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      Effect of mineralocorticoid receptor antagonists on cardiac function in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials

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          Heart failure with preserved ejection fraction (HFpEF) is a disease with limited evidence-based treatment options. Mineralocorticoid receptor antagonists (MRA) offer benefit in heart failure with reduced ejection fraction (HFrEF), but their impact in HFpEF remains unclear. We therefore evaluated the effect of MRA on echocardiographic, functional, and systemic parameters in patients with HFpEF by a systematic review and meta-analysis. We searched MEDLINE, EMBASE,, and Cochrane Clinical Trial Collection to identify randomized controlled trials that (a) compared MRA versus placebo/control in patients with HFpEF and (b) reported echocardiographic, functional, and/or systemic parameters relevant to HFpEF. Studies were excluded if: they enrolled asymptomatic patients; patients with HFrEF; patients after an acute coronary event; compared MRA to another active comparator; or reported a follow-up of less than 6 months. Primary outcomes were changes in echocardiographic parameters. Secondary end-points were changes in functional capacity, quality of life measures, and systemic parameters. Quantitative analysis was performed by generating forest plots and calculating effect sizes by random-effect models. Between-study heterogeneity was assessed through Q and I 2 statistics. Nine trials with 1164 patients were included. MRA significantly decreased E/e′ (mean difference − 1.37, 95% confidence interval − 1.72 to − 1.02), E/A (− 0.04, − 0.08 to 0.00), left ventricular end-diastolic diameter (− 0.78 mm, − 1.34 to − 0.22), left atrial volume index (− 1.12 ml/m 2, − 1.91 to − 0.33), 6-min walk test distance (− 11.56 m, − 21 to − 2.13), systolic (− 4.75 mmHg, − 8.94 to − 0.56) and diastolic blood pressure (− 2.91 mmHg, − 4.15 to − 1.67), and increased levels of serum potassium (0.23 mmol/L, 0.19 to 0.28) when compared with placebo/control. In patients with HFpEF, MRA treatment significantly improves indices of cardiac structure and function, suggesting a decrease in left ventricular filling pressure and reverse cardiac remodeling. MRA increase serum potassium and decrease blood pressure; however, a small decrease in 6-min-walk distance is also noted. Larger prospective studies are warranted to provide definitive answers on the effect of MRA in patients with HFpEF.

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          Most cited references 25

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          Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.

          Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas).
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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.

            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. 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. 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. 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. 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. 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. 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. Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.
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              Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.

              The objectives of the present study were to describe epidemiology and outcomes in ambulatory heart failure (HF) patients stratified by left ventricular ejection fraction (LVEF) and to identify predictors for mortality at 1 year in each group.

                Author and article information

                +30 6980 489580 , ,
                Heart Fail Rev
                Heart Fail Rev
                Heart Failure Reviews
                Springer US (New York )
                7 January 2019
                7 January 2019
                : 24
                : 3
                : 367-377
                [1 ]ISNI 0000 0001 0789 5319, GRID grid.13063.37, Department of Health Policy, , The London School of Economics and Political Science, ; London, UK
                [2 ]ISNI 0000 0004 0621 2848, GRID grid.411565.2, Cardiology Department, , Laiko General Hospital, ; 17 Agiou Thoma Street, 11 527 Athens, Greece
                [3 ]Augusta University—University of Georgia Medical Partnership, Athens, GA USA
                [4 ]ISNI 0000 0004 0493 2307, GRID grid.418466.9, Department of Cardiology and Angiology II, , University Heart Center Freiburg • Bad Krozingen, ; Bad Krozingen, Germany
                [5 ]ISNI 0000 0004 0571 546X, GRID grid.413548.f, Heart Failure Department, , Heart Hospital, Hamad Medical Corporation, ; Doha, Qatar
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funded by: London School of Economics and Political Science
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