Efficacy and Safety of Supramaximal Titrated Inhibition of Renin-Angiotensin-Aldosterone System in Idiopathic Dilated Cardiomyopathy

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>