Staging the Benefit: Tafamidis Outcomes in ATTR-CM Depend on Timing

Early diagnosis and timely treatment remain critical challenges in the care of patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), so exploring interventions and strategies that may optimize detection and management are crucial.

For that reason, a post hoc analysis published in June 2025 in the European Journal of Heart Failureaimed to investigate how the clinical benefits of tafamidis connect to disease stage at treatment initiation. Drawing on data from the 30-month Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its 60-month long-term extension (LTE), the analysis provides compelling long-term evidence that tafamidis’ benefits are closely tied to disease stage at treatment initiation.

Here's a look at ATTR-ACT, the post hoc analysis, and what these results could mean for ATTR-CM care.

How Was the Analysis Designed?

For context, ATTR-ACT was a multicenter, international, double-blind, placebo-controlled, parallel-design, randomized, phase 3 trial of tafamidis in patients with ATTR-CM. Patients were randomized 2:1:2 to receive tafamidis meglumine—either 80  or 20 milligrams—or placebo for 30 months, stratified by TTR genotype (wild-type or variant) and New York Heart Association functional class.

After completing ATTR-ACT, patients were eligible to join the LTE and received tafamidis for up to 60 months. Patients receiving tafamidis meglumine in ATTR-ACT initially continued this dose in the LTE. Patients receiving placebo in ATTR-ACT were randomized 2:1 to receive tafamidis 80 or 20 milligrams, stratified by TTR genotype, in the LTE.

The post hoc analysis followed 350 patients with wild-type or variant ATTR-CM who received either continuous tafamidis or placebo in ATTR-ACT, followed by tafamidis in the LTE. Patients were stratified at baseline into National Amyloidosis Centre (NAC) stages I through III, based on N-terminal pro-B-type natriuretic peptide levels (NT-proBNP) and estimated glomerular filtration rate, with the following distributions:

• Stage I: 42 percent
• Stage II: 38 percent
• Stage III: 20 percent

Outcomes assessed included all-cause and CV related mortality, CV-related hospitalizations, and patient-reported health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ), with follow-up extending to 90 months.

What Did the Analysis Find?

Looking at the results, a clear gradient in treatment benefit emerged across NAC stages. Among patients with stage I disease, continuous tafamidis reduced all-cause mortality from 61 percent to 36 percent compared with delayed treatment (hazard ratio 0.43, p<0.001). In stage II, mortality was 74 percent in the delayed group versus 55 percent in the continuous tafamidis group (HR 0.51, p=0.003). In stage III, all-cause mortality remained high in both groups—88 percent with delayed tafamidis and 69 percent with continuous treatment—but the difference did not reach statistical significance (HR 0.75, p=0.298).

Kaplan-Meier survival curves further illustrated this effect. In the stage I cohort, survival curves began separating early and remained widely divergent over time. In stages II and III, separation occurred later and with less magnitude. Similar trends were observed for CV-related mortality, again showing significant reductions in stages I and II, and a non-significant trend in stage III.

Hospitalization data also supported the benefit of early intervention. Total annual rates of CV-related hospitalizations were lower in the continuous tafamidis arm across all stages. However, relative risk reductions reached statistical significance in stage I (39 percent) and stage II (51 percent), but not in stage III (44 percent; p=0.29), highlighting a diminishing treatment effect with advancing disease.

Patient-reported outcomes reflected these clinical trends. Declines in KCCQ overall and clinical summary scores were smaller in patients who received tafamidis continuously, particularly among those in NAC stages I and II. Statistically significant differences in KCCQ scores emerged by 18 to 30 months. While patients in stage III still showed a trend toward benefit, between-group differences were not statistically significant.

How Could These Results Impact ATTR-CM Treatment?

Taken altogether, the findings suggest that the earlier tafamidis is initiated, the greater and more sustained its clinical impact. Even among patients with advanced ATTR-CM, such as those classified as NAC stage IV in supplementary analyses, continuous tafamidis was associated with a directional survival benefit, though confidence intervals were wide. Notably, the authors highlight that ATTR-ACT remains the only phase 3 trial to include patients with severe disease, including those with NT-proBNP levels over 10,000 ng/L.

For clinicians, these data highlight the importance of staging not only as a prognostic framework but as a guide for therapeutic urgency. Identifying patients in NAC stage I or II should prompt early initiation of tafamidis, where its impact on mortality, hospitalization, and quality of life is most clearly demonstrated. Although tafamidis may still offer benefit in later stages, the window for altering long-term outcomes narrows progressively with advancing disease. As disease-modifying therapies become more accessible for patients with ATTR-CM, early diagnosis and timely intervention remain critical to achieving the best possible outcomes.