Real-world effectiveness of tafamidis in a contemporary, matched cohort of patients with variant and wild-type transthyretin amyloid cardiomyopathy

Abstract Background Tafamidis (meglumine 80 mg/free acid 61 mg) is approved to treat variant or wild-type transthyretin amyloid cardiomyopathy (ATTR-CM). Variant ATTR-CM results from a pathogenic variant in the transthyretin (TTR) gene, whereas wild-type ATTR-CM results from age-related accumulation of wild-type TTR protein. Untreated variant ATTR-CM generally presents with a more aggressive disease progression and with a poorer prognosis than the wild-type form (1,2). In the pivotal phase 3 study ATTR-ACT, tafamidis vs placebo reduced all-cause mortality (ACM) and functional decline in both disease subtypes, but there was a differential benefit observed in cardiovascular-related hospitalisations (CVHs) in the wild-type vs variant cohort (3). Purpose To evaluate mortality and hospitalisations in a real-world cohort of patients with ATTR-CM treated with the approved dose of tafamidis by variant and wild-type genotype. Methods This study pooled a contemporary cohort of patients with ATTR-CM who received early access to tafamidis in the ATTR-ACT long-term extension study but did not participate in the parent study, and a contemporary cohort of patients from the Transthyretin Amyloidosis Outcomes Survey with predominantly cardiac or mixed phenotype ATTR-CM enrolled between 2019–2023 who received tafamidis throughout the study. THAOS was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic gene carriers. Patients with variant ATTR-CM were matched 1:1 to patients with wild-type ATTR-CM based on baseline age, sex, modified body mass index, New York Heart Association (NYHA) class, and phenotype (cardiac, mixed). Outcomes were time to event of ACM, first all-cause hospitalisation (ACH), first CVH, and ACM or first CVH. Results A total of 352 patients (176 variant, 176 wild-type) were included. In patients with variant and wild-type ATTR-CM, respectively, median age at enrolment was 72.8 and 73.0 years, and 76.7% and 80.1% were male; 14.2% and 12.5% were in NYHA class I, 51.1% and 50.0% in class II and 34.7% and 37.5% in class III. The estimated adjusted survival probabilities (95% CI) for ACM in patients with variant and wild-type ATTR-CM, respectively, were 66.8% (58.4–76.5) and 70.9% (62.5–80.5) at 30 months and 61.3% (52.1–72.1) and 65.8% (56.2–77.1) at 40 months (Figure). Patients with wild-type ATTR-CM showed slightly better survival rates on 3 of the 4 outcomes: time to ACM, time to first CVH and time to ACM or first CVH (Table). Conclusions This matched-cohort, real-world analysis showed that tafamidis benefited patients with variant and wild-type ATTR-CM in terms of mortality and hospitalisations. However, patients with wild-type ATTR-CM had slightly better outcomes, consistent with previous findings that the variant form has a poorer prognosis and/or poorer therapy response.

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