Spironolactone Boosts Exercise Capacity in Preserved-EF Heart-Failure Study

Pam Harrison

October 24, 2016

HOBART, AUSTRALIA — The addition of spironolactone to standard treatment in patients with heart failure and preserved ejection fraction (HFpEF) and reduced exercise capacity significantly improves functional capacity by the end of 6 months, a small randomized trial indicates[1].

"Most of the previous work has examined survival, which may not be the best metric in these patients who are old, have comorbidities, and may die from other things," senior author Dr Thomas Marwick (University of Tasmania, Hobart, Australia) told heartwire from Medscape by email.

"The thing that makes this study different from other approaches is that we appended E/e' . . . to exercise echo," he added. That Doppler-echo variable, the ratio between early mitral inflow velocity and mitral annular early diastolic velocity, reflects LV filling pressure.

"And we think doing a stress echo is a prudent step in HFpEF because dyspnea in some of these patients is an angina equivalent."

The study, called the Spironolactone in Myocardial Dysfunction With Reduced Exercise Capacity (STRUCTURE) trial, was published in the October 25, 2016 issue of the Journal of the American College of Cardiology with lead author Dr Wojciech Kosmala (Wrocław Medical University, Poland).

It somewhat contrasts with results of the larger Aldo-DHF study, in which there was no spironolactone benefit with respect to exercise capacity, symptoms, or quality of life in patients with HFpEF. However, both Aldo-DHF and STRUCTURE saw significant positive effects of spironolactone on echocardiographic diastolic function.

STRUCTURE evaluated spironolactone at a dose of 25 mg a day for 6 months for its effect on exercise tolerance in HFpEF patients who had an abnormal LV diastolic response to exercise. Its investigators documented changes in exercise capacity at the end of 6 months by looking at exercise-induced changes in the echo-Doppler–derived E/e' ratio.

At baseline, participants had a mean peak VO2 of 64% of predicted exercise capacity. Participants were also in NYHA functional class 2–3 with a postexercise E/e' in excess of 13. After 6 months of treatment, 64 patients on spironolactone remained in the study, as did 67 patients on placebo.

At 6 months, patients treated with spironolactone had a significant 2.9-mL/min/kg improvement in their peak VO2 compared with a 0.3-mL/min/kg improvement for placebo controls (P<0.001).

Spironolactone also led to favorable changes in anaerobic thresholds as well as the respiratory exchange ratio and the oxygen-uptake efficiency slope, while reducing the exercise-induced increase in E/e' at the same time.

Exercise-Associated Changes With Spironolactone vs Placebo

Outcome Spironolactone Placebo P
Anaerobic thresholds, mL/min/kg +2.0 -0.9 0.03
Peak respiratory exchange ratio +0.06 +0.01 0.004
Oxygen-uptake efficiency slope 0.19 -0.07 0.002
Mean E/e' -2.4 0 <0.001

By echocardiography, active treatment was associated with improved resting LV diastolic function compared with placebo, while significant improvements were also seen in peak heart rate during exercise as well as heart-rate reserve at the end of the study.

Adverse events were rare, the groups writes, and included an unsurprising '"small increase" in serum potassium with active therapy.

Marwick said the benefits of spironolactone observed in the current study may be attributed to the drug's antifibrotic effects, although changes in blood pressure or intravascular volume might have contributed to observed gains in functional capacity.

In an accompanying editorial[2], Drs Brent Lampert and William Abraham (Ohio State University, Columbus) point out that many patients with HFpEF are so limited that they can't walk a block or two at a normal pace.

"The use of exercise capacity as the primary outcome [of a clinical trial] is an important concept that should carry more significance in future HFpEF trials, as exercise limitation is often severe in patients with HFpEF," they write.

"The use of such patient-centered end points as exercise capacity and quality of life should be encouraged in HFpEF studies, where a generally elderly HFpEF population may be more concerned about improving functional status than prolonging survival."

The group cautions that the current study was single center and small and therefore limited. Still, "a therapy that makes patients with HFpEF feel better with a neutral effect on survival should be viewed as beneficial and should achieve a high level of recommendation in clinical-practice guidelines."

The study was funded by the Wroc ław Medical University and the Royal Hobart Hospital Foundation. None of the STRUCTURE study authors reported any relevant financial relationships, nor did Lampert or Abraham.

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