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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 Feb 27; 309(8):781-91.JAMA

Abstract

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.

Authors+Show Affiliations

Department of Cardiology and Pneumology, Heart Center, University of Göttingen, Göttingen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23443441

Citation

Edelmann, Frank, 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, vol. 309, no. 8, 2013, pp. 781-91.
Edelmann F, Wachter R, Schmidt AG, 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;309(8):781-91.
Edelmann, F., Wachter, R., Schmidt, A. G., Kraigher-Krainer, E., Colantonio, C., Kamke, W., Duvinage, A., Stahrenberg, R., Durstewitz, K., Löffler, M., Düngen, H. D., Tschöpe, C., Herrmann-Lingen, C., Halle, M., Hasenfuss, G., Gelbrich, G., & Pieske, B. (2013). 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, 309(8), 781-91. https://doi.org/10.1001/jama.2013.905
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 Feb 27;309(8):781-91. PubMed PMID: 23443441.
* Article titles in AMA citation format should be in sentence-case
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 - ,, PY - 2013/2/28/entrez PY - 2013/2/28/pubmed PY - 2013/3/1/medline SP - 781 EP - 91 JF - JAMA JO - JAMA VL - 309 IS - 8 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/23443441/Effect_of_spironolactone_on_diastolic_function_and_exercise_capacity_in_patients_with_heart_failure_with_preserved_ejection_fraction:_the_Aldo_DHF_randomized_controlled_trial_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2013.905 DB - PRIME DP - Unbound Medicine ER -