Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial

TY - JOUR

T1 - Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial

AU - Edelmann, Frank

AU - Wachter, Rolf

AU - Schmidt, Albrecht G

AU - Kraigher-Krainer, Elisabeth

AU - Colantonio, Caterina

AU - Kamke, Wolfram

AU - Duvinage, André

AU - Stahrenberg, Raoul

AU - Durstewitz, Kathleen

AU - Löffler, Markus

AU - Düngen, Hans-Dirk

AU - Tschöpe, Carsten

AU - Herrmann-Lingen, Christoph

AU - Halle, Martin

AU - Hasenfuss, Gerd

AU - Gelbrich, Götz

AU - Pieske, Burkert

AU - Aldo-DHF Investigators

AU - Westermann, Dirk

PY - 2013/2/27

Y1 - 2013/2/27

N2 - IMPORTANCE: Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression.OBJECTIVE: To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction.DESIGN AND SETTING: The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction.INTERVENTION: Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up.MAIN OUTCOME MEASURES: The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months.RESULTS: Diastolic function (E/e') decreased from 12.7 (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% CI, -2.0 to -0.9; P < .001). Peak VO2 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 = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations.CONCLUSIONS AND RELEVANCE: In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations.TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.

AB - IMPORTANCE: Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression.OBJECTIVE: To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction.DESIGN AND SETTING: The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction.INTERVENTION: Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up.MAIN OUTCOME MEASURES: The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months.RESULTS: Diastolic function (E/e') decreased from 12.7 (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% CI, -2.0 to -0.9; P < .001). Peak VO2 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 = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations.CONCLUSIONS AND RELEVANCE: In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations.TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.

KW - Aged

KW - Diastole/physiology

KW - Double-Blind Method

KW - Echocardiography

KW - Exercise Test

KW - Female

KW - Heart Failure, Diastolic/drug therapy

KW - Humans

KW - Male

KW - Middle Aged

KW - Mineralocorticoid Receptor Antagonists/therapeutic use

KW - Prospective Studies

KW - Quality of Life

KW - Spironolactone/therapeutic use

KW - Stroke Volume

KW - Treatment Outcome

KW - Ventricular Function, Left/drug effects

KW - Ventricular Remodeling

U2 - 10.1001/jama.2013.905

DO - 10.1001/jama.2013.905

M3 - SCORING: Journal article

C2 - 23443441

VL - 309

SP - 781

EP - 791

JO - JAMA-J AM MED ASSOC

JF - JAMA-J AM MED ASSOC

SN - 0098-7484

IS - 8

ER -