Marino, Valentina

Abstract Background Tafamidis (meglumine 80 mg/free acid 61 mg) is approved to treat transthyretin amyloid cardiomyopathy (ATTR-CM). In the pivotal phase 3 study ATTR-ACT, tafamidis significantly reduced all-cause mortality (ACM) and cardiovascular-related hospitalisations in patients with ATTR-CM (1). Real-world data further extend and support the benefit of long-term tafamidis for improving survival in contemporary patients with ATTR-CM (2). Purpose To further compare survival in a contemporary, real-world, pooled, matched cohort of patients with ATTR-CM treated vs not treated with tafamidis, adjusted for potential prognosticators of treatment effect. Methods Data were pooled from 2 studies. One study included a contemporary cohort of patients with ATTR-CM who received early access to tafamidis in the ATTR-ACT long-term extension (LTE) study but did not participate in the parent study. The other study included a contemporary cohort of patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS; NCT00628745) with predominantly cardiac or mixed phenotype ATTR-CM enrolled between 2019–2023 who received tafamidis throughout the study or never received tafamidis. THAOS was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic gene carriers. Treated patients were pooled from the 2 studies; all received the approved dose of tafamidis. Untreated patients were from THAOS. A propensity score matching procedure was used to match treated and not treated patients 1:1 on 3 significant variables identified from a multivariate logistic regression analysis: baseline age, New York Heart Association (NYHA) class and phenotype (cardiac, mixed); other variables considered were sex, estimated glomerular filtration rate (eGFR), follow-up time and modified body mass index (mBMI). Results In all, 566 patients (283 treated, 283 not treated) were included; 85 treated patients were from the LTE study and 198 were from THAOS. In treated and not treated patients, respectively, median age at enrolment was 78.0 and 78.7 years, and 89.0% and 83.4% were male (Table). The estimated adjusted survival probabilities for ACM for treated vs not treated patients were 78.0% vs 67.9% at 30 months and 70.2% vs 57.9% at 42 months (Figure). The hazard ratio (HR) for time to event for ACM was 0.62 (95% CI 0.41–0.92), favouring tafamidis. Conclusions This matched-cohort analysis showed better survival in a contemporary, real-world cohort of patients with ATTR-CM receiving the approved dose of tafamidis vs those not treated. These findings further extend results of ATTR-ACT to contemporary populations of patients with ATTR-CM treated clinically with tafamidis. These data show greater effectiveness of tafamidis for ATTR-CM in clinical practice than observed in earlier clinical trials, which may reflect earlier diagnosis and treatment in contemporary patients.

Abstract Background The clinical efficacy of tafamidis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) was demonstrated during the phase 3, multinational, randomised, placebo-controlled Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT).(1) In ATTR-ACT, the risk of any cardiovascular (CV)-related hospitalisation was significantly reduced among patients who received tafamidis meglumine 80 mg (the approved dose) vs placebo (relative risk ratio 0.70 [95% CI 0.57, 0.85]; P=0.0005).(2) The benefit of tafamidis treatment was largest among patients with New York Heart Association (NYHA) class I/II vs III symptoms at baseline.(1,3,4) Purpose ATTR-CM is a progressive disease with a natural history that typically includes an increasing frequency of CV-related hospitalisation as the condition worsens. This post hoc analysis adds to current knowledge by evaluating the risk of recurrent (≥1) CV-related hospitalisation by baseline NYHA class in ATTR-ACT patients taking the approved dose of tafamidis or placebo. Methods Patients aged 18 to 90 years with biopsy-confirmed wild-type or variant ATTR-CM and NYHA class I-III symptoms took part in ATTR-ACT between 2013 and 2018. During the trial, the cause of hospitalisation was adjudicated by an independent committee. The hazard ratio (HR) for first CV-related hospitalisation was calculated using a Cox proportional hazards model. The HR for recurrent CV-related hospitalisation was calculated using the Liu-Wei-Yang-Ying (LWYY; also known as the modified Anderson-Gill) model. Models compared tafamidis meglumine 80 mg vs placebo and adjusted for transthyretin genotype (wild-type or variant). In the overall population, the LWYY model was also adjusted for baseline NYHA class. Results The frequency of adjudicated CV-related hospitalisations during ATTR-ACT by NYHA class are shown in the Figure. Across patients who were NYHA class I-III at baseline, the risk of recurrent CV-related hospitalisation was 37% lower in those who received tafamidis vs placebo treatment (HR 0.627 [95% CI 0.463, 0.848]; P=0.0025; Table). Among those who were NYHA class I/II at baseline, a lower proportion of tafamidis- vs placebo-treated patients (44% vs 61%) had ≥1 CV-related hospitalisation. The risks of first and recurrent CV-related hospitalisation were 40% (HR 0.601 [95% CI 0.420, 0.861]; P=0.0055) and 55% (HR 0.449 [95% CI 0.305, 0.661]; P<0.0001) lower with tafamidis vs placebo treatment. Consistent with the survivor bias previously observed in ATTR-ACT,(1-4) the risk of recurrent CV-related hospitalisation was statistically similar in tafamidis- and placebo-treated patients who were NYHA class III at baseline (HR 1.113 [95% CI 0.688, 1.799]; P=0.6624). Conclusions Building on previous findings, this analysis found the risk of recurrent CV-related hospitalisation to be reduced by tafamidis meglumine 80 mg treatment in patients with early stage ATTR-CM.