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

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. 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. 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. 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. ClinicalTrial.gov identifiers: NCT01994889; NCT02791230. Transthyretin amyloid cardiomyopathy (called ATTR-CM) is a disease that affects the heart and can cause heart failure. Patients with ATTR-CM are frequently hospitalized as a result of cardiovascular problems. Tafamidis is approved for the treatment of ATTR-CM. In the phase 3 ATTR-ACT, patients treated with tafamidis were less likely to be hospitalized or die because of heart-related problems compared to those treated with placebo. In this analysis, the investigators looked at the frequency and risk of cardiovascular events (both hospitalizations and death) during ATTR-ACT and the long-term extension study that followed. This analysis included 176 patients who took tafamidis during ATTR-ACT (which lasted 2.5 years) and the long-term extension study (which lasted 5 years), and 177 patients who took placebo during ATTR-ACT switched to tafamidis during the long-term extension study. After 1.5 years of treatment and until the end of the long-term extension study, fewer patients taking tafamidis experienced cardiovascular-related events compared to patients who first took placebo and then switched to tafamidis. The risk for heart-related events and heart-related death was significantly lower after 2 years of treatment with tafamidis compared to placebo. The risk remained significantly lower until the end of the long-term extension study for patients who took tafamidis from the start compared to patients who switched from placebo to tafamidis. In summary, treatment with tafamidis reduced the risk of heart-related events and death for up to 7.5 years.