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

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.