Tafamidis Tied to 74% Lower Death Risk in Matched Real-World Heart Amyloidosis Cohort

Patients with transthyretin amyloid cardiomyopathy who took the approved dose of tafamidis had markedly better survival than comparable untreated patients in a new matched-cohort analysis published in the journal Cardiology and Therapy. Among 283 treated and 283 propensity-matched untreated patients, estimated adjusted survival at 42 months was 85.3% for those on tafamidis versus 67.5% for those who never received the drug. Treated patients had a 74% lower risk of death from any cause, with a hazard ratio of 0.26 and a 95% confidence interval of 0.13 to 0.51.

Transthyretin amyloid cardiomyopathy, or ATTR-CM, is a progressive and life-threatening disease in which transthyretin amyloid fibrils deposit in the interstitial space of the heart muscle. These fibrils form when the native transthyretin tetramer dissociates into monomers that misfold and aggregate into amyloid. The deposits stiffen the myocardium, causing diastolic dysfunction and increased wall thickness, which lead in turn to arrhythmias, conduction disorders and progressive heart failure. Some patients also develop extracardiac signs and symptoms as amyloid accumulates in other tissues.

The disease comes in two subtypes. Wild-type ATTR-CM arises from age-related destabilization of the normal transthyretin protein, while the variant form results from genetic variants that produce a less stable protein. Left untreated, median survival is approximately five years for wild-type disease and between 2.5 and six years for variant disease, depending on the specific variant involved.

Tafamidis was the first disease-modifying therapy approved for ATTR-CM and remains the only oral transthyretin kinetic stabilizer given once daily. Its approval rested on the phase 3 ATTR-ACT trial, in which pooled doses of 20 mg and 80 mg significantly reduced all-cause mortality compared with placebo, with a hazard ratio of 0.70, and cut the annual rate of cardiovascular-related hospitalizations by roughly a third, with a relative risk ratio of 0.68. In a long-term extension study, an interim analysis with about five years of follow-up showed that patients who received continuous tafamidis 80/61 mg had lower mortality than those who initially received placebo and later switched to the drug.

The new analysis pooled data from two sources: an early access cohort, in which patients with ATTR-CM received tafamidis for up to 60 months before commercial availability, and the Transthyretin Amyloidosis Outcomes Survey, or THAOS, a global observational registry initiated in December 2007 and completed in June 2023. The researchers included THAOS patients enrolled between 2019 and 2023 with a predominantly cardiac or mixed phenotype who either received only the approved tafamidis dose or never received the drug. Of the 283 treated patients, 198 came from THAOS and 85 from the early access cohort; all untreated patients came from THAOS.

Because earlier THAOS analyses could not match patients, baseline differences between treated and untreated groups complicated their interpretation. To address this, the team used nearest-neighbor propensity score matching without replacement on the covariates that significantly predicted treatment status: age, New York Heart Association class and phenotype. A Kolmogorov–Smirnov test yielded a p value of 0.999, indicating that propensity score distributions were well balanced after matching. The resulting groups were closely aligned: mean age at enrollment was 76.9 years in treated patients versus 77.4 years in untreated patients, 89.0% versus 83.4% were male, and 80.9% versus 73.1% had the wild-type form of the disease. Mean follow-up was 1.6 years in both groups.

In total, 38 treated patients, or 13.4%, died during the observation period, compared with 67 untreated patients, or 23.7%. Beyond the headline hazard ratio, the adjusted model revealed other predictors of survival. Patients with variant ATTR-CM had a 78% lower risk of all-cause mortality than those with wild-type disease, and each quartile increase in N-terminal pro-B-type natriuretic peptide, a marker of heart failure severity, was associated with a 2.5-fold increase in mortality risk. Troponin T showed no statistically significant association with all-cause mortality in the adjusted analysis. For cardiovascular-related mortality specifically, treated patients had a 58% lower risk, with a hazard ratio of 0.42.

Unadjusted Kaplan–Meier estimates told a consistent story. At 30 months, survival was 79.4% for treated patients and 70.3% for untreated patients; at 42 months, the corresponding figures were 71.2% and 59.1%. The survival gap appeared across disease severity subgroups defined by National Amyloidosis Centre stage. In stage I, 42-month survival was 93.2% for treated versus 82.7% for untreated patients; in stage II, 84.2% versus 51.6%; and in stage III, 49.9% versus 30.7%. Among patients with wild-type disease alone, 42-month survival was 69.1% for treated versus 56.9% for untreated patients.

Safety findings were reassuring. Overall, 49.5% of treated patients experienced adverse events and 32.9% had serious adverse events, rates the authors described as consistent with expectations for this patient population. Only 3.5% of patients discontinued treatment, permanently or temporarily, because of adverse events, and no new safety signals were identified.

The authors acknowledged important limitations. The observational design introduces possible selection and ascertainment bias, since physicians decided which patients entered the registry. Clinical data such as natriuretic peptide levels and disease stage were missing for a substantial proportion of patients, the cohorts were not balanced on disease stage, and treated patients were more likely to receive concomitant heart failure medications, which may have contributed to better outcomes. There is also potential for immortal time bias, because treated patients had to survive long enough to start therapy. Early access patients were assumed to have the cardiac phenotype without formal assessment, and matching did not include transthyretin genotype, though genotype was adjusted for in the mortality model. Even so, the authors conclude that these findings extend the results of ATTR-ACT to contemporary clinical populations and reinforce earlier real-world evidence supporting tafamidis use in routine practice.

Subject of Research: Survival outcomes with tafamidis treatment versus no treatment in matched real-world patients with transthyretin amyloid cardiomyopathy

Article Title: Survival in a Contemporary, Real-World, Matched Cohort of Patients with Transthyretin Amyloid Cardiomyopathy Treated vs Not Treated with Tafamidis

Article References: aus dem Siepen, F., Dispenzieri, A., Hanna, M., Carlsson, M., & Garcia-Pavia, P. (2026). Survival in a Contemporary, Real-World, Matched Cohort of Patients with Transthyretin Amyloid Cardiomyopathy Treated vs Not Treated with Tafamidis. Cardiology and Therapy, 15(S1), 49-60. https://doi.org/10.1007/s40119-026-00464-6

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00464-6

Keywords: tafamidis, transthyretin amyloid cardiomyopathy, ATTR-CM, THAOS registry, propensity score matching, all-cause mortality, cardiovascular mortality, real-world evidence, heart failure, amyloidosis, survival analysis, drug safety