials, the current Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial does little for hopes that aldosterone blockade might turn out to be the long-sought drug therapy with clear hard-end-point benefits in preserved-EF heart failure.

Aldo-DHF is published online today in the Journal of the American Medical Association with lead author Dr Frank Edelmann (University of Göttingen, Germany). The trial was reported last year by heartwire , with essentially the same numbers, from the European Society of Cardiology (ESC) 2012 Congress.

"They are certainly somewhat disappointing results. We don't see a change in functional capacity, which is really important for this population,"Dr Adrian Hernandez (Duke University, Durham, NC), who wasn't involved in Aldo-DHF, told heartwire . Diastolic function improved, but there were "no changes in things that matter to patients," he said.

"I was more hopeful, because I think there are a lot of preliminary data suggesting that spironolactone would have a big benefit."

 
I was more hopeful, because I think there are a lot of preliminary data suggesting that spironolactone would have a big benefit.
 

Aldo-DHF patients had been followed for 12 months for co–primary end points of exercise capacity (peak VO2) and diastolic function (E/e' by tissue-Doppler echo). Hernandez speculates that a year of treatment may not have been long enough to see diastolic functional gains turn into improved exercise capacity.

Don't Rule Out Spironolactone

He and other heart-failure experts have conveyed hopes to heartwire that spironolactone will emerge as a solid, reliable drug therapy for preserved-EF heart failure in a completed but yet unreported large randomized mortality trial called TOPCAT [2]. The trial, with primary outcomes expected at a meeting later this year, randomized 3445 heart-failure patients with an LVEF >45% and is following them for the primary end point of cardiovascular death, hospitalization for HF, or aborted cardiac arrest.

"So I wouldn't rule out that [spironolactone] may have some benefit," Hernandez said. "The TOPCAT trial will really define whether it exists or not. And if the trial comes up [negative], then we will have to look elsewhere for a solution for this problematic syndrome."

He pointed out that a trial slated for presentation at the upcoming March American College of Cardiology 2013 Scientific Sessions explored another familiar drug for functional effects in preserved-EF heart failure. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial randomized 216 patients in NYHA class 2 to 4 to receive sildenafil (Revatio/Viagra, Pfizer) or placebo for 24 weeks and followed them for the primary end point of peak oxygen uptake.

Aldo-DHF

The Aldo-DHF trial, conducted at 10 sites in Germany and Austria, randomized 422 patients with NYHA class 2–3 heart failure, an LVEF >50%, echocardiographic evidence of diastolic dysfunction, and peak a VO2 of <25 mL/kg/min to either spironolactone 25 mg/day or placebo.

When reporting the trial at last year's ESC sessions, senior author Dr Burkert Pieske (Medical University Graz, Austria) described the trial's "relatively stable" patients as having primarily NYHA class 2 heart failure with hypertension as the etiology. All told, he said, they probably represented "a population with hypertensive heart disease that had evolved into a symptomatic stage of heart failure with preserved ejection fraction and diastolic dysfunction."

 
It is not clear whether the observed cardiac dysfunction was severe enough to account for symptoms or reduced exercise capacity.
 

Spironolactone vs placebo was associated with significant improvements in diastolic function (p<0.001) and LV mass index (p=0.009) and favorable changes in natriuretic peptides (p=0.03).

Beyond a lack of benefit in peak VO2, symptoms, and quality of life on aldosterone blockade, six-minute-walk distance and estimated glomerular filtration rate both suffered slightly (p=0.03 and p<0.001, respectively) and serum potassium levels went up (p<0.001).

In an accompanying editorial [3], Drs John GF Cleland and Pierpaolo Pellicori (University of Hull, Kingston-upon-Hull, UK) speculate on the apparent disconnect between results for the two co–primary end points. "In Aldo-DHF, it is not clear whether the observed cardiac dysfunction was severe enough to account for symptoms or reduced exercise capacity."

They pointed to clues that it may indeed not have been that severe, including less-than-dire values for E/e', LV shape, left atrial volume, plasma natriuretic peptides, peak oxygen consumption, and six-minute-walk distance in the trial's population.

If the cardiac dysfunction was not severe enough to cause symptoms or dampen exercise capacity, that "could account for the lack of effect of spironolactone."

Aldo-DHF was publicly funded; Edelmann discloses having been an investigator, speaker, or consultant for Berlin Chemie, Novartis, Pfizer, Servier, Bayer, Gilead, CVRx, Relypsa, Sanofi, and AstraZeneca. At the time they reported at the ESC sessions, Pieske and the trial's other investigators had no disclosures. Cleland and Pellicori declared no conflicts of interest.

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