Impact of Heart Failure Severity on Vutrisiran Efficacy in Transthyretin Amyloidosis With Cardiomyopathy.

Abstract

Vutrisiran reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149). This study sought to assess the effect of vutrisiran in HELIOS-B patients with different heart failure severities. HELIOS-B randomized patients with ATTR-CM with NYHA functional class I-III (functional class IV or functional class III with National Amyloidosis Centre [NAC] stage 3 were excluded) 1:1 to vutrisiran 25 mg or placebo every 3 months for up to 36 months. This exploratory subgroup analysis assessed the primary composite endpoint of ACM and recurrent CV events, ACM, and additional functional and biomarker endpoints. Of 654 patients, 84 (13%), 508 (78%), and 62 (9%) were in NYHA functional class I, II, and III, respectively. Median baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 1,920 ng/L. Lower risk of ACM and recurrent CV events was observed with vutrisiran vs placebo across baseline severity subgroups: respective HRs were 0.54 (95% CI: 0.27-1.10), 0.77 (95% CI: 0.57-1.03), and 0.68 (95% CI: 0.33-1.41) in NYHA functional classes I, II, and III, respectively; 0.52 (95% CI: 0.30-0.88), 0.61 (95% CI: 0.37-1.00), and 0.93 (95% CI: 0.64-1.35) in NT-proBNP tertiles <1,368 ng/L, ≥1,368 and <2,691 ng/L, and ≥2,691 ng/L; 0.49 (95% CI: 0.34-0.72) and 1.08 (95% CI: 0.74-1.56) in NAC stages 1 and 2/3, respectively; and 0.69 (95% CI: 0.45-1.07) and 0.74 (95% CI: 0.53-1.02) in Columbia early and intermediate/late stages, respectively. Similar effects were observed in the monotherapy population (patients not on tafamidis at baseline) and across the additional endpoints evaluated. Vutrisiran demonstrated evidence of benefit across the range of baseline disease severities in HELIOS-B, with the greatest benefit in earlier, less severe disease. (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy [HELIOS-B]; NCT04153149).