Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction: The Aldo-DHF Randomized Controlled Trial
What is the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction (HFPEF)?
The Aldo-DHF (Aldosterone Receptor Blockade in Diastolic Heart Failure) trial was a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012, at 10 German and Austrian sites. Eligible patients had chronic New York Heart Association class II or III HF, left ventricular EF (LVEF) of 50% or greater, and echocardiographic evidence of diastolic dysfunction or atrial fibrillation. Patients were randomized to receive 25 mg of spironolactone once daily (n = 213) or matching placebo (n = 209), with 12 months of follow-up. The primary endpoints were changes in diastolic dysfunction (E/e’) on echocardiography and maximal exercise capacity on cardiopulmonary testing, both measured at 12 months. Quality of life was assessed with validated self-rating scales.
Diastolic function (E/e’) decreased/improved from 12.7 (standard deviation [SD], 3.6) to 12.1 (SD, 3.7) with spironolactone, and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% confidence interval [CI], -2.0 to -0.9; p < 0.001). Maximal exercise capacity did not significantly change with spironolactone vs. placebo (from 16.3 [SD, 3.6] ml/min/kg to 16.8 [SD, 4.6] ml/min/kg, and from 16.4 [SD, 3.5] ml/min/kg to 16.9 [SD, 4.4] ml/min/kg, respectively; adjusted mean difference, +0.1 ml/min/kg; 95% CI, -0.6 to +0.8 ml/min/kg; p = 0.81). Spironolactone did not improve HF symptoms or quality of life. Spironolactone increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; p < 0.001) and decreased estimated glomerular filtration rate (-5 ml/min/1.73 m2; 95% CI, -8 to -3 ml/min/1.73 m2; p < 0.001).
Twelve months of therapy with spironolactone in this randomized controlled trial had a modest, clinically uncertain impact on diastolic function without improving exercise capacity, patient symptoms, or validated measures of quality of life.
Patients with HFPEF account for 50% of the total HF population, and have mortality rates that are similar to HF patients with reduced EF. Yet, no pharmacotherapies to date have shown improvements in diastolic dysfunction, cardiac remodeling, or cardiovascular outcome. While the Aldo-DHF study may offer some promise by demonstrating that aldosterone receptor blockade may improve LV diastolic function, these beneficial effects are not associated with any meaningful clinical improvement in this study, and came at the expense of adverse effects (mild increase in potassium levels, worsening and unexplained anemia, and gynecomastia). Further studies should better characterize the impact of improving diastolic function on clinical endpoints, and clarify the risks and benefits of long-term aldosterone blockade in patients with HFPEF. The international TOPCAT trial will provide insight into whether mineralocorticoid receptor antagonists may improve prognosis in patients with HFPEF.
Keywords: Uncertainty, Follow-Up Studies, Mineralocorticoid Receptor Antagonists, Exercise, Spironolactone, New York, Signal Transduction, Potassium, Quality of Life, Cardiomyopathies, Cardiology, Heart Failure, Stroke Volume, Glomerular Filtration Rate, Confidence Intervals, Diastole, Heart Ventricles, Echocardiography
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