1. Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients with Heart Failure with preserved Ejection Fraction Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients with Heart Failure with preserved Ejection Fraction - The Aldo-DHF Randomized Controlled Trial - Frank Edelmann, Wachter R, Schmidt AG, et al JAMA, February 27, 2013—Vol 309, No. 8 R4 황인경 / pf. 김권삼

2. Introduction Heart failure(HF) with preserved ejection fraction(EF) accounts for more than 50% of the total HF population Community-based cohort studies have shown that mortality rates are similar in HF with preserved EF compared with HF with reduced EF Pharmacotherapies tested to date have not shown improvements in diastolic dysfunction, cardiac remodeling, or cardiovascular outcome

3. Introduction Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of HF including sodium retention, potassium loss, endothelial dysfunction, vascular inflammation, fibrosis, and hypertrophy The mineralocorticoid receptor antagonists spironolactone and eplerenone reduce total and cardiovascular mortality across the spectrum of HF with reduced EF The Aldosterone Receptor blockade in Diastolic Heart Failure (Aldo-DHF) trial was designed by evaluating the effects of spironolactone on diastolic function and exercise capacity in patients with diastolic HF

4. Methods Aldo-DHF Trial design and oversight – a multicenter, randomized, placebo-controlled, double-blind, two-armed, parallel-group study that enrolled patients from 10 trial sites in Germany and Austria

5. Methods Participants – Eligibility criteria : ≥ 50 years old : current HF symptoms consistent with NYHA II or III, LVEF ≥50%, echocardiographic diastolic dysfunction (grade ≥I) or A fib., and maximum exercise capacity (peak VO₂) ≤25mL/kg/min – Major exclusion criteria : LVEF ≤40%, significant coronary artery disease, MI or CABG within 3months, clinically relevant pulmonary disease, significant lab abnormalities, known contraindications for spironolactone or therapy with a mineralocorticoid receptor antagonist within the last 3 months, etc.

6. Methods Study Drug Administration and Study Procedures – The randomization ratio was 1:1 for spironolactone (25 mg/d) or placebo using the Pocock minimization algorithm – Randomization was stratified by grade of diastolic dysfunction (I vs II-III), rhythm (sinus vs other), and study center – The study drug could be decreased or stopped d/t hyperkalemia, significant renal impairment, breast pain, gynecomastia – At baseline and the 6- and 12-month follow-up visit, physical examination, echocardiography, cardiopulmonary exercise testing, 6-minute walk testing, quality-of-life assessment, and blood sampling were conducted

7. Methods Study Objectives and End Points – Primary objective : whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with HF with preserved EF – Primary end points : the change in E/e’ at 12months and the change in maximum exercise capacity(peak V˙O₂) at 12 months compared with baseline – Secondary end points : changes in echocardiographic measures of cardiac function and remodeling, measures of maximal exercise capacity, serum biomarkers, and quality of life – Safety end point : clinical tolerability – Exploratory end points : morbidity and mortality Statistical Analyses – All analyses were based on the intention-to-treat principle – primary end points were carried out using 2-sided Mann- Whitney U tests

8. Results Patients – 795 pts screened from March 2007 to April 2011, 422 were included and randomized to receive spironolactone or placebo – Mean length of follow-up was 11.6 months – Mean daily dose of spironolactone was 21.6mg – Baseline characteristics were similar between treatment groups

9. Results Primary end points – Spironolactone significantly improved diastolic function compared with placebo – Peak VO₂ is no difference between the two groups

10. Results Secondary Echocardiographic End Points – Spironolactone improved major measures of cardiac function and remodeling

11. Results Secondary Echocardiographic End Points – LVEF increased while LV end-diastolic diameter and LV mass index decreased significantly in the spironolactone group compared placebo group

12. Results Secondary Exercise Performance End Points – slope of V E /V CO ₂ slightly increased, but there were no other significant differences between groups

13. Results Secondary Clinical Outcome End Points

14. Results Safety and Adherence – A mild increase in K levels and a decrease in eGFR in spironolactone group – Significantly greater proportion of pts randomized to spironolactone experienced K level greater than 5.0mmol/L, but no difference between groups in the incidence of serious hyperkalemia (>5.5 mmol/L) and no pts were hospitalized – Only gynecomastia and an increase of K levels to greater than 5.0mmol/L during f/u were significantly associated with subjective intolerance or reduction or stopping of the study medication.

15. Conclusion 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

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