Efficacy and safety of supramaximal titrated inhibition of renin-angiotensin-aldosterone system in idiopathic dilated cardiomyopathy

Abstract

Aims: The optimal dosing strategies for blocking the renin-angiotensin-aldosterone system in idiopathic dilated cardiomyopathy (IDCM) are poorly known. We sought to determine the long-term efficacy and safety of supramaximal titration of benazepril and valsartan in patients with IDCM.

Methods and results: 480 patients with IDCM in New York Heart Association functional class II-IV and with left ventricular ejection fraction ≤35% were randomly assigned to extended-release metoprolol (mean 152 mg/day, range 23.75-190), low-dose benazepril (20 mg/day), low-dose valsartan (160 mg/day), high-dose benazepril (mean 69 mg/day, range 40-80), and high-dose valsartan (mean 526 mg/day, range 320-640). After a median follow-up of 4.2 years, high-dose benazepril and valsartan, compared with their respective low dosages, resulted in 41% and 52% risk reduction in the primary endpoint of all-cause death or admission for heart failure (P = 0.042 and 0.002), promoted functional improvement, and reversed remodelling as assessed by New York Heart Association classes, quality-of-life scores, and echocardiographic recording of left ventricular ejection fraction, left ventricular end-diastolic volume, mitral regurgitation, and wall motion score index. Compared with metoprolol, high-dose valsartan reduced risk for the primary endpoint by 46% (P = 0.006), whereas high-dose benazepril and both low-dose groups showed no significant difference. Major adverse events involved hypotension and renal impairment but were largely tolerated.

Conclusions: Supramaximal doses of benazepril and valsartan were well tolerated and produced extra benefit than their low dosages in clinical outcome and cardiac reverse remodelling in patients with IDCM and modest-severe heart failure. ClinicalTrials.gov identifier: NCT01917149.

Keywords: Angiotensin II receptor blocker; Angiotensin-converting enzyme inhibitor; Cardiac remodelling; Dilated cardiomyopathy; Heart failure.

© 2015 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Figures

Figure 1

Trial profile.

Figure 2

Kaplan–Meier cumulative event curves for primary endpoint of all‐cause death or admission for heart failure, according to (A) intention‐to‐treat or (B) per‐protocol principal.

Figure 3

Clinical and echocardiographic evaluation of cardiac function over 4 years of follow‐up. Changes from baseline to 4 years of follow‐up in (A) New York Heart Association (NYHA) functional classes, (B) distribution of patients in each of the four NYHA classes, (C) score of the Minnesota Living with Heart Failure Questionnaire, (D) left ventricular ejection fraction (LVEF), and (E) total LVEF increase. *P < 0.001 vs. metoprolol, #P < 0.001 vs. high‐dose benazepril.

Figure 4

Left ventricular remoulding evaluated by echocardiography. Changes from baseline to 4 years of follow‐up in (A) left ventricular end‐diastolic diameter (LVEDD), (B) total LVEDD reduction, (C) left ventricular end‐diastolic volume (LVEDV)/body surface area (BSA), (D) peak instantaneous volume of mitral regurgitation, (E) wall motion score index (WMSI), and (F) total WMSI reduction. *P < 0.05, **P < 0.01, ***P < 0.001 vs. metoprolol, #P < 0.05, ###P < 0.001 vs. high‐dose benazepril.

Figure 5

Significant improvement in left ventricular function and remodelling in a representative patient with idiopathic dilated cardiomyopathy and heart failure under high‐dose valsartan treatment. Left ventricular ejection fraction (LVEF) and left ventricular end‐diastolic diameter (LVEDD) were evaluated via apical four chamber view and M‐mode estimation of left ventricular wall motion was recorded from 1 month to 3 years of follow‐up.