Effect of Vutrisiran According to Baseline Tafamidis Use in Transthyretin Amyloidosis With Cardiomyopathy

BACKGROUND: Vutrisiran, an RNA interference therapeutic that suppresses hepatic transthyretin production, improved survival and cardiovascular outcomes in transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy). Tafamidis, a transthyretin stabilizer, also improves clinical outcomes. Although combining these therapies is mechanistically appealing, clinical evidence supporting this approach is limited. OBJECTIVES: We sought to evaluate whether the treatment effects of vutrisiran differed according to baseline tafamidis use in HELIOS-B. METHODS: In HELIOS-B, patients with ATTR-CM were randomized to vutrisiran 25 mg or placebo every 3 months for up to 36 months, with tafamidis use permitted and stratified. We assessed treatment effects according to baseline tafamidis use for the primary outcome of all-cause mortality and recurrent cardiovascular events and secondary endpoints, including individual components of the primary outcome, composite of all-cause mortality, cardiovascular events and outpatient worsening heart failure events, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire-overall summary score [KCCQ-OSS]). RESULTS: = 0.24), whereas improvement in KCCQ-OSS appeared attenuated among patients receiving tafamidis at baseline. CONCLUSIONS: Treatment effect estimates for vutrisiran on clinical outcomes were consistent across baseline tafamidis strata, with no statistically significant interaction according to baseline tafamidis use, with reduced effect size noted in those receiving baseline stabilizers in comparison to monotherapy. These data underscore the need for future prospective studies examining combination therapy in this population. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).