Cardiovascular-Related Mortality and Hospitalizations in Patients with Transthyretin Amyloid Cardiomyopathy Treated with Tafamidis: A Post Hoc Analysis of the Phase 3 ATTR-ACT and Long-Term Extension

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) are at high risk of cardiovascular (CV)-related hospitalizations (CVH), which are associated with higher mortality. In the phase 3 study ATTR-ACT, treatment with tafamidis significantly reduced CVH versus placebo. Methods: This post hoc analysis included patients from ATTR-ACT (30 months) and its long-term extension (LTE; 60 months) receiving tafamidis 80 mg (n = 176) or placebo in ATTR-ACT and switched to tafamidis 80 mg in the LTE (n = 177). CV-related events (CV-related mortality [CVM] and/or recurrent CVH) and CVM were evaluated. Liu-Wei-Yang-Ying and Cox proportional hazard models were used to evaluate time to recurrent CV-related events and CVM, respectively. Results: During ATTR-ACT, cumulative incidence of first and recurrent CV-related events in the tafamidis group was lower versus placebo from month 9 and incidence of CVM was lower from month 18. These trends continued throughout the LTE. At month 24, a significant 29% hazard reduction was observed for CV-related events with tafamidis 80 mg versus placebo (incidence 48% vs 61%; hazard ratio [HR] 0.713 [95% CI 0.524-0.970]; p = 0.0310). Hazard reduction remained significant until month 90 with continuous tafamidis 80 mg and was 37% at month 90 (incidence 77% vs 79%; HR 0.629 [95% CI 0.491-0.806; p = 0.0002]). Incidence of CVM with continuous tafamidis 80 mg was lower versus placebo(/tafamidis 80 mg) at month 24 (21% vs 29%) and month 90 (39% vs 47%), with significant hazard reductions of 38% (HR 0.618 [95% CI 0.401-0.954]; p = 0.0299) and 39% (HR 0.607 [95% CI 0.436-0.843]; p = 0.0029), respectively. Similar trends were observed in patients with baseline New York Heart Association (NYHA) functional class I/II but not with baseline NYHA class III. Conclusion: Treatment with tafamidis significantly reduced the risk of CV-related events, including recurrent CVH and CVM, as early as month 24. This benefit continued for ≤ 90 months. Graphical abstract available for this article. Trial registry: ClinicalTrial.gov identifiers: NCT01994889; NCT02791230.