Effects of Vutrisiran on Cardiac Function and Outcomes in Patients With Transthyretin Amyloidosis With Cardiomyopathy

BACKGROUND Transthyretin amyloid cardiomyopathy (ATTR-CM), caused by deposition of transthyretin amyloid fibrils in the heart, is associated with high morbidity and mortality. In HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), the RNA interference therapeutic agent vutrisiran reduced rates of the primary composite outcome of all-cause death and recurrent cardiovascular events among patients with ATTR-CM and had beneficial effects on cardiac structure and function over 30 months. OBJECTIVES The purpose of this study was to investigate associations of echocardiographic measures of cardiac structure and function with the primary outcome and to assess whether favorable changes in cardiac structure and function with vutrisiran were associated with improvements in outcomes. METHODS HELIOS-B randomized 655 patients with ATTR-CM to vutrisiran (25 mg subcutaneously every 12 weeks) or placebo. Echocardiograms were performed at baseline and months 12, 18, 24, and 30. Associations of baseline echocardiographic parameters with the primary outcome were analyzed using modified Andersen-Gill models adjusted for age, sex, ATTR disease type, and National Amyloidosis Centre stage, and stratified by baseline tafamidis use and treatment assignment. Changes in cardiac function from baseline to month 18 were compared between treatment arms and related to outcomes in landmark analyses. RESULTS Among the 654 participants with available echocardiographic data (median age 77 years, 93% male, 88% wild-type transthyretin), baseline left and right ventricular systolic and diastolic function were independently associated with the primary outcome (HR per unit increase, left ventricular ejection fraction, 0.90 per 5% increase, 95% CI: 0.86-0.95; absolute global longitudinal strain, 0.92 per 1% increase, 95% CI: 0.89-0.96; tricuspid annular systolic myocardial velocity, 0.94 per 1-cm/s increase, 95% CI: 0.90-0.98; average E/e', 1.03 per 1-U increase, 95% CI: 1.01-1.04). At 18 months, vutrisiran attenuated declines in left ventricular and right ventricular systolic function (least squares mean difference: left ventricular ejection fraction, 1.6%, 95% CI: 0.1-3.2; absolute global longitudinal strain, 0.7%, 95% CI: 0.3-1.2; tricuspid annular systolic myocardial velocity, 0.5 cm/s, 95% CI: 0.1-0.9). Worsening in these parameters at 18 months was associated with a heightened risk of the primary outcome. CONCLUSIONS Echocardiographic measures of biventricular systolic and diastolic function provide important prognostic information beyond National Amyloidosis Centre stage in patients with ATTR-CM. Vutrisiran improved diastolic function and attenuated declines in left ventricular and right ventricular systolic function over 18 months. The benefits on cardiac function with vutrisiran may partly underlie its beneficial effects on clinical outcomes.