Effect of Sacubitril/Valsartan on Functional and Structural Cardiac Parameters in Adults With Nonobstructive Hypertrophic Cardiomyopathy: A Randomized Controlled Trial.

BACKGROUND

Developing effective therapy for symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM) is a major unmet need. Sacubitril/valsartan (LCZ696) is an angiotensin II receptor-neprilysin inhibitor that increases circulating natriuretic peptides and has proven to be beneficial in heart failure but has not been evaluated for nHCM.

OBJECTIVES

This phase II, multicenter, double-blinded, randomized, placebo-controlled clinical trial assessed the safety, tolerability, and efficacy of LCZ696 in improving exercise capacity in patients with nHCM.

METHODS

Adult patients with nHCM and reduced exercise capacity (% predicted peak oxygen consumption ≤80%) were randomized 1:1 to placebo or LCZ696 (uptitrated to 200 mg twice daily). The primary endpoint was change from baseline in peak oxygen uptake (pVO2) as measured by cardiopulmonary exercise testing after 50 weeks. Additional analyses included changes in echocardiographic features, heart failure serum biomarkers, and standardized changes in clinically important nHCM parameters as a single composite z-score.

RESULTS

Forty participants (median age: 57.5 years; 80% NYHA functional class II; mean % predicted pVO2: 67.7%) were randomized. There was no difference in change from baseline in pVO2 between LCZ696 and placebo (P = 0.55). Interventricular septal thickness decreased by 4.7 mm (P = 0.0001) and left ventricular mass index decreased by 22.5 g/m2 (P = 0.02) at 50 weeks in LCZ696 compared with the placebo. Composite z-score also improved in the LCZ696 group (P = 0.015), driven by changes in wall thickness, left ventricular mass index, and troponin. Rates of mild to moderate hypotension and mild renal impairment were similar to those observed in prior LCZ696 studies in heart failure.

CONCLUSIONS

Although LCZ696 treatment did not improve pVO2 after 50 weeks, the favorable cardiac structural remodeling suggests a potential benefit in this patient group.