Tafamidis Cuts Cardiovascular Death and Hospitalization Risk for Up to 90 Months

Patients with transthyretin amyloid cardiomyopathy who took the stabilizer tafamidis continuously for up to seven and a half years experienced significantly fewer cardiovascular deaths and cardiovascular-related hospitalizations than patients who began treatment late, according to a post hoc analysis of the phase 3 ATTR-ACT trial and its long-term extension published in Cardiology and Therapy. The analysis, the longest evaluation of transthyretin inhibition on cardiovascular events in this disease to date, found a 29 percent reduction in the hazard of combined cardiovascular-related events at month 24 that deepened to 37 percent by month 90 among patients who received tafamidis 80 mg throughout both studies.

Transthyretin amyloid cardiomyopathy, or ATTR-CM, arises when misfolded transthyretin monomers form fibrils that accumulate in tissues including the heart muscle, producing ventricular stiffness and cardiac dysfunction. Left untreated, median survival is reported at 3.5 years for patients with the wild-type form and 2.5 years for those with mutations in the TTR gene. As the disease progresses, severe heart failure becomes common, and hospitalizations for worsening heart failure have been associated with a significantly elevated risk of mortality. A European study spanning several North European countries found that patients with ATTR-CM face a higher risk and greater number of hospitalizations than patients with other forms of heart failure, with hospitalizations and hospitalization days climbing steadily in the three years before diagnosis and rising sharply in the first year after it.

Tafamidis is a once-daily oral kinetic stabilizer of transthyretin and was the first disease-modifying therapy approved for ATTR-CM. In the original phase 3 ATTR-ACT trial, it produced a statistically significant reduction in mortality and cardiovascular-related hospitalizations compared with placebo over 30 months. Open-label extension data and an early-access cohort subsequently confirmed benefits on these outcomes with follow-up extending to 71 months. The new analysis extends that picture by evaluating a combined endpoint of cardiovascular-related mortality and recurrent cardiovascular-related hospitalizations over a follow-up of up to 90 months.

The study population came from ATTR-ACT, in which patients aged 18 to 90 with biopsy-confirmed ATTR-CM and New York Heart Association class I to III symptoms were randomized 2:1:2 to tafamidis meglumine 80 mg, tafamidis 20 mg, or placebo for up to 30 months. This post hoc analysis excluded patients who received tafamidis 20 mg, leaving 176 patients on tafamidis 80 mg and 177 on placebo. Patients who completed the double-blind period could enter the open-label long-term extension, where those who had received placebo were randomized 2:1 to tafamidis 80 or 20 mg for up to 60 months. Following a protocol amendment from July 20, 2018, all patients receiving tafamidis in the extension switched to the bioequivalent tafamidis free acid 61 mg.

The investigators used a Liu–Wei–Yang–Ying model, a modified Andersen–Gill approach with a robust covariance estimator, to assess time to recurrent cardiovascular events, and a Cox proportional hazard model for cardiovascular-related mortality alone. Both models adjusted for baseline transthyretin genotype, log-transformed baseline NT-proBNP, and baseline estimated glomerular filtration rate, with New York Heart Association class adjusted in the overall cohort. Cardiovascular-related mortality was defined as death from a cardiovascular event, heart transplant, or implantation of a cardiac mechanical assist device. Analyses were based on original randomization, with patients who did not enroll in the extension censored.

The results showed a widening gap between treatment strategies over time. During ATTR-ACT, cumulative incidence of first and recurrent cardiovascular-related events in the tafamidis group fell below placebo from month 9, and cardiovascular mortality separated from month 18. At month 24, cumulative incidence of cardiovascular-related events was 48 percent with tafamidis 80 mg versus 61 percent with placebo, a 29 percent hazard reduction (hazard ratio 0.713, 95 percent confidence interval 0.524 to 0.970; p = 0.0310). By month 90, incidence had risen in both arms to 77 and 79 percent respectively, but the hazard reduction with continuous tafamidis remained significant at 37 percent (hazard ratio 0.629, 95 percent confidence interval 0.491 to 0.806; p = 0.0002).

Cardiovascular-related mortality followed a parallel course. In the overall cohort, cumulative incidence at month 24 was 20 percent with continuous tafamidis versus 29 percent with placebo followed by tafamidis, a 38 percent hazard reduction (hazard ratio 0.618, 95 percent confidence interval 0.401 to 0.954; p = 0.0299). At month 90 the incidence was 39 percent versus 47 percent, with a 39 percent hazard reduction (hazard ratio 0.607, 95 percent confidence interval 0.436 to 0.843; p = 0.0029). The number needed to treat for mortality ranged from 10 to 14 throughout both studies. During the first year of ATTR-ACT itself, mortality incidence was similar between arms before diverging from month 18 onward.

Disease severity at baseline strongly shaped the treatment effect. In patients with New York Heart Association class I or II symptoms, hazard reduction for cardiovascular-related events held steady at roughly 54 to 56 percent from month 24 to month 90 (month 24: hazard ratio 0.454, 95 percent confidence interval 0.290 to 0.711; month 90: hazard ratio 0.456, 95 percent confidence interval 0.331 to 0.628), with the number needed to treat between 5 and 8 until month 78. Cardiovascular mortality hazard reduction in this subgroup was 50 percent at month 30 and 43 percent at month 90. In contrast, no significant hazard reduction for either endpoint was observed in patients with baseline class III symptoms, a pattern the authors attribute to survival bias previously seen in ATTR-ACT, since patients with higher disease burden had generally higher event incidence regardless of treatment.

The authors frame the findings as underscoring the value of early treatment initiation, since the benefit of continuous tafamidis persisted even after patients who initially received placebo switched to the drug at 30 months. The analysis also situates ATTR-CM within the broader hospitalization burden of heart failure: a European study reported 3.3 all-cause hospitalizations in the first year after diagnosis versus 2.5 in other heart failure types, with mean stays of 21.7 versus 15.2 days, while a South Korean database analysis found a 3.8-fold increase in admissions and a 5.1-fold increase in length of stay after diagnosis. Within ATTR-ACT itself, tafamidis reduced annual rates of cardiovascular-related hospitalizations and shortened mean stay per event, preventing an estimated 2.6 cardiovascular-related hospitalization days per patient per year.

The investigators acknowledge the limitations inherent in the design: the analysis was post hoc, sample sizes were small, particularly toward the end of the extension, and no multiplicity adjustments were applied because no multiple comparisons were performed within a single dataset. Strengths cited include the length of follow-up, adjudication of cardiovascular events during ATTR-ACT, and a prespecified definition of such events in the extension. Baseline characteristics were broadly balanced, with mean ages between 73 and 76 years, at least 81.8 percent of patients male, and a majority having wild-type disease, although patients who did not continue into the extension were more likely to be Black, have variant ATTR-CM, or have class III symptoms. The trial was registered as NCT01994889 and NCT02791230, and the authors conclude that tafamidis significantly reduced the risk of cardiovascular-related events, including recurrent hospitalizations and cardiovascular mortality, as early as month 24, with the benefit continuing for up to 90 months in patients treated from the start.

Subject of Research: Post hoc analysis of cardiovascular mortality and hospitalizations with tafamidis in transthyretin amyloid cardiomyopathy

Article Title: 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

Article References: Damy, T., Witteles, R., Cappelli, F., Wang, R., & Grogan, M. (2026). 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. Cardiology and Therapy, 15(S1), 19-36. https://doi.org/10.1007/s40119-026-00470-8

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00470-8

Keywords: transthyretin amyloid cardiomyopathy, tafamidis, ATTR-ACT, cardiovascular mortality, hospitalizations, long-term extension, NYHA class, hazard ratio, heart failure, TTR stabilizer, post hoc analysis, Cardiovascular-Related