Research Summary

Long-Term Tafamidis Outcomes by NAC Stage in ATTR-CM

Edited by:
Anthony Calabro, MA

Key Highlights

  • Continuous tafamidis was associated with lower all-cause and cardiovascular mortality in National Amyloidosis Center (NAC)stages I and II compared with delayed therapy.
  • Cardiovascular hospitalization rates were reduced in earlier-stage disease.
  • Survival curves separated earlier in NAC stage I than in more advanced stages.
  • Quality-of-life decline was attenuated with continuous therapy in stages I and II.

In a recent post-hoc analysis of the ATTR-ACT trial published in European Journal of Heart Failure, Damy and colleagues found that continuous tafamidis therapy was associated with reduced risks of mortality and cardiovascular (CV) hospitalization in patients with earlier-stage transthyretin amyloid cardiomyopathy (ATTR-CM), with favorable numerical trends in more advanced stages.

The ATTR-ACT was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial including 350 of 353 patients aged 18 to 90 years with biopsy-confirmed wild-type or variant ATTR-CM, heart failure symptoms, interventricular septal wall thickness greater than 12 mm, 6-minute walk distance greater than 100 m, and N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration of 600 ng/L or greater. Patients were randomized 2:1:2 to tafamidis meglumine 80 mg or 20 mg (pooled) or placebo for 30 months. Patients completing ATTR-ACT were eligible for the long-term extension (LTE) portion of the trial, in which all participants received tafamidis for up to 60 additional months.

All patients had evaluable National Amyloidosis Center (NAC) staging at baseline. At study entry, 42% were NAC stage I, 38% stage II, and 20% stage III. Outcomes were assessed through up to 90 months of follow-up.

Study Findings

At the end of follow-up, all-cause mortality in the continuous tafamidis vs placebo-to-tafamidis groups was 36% vs 61% in NAC stage I (hazard ratio [HR], 0.43; P < .001) and 55% vs 74% in NAC stage II (HR, 0.51; P = .003). In NAC stage III, mortality was 69% vs 88% (HR, 0.75; P = .30). No significant interaction was observed between treatment and NAC stage.

CV-related mortality followed a similar pattern. In NAC stage I, CV mortality was 25% with continuous tafamidis vs 46% with delayed therapy (HR, 0.39; P = .001). In stage II, rates were 42% vs 58% (HR, 0.51; P = .009), and in stage III, 61% vs 76% (HR, 0.75; P = .32). Kaplan–Meier curves demonstrated earlier divergence in stage I and later separation in higher stages.

Total annual CV-related hospitalization rates were lower with continuous tafamidis in NAC stage I (0.19 vs 0.31; relative risk, 0.61; P = .007) and stage II (0.14 vs 0.29; relative risk, 0.49; P = .008). In stage III, rates were numerically lower (0.13 vs 0.23; P = .29). Smaller declines in Kansas City Cardiomyopathy Questionnaire overall summary and clinical summary scores were frequently observed with continuous therapy in NAC stages I and II; no statistically significant differences were seen in stage III.

Clinical Implications

According to the study authors, continuous tafamidis treatment reduced all-cause mortality, CV-related mortality, and CV-related hospitalizations, and attenuated deterioration in symptoms and health-related quality of life among patients with NAC stages I and II ATTR-CM. Benefits were observed earlier and were greater in magnitude in patients with lower baseline stage, reinforcing the importance of early diagnosis and initiation of disease-modifying therapy.

This study had limitations. For example, this was a post hoc and exploratory trial, and neither ATTR-ACT nor the LTE was powered to assess treatment effects by NAC stage. Patient numbers in advanced stages were also limited, and all participants received tafamidis during the LTE, which may weaken differences compared with a persistent placebo group.

Expert Commentary

“Continuous tafamidis treatment reduced all-cause mortality, CV-related mortality, and CV-related hospitalizations, and minimized the worsening of symptoms and decline in quality of life among patients with ATTR-CM in NAC stages I and II. These reductions were largest and occurred earliest in patients at NAC stage I,” the researchers concluded.

Reference
Damy T, Wang R, Maurer MS, Gillmore JD, Fontana M. Long-term efficacy of tafamidis in patients with transthyretin amyloid cardiomyopathy by National Amyloidosis Centre stage. Eur J Heart Fail. 2025;27(12):2998-3009. doi:10.1002/ejhf.3696.