Effect van MRA op diastolische functie

Literatuur - Edelmann et al - 2013 JAMA 309(8):781-791

Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With HeartFailure With Preserved Ejection Fraction

The Aldo-DHF Randomized Controlled Trial
Edelmann et al., 2013 JAMA 309(8):781-791


Hartfalen met behoud van ejectiefractie (EF) gaat vaak gepaard met linker ventrikel (LV) diastolische disfunctie en ‘adverse cardiac remodeling’. Totnogtoe is geen farmacotherapie bekend die verbetering in diastolische disfunctie, cardiac remodeling of cardiovasculaire uitkomst geeft [1-4].
Activatie van de mineralocorticoid receptor  door aldosteron verergert pathofysiologie van hartfalen (met of zonder behoud van EF) [5,6]. De mineralocorticoid receptor antagonisten spironolacton en eplerenone verminderen mortaliteit bij hartfalen met verminderd EF en bij acuut myocard infarct met LV disfunctie [7-9].
De Aldosteron Receptor Blockade in Diastolic Heart Failure (Aldo-DHF)-trial evalueert het effect van spironolacton op diastolische functie en uithoudingsvermogen in patiënten met hartfalen met behoud van EF [10]. In een multi-center, gerandomiseerde, placebogecontroleerde dubbelblinde studie in Duitsland en Oostenrijk werden 422 patiënten (50 jaar en ouder) met chronisch hartfalen (New York Heart Association
(NYHA) class II or III,) met behoud van EF van 50% of groter en aanwijzing voor diastolische disfunctie geïncludeerd. Een groep ontving gedurende een jaar eenmaal daags 25 mg spironolacton en de andere groep ontving een placebo.

Belangrijkste resultaten

  • Spironolacton verbeterde (p<0.001) diastolische functie in vergelijking tot placebo: E/e’ was na een jaar in de spironolactongroep verminderd van  12.7 naar 12.1 en in de placebogroep verhoogd (12.8 naar 13.6).
  • Er werd geen verschil geobserveerd in maximaal uithoudingsvermogen (Peak VO2) tussen spironolacton- of placebobehandeling.
  • Na spironolactonbehandeling waren de LV einddiastolische vulling en remodeling en neurohumorale activatie vergroot en de LV massa index en enddiastolische diameter verlaagd, terwijl de kwaliteit van leven onveranderd bleef.


Een jaar lang eenmaal daags spironolacton heeft een gunstig effect op belangrijke maten van hartfunctie en cardiac remodeling, zonder klinische verbetering te bewerkstellingen. Vervolgstudies moeten uitwijzen wat het precieze effect van verbeterde diastolische functie is op symptomen, functionaliteit en klinische uitkomst.

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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.

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 evidenceof 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.

Main Outcome Measures
The equally ranked co–primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peakV˙O2) 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). PeakV˙ O2 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/kgand from 16.4 [SD, 3.5]mL/min/kgto 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 (–15m;95%CI, –27 to –2m;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/1.73m2; 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.

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