Real-World Data Suggest Acoramidis Outperforms Tafamidis in Heart Amyloidosis

Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) who started treatment with the newer drug acoramidis experienced fewer signs of worsening heart failure than comparable patients who started the older drug tafamidis, according to a retrospective analysis of United States insurance claims published in the journal Cardiology and Therapy. The study, which the authors describe as the first real-world head-to-head comparison of the two approved TTR stabilizers, found a 43 percent lower hazard of diuretic intensification and a 34 percent lower hazard of a composite endpoint combining diuretic intensification, heart failure-related hospitalization, and death among acoramidis users.

The disease typically announces itself through congestion that requires diuretic treatment, and it often advances to heart failure-related hospitalization, which in turn raises the risk of death. Because outpatient intensification of diuretic therapy is associated with increased mortality, clinicians view it as an early marker of disease progression, and monitoring oral loop diuretic use every twelve months is a recommended way to track whether the disease is moving in the wrong direction.

Two drugs are approved to treat the condition by stabilizing transthyretin and preventing it from misfolding. Tafamidis received approval in 2019 and stood as the only available therapy for ATTR-CM until acoramidis was approved in November 2024. Acoramidis achieves near-complete stabilization of the protein, at ninety percent or more. In placebo-controlled trials, both stabilizers reduced mortality and cardiovascular-related hospitalization compared with placebo. What has been missing is any randomized head-to-head trial directly comparing the two agents, leaving clinicians without direct evidence on which to base treatment choices for newly diagnosed patients.

To fill that gap, a research team led by Richard Wright, with co-authors including Trejeeve Martyn, Allison Keshishian, David Lanfear, and senior author Daniel P. Judge, turned to real-world data. They analyzed the Komodo Healthcare Map, a national United States claims database, with acoramidis prescription records tokenized through Claritas, a data aggregator that consolidates prescription information between specialty pharmacies and the drug manufacturer’s hub. Because the data were deidentified and the study complied with the Health Insurance Portability and Accountability Act, patient consent and institutional review board approval were not required. The analysis followed International Society for Pharmacoeconomics and Outcomes Research guidelines for comparative effectiveness research, with a prespecified statistical analysis plan covering eligibility criteria, potential biases, outcome measures, and the handling of missing data.

The study population consisted of adults aged eighteen or older who newly initiated either acoramidis or tafamidis between December 11, 2024, and April 30, 2025, with at least one prescription claim defining the index date. Patients needed at least six months of continuous enrollment before that date and were excluded if they had multiple myeloma, light chain amyloidosis, or hematopoietic stem cell treatment, if they had previously received tafamidis, acoramidis, or a TTR silencer, or if they had more than one ATTR-CM treatment on the index date. Follow-up continued until disenrollment, death, treatment switch, or the study end date of July 31, 2025. In total, 175 patients newly treated with acoramidis and 697 newly treated with tafamidis met all inclusion and exclusion criteria.

Because patients were not randomized, the investigators used propensity score weighting to balance the two groups on demographics, disease severity, comorbidity burden, and baseline medication use, including loop diuretics. A logistic regression model estimated each patient’s probability of receiving acoramidis conditional on the prespecified covariates, and adequate balance was defined in advance as absolute standardized mean differences below 0.1 for all covariates. After weighting, the acoramidis group comprised 170 patients and the weighted tafamidis group comprised 448, and the two groups were comparable at baseline. Mean follow-up was 139 days for acoramidis patients and 143 days for tafamidis patients. During follow-up, 4.6 percent of acoramidis patients and 7.7 percent of tafamidis patients switched treatments and were censored at that point.

The primary outcome was diuretic intensification, defined as initiation or dose-equivalent escalation of oral loop diuretics, use of parenteral loop diuretics, or the addition of a thiazide-type diuretic. The secondary outcome was a composite of diuretic intensification, heart failure-related hospitalization, defined as an inpatient admission with a heart failure-related ICD-10-CM diagnosis code in any position, and mortality. A subanalysis focused on oral loop diuretic intensification alone. Time-to-event outcomes were assessed with weighted Cox proportional hazards models using robust sandwich standard errors, with tafamidis as the reference group. The proportional hazards assumption was tested with scaled Schoenfeld residuals and graphical diagnostics, and Kaplan-Meier estimates were used to chart cumulative incidence.

The results showed that cumulative incidence curves for the first event of diuretic intensification, for the composite endpoint, and for oral loop diuretic intensification separated within weeks of treatment initiation and remained divergent over the observation period. Acoramidis was associated with significantly reduced diuretic intensification events, occurring in 11.8 percent of acoramidis patients versus 20.5 percent of tafamidis patients, a hazard ratio of 0.57 with a 95 percent confidence interval of 0.35 to 0.92 and a p value of 0.021. Composite events occurred in 17.6 percent versus 26.4 percent, a hazard ratio of 0.66 with a 95 percent confidence interval of 0.44 to 0.99 and a p value of 0.046. Oral loop diuretic intensification occurred in 10.0 percent versus 18.9 percent, a hazard ratio of 0.52 with a 95 percent confidence interval of 0.31 to 0.87 and a p value of 0.014. Results in the weighted population were consistent with those in the unweighted population.

Not every component of the composite reached statistical significance on its own. The proportion of patients experiencing heart failure-related hospitalization was 10.6 percent with acoramidis versus 12.3 percent with tafamidis, a hazard ratio of 0.90 with a 95 percent confidence interval of 0.53 to 1.55 and a p value of 0.71. Mortality occurred in 1.2 percent versus 2.3 percent, a hazard ratio of 0.52 with a 95 percent confidence interval of 0.11 to 2.42 and a p value of 0.41. To probe for residual confounding, the researchers examined falsification outcomes, namely any fracture, pneumonia, and urinary tract infection, all of which were nonsignificant, and they calculated E-values of 2.31 for the diuretic intensification result and 2.00 for the composite result to gauge how strong an unmeasured confounder would need to be to explain away the findings.

The authors caution that the study has meaningful limitations. Claims data lack clinical information such as frailty, New York Heart Association class, extent of fibrosis, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, troponin, echocardiogram parameters, genotype, and the reason a particular drug was prescribed. Cardiac events were not adjudicated, follow-up was limited to a maximum of roughly eight months because acoramidis was approved only on November 22, 2024, and censoring due to treatment switching may have introduced informative censoring bias. The authors argue that any such bias would have favored tafamidis, since a higher proportion of tafamidis patients were censored after switching, likely reflecting clinical instability, which would enrich the tafamidis group with more stable patients and yield a more conservative estimate of acoramidis’s effect. They also note that the dataset included higher proportions of under-represented populations, notably Black and female patients, than most ATTR-CM trials, and that before weighting more tafamidis patients had longer-standing diagnoses without treatment, a difference balanced by including year of diagnosis as a covariate. The team concludes that the findings may inform treatment selection for newly diagnosed patients and potentially support switching from tafamidis to acoramidis, while emphasizing that further evaluation with longer follow-up, larger cohorts, and prospective clinical outcomes is warranted.

Subject of Research: Real-world comparative effectiveness of the TTR stabilizers acoramidis and tafamidis in newly treated transthyretin amyloid cardiomyopathy

Article Title: Comparative Effectiveness of TTR Stabilizers for the Treatment of ATTR-CM Using Real-World Evidence

Article References: Wright, R., Martyn, T., Keshishian, A., Nagelhout, E., Zeldow, B., Udall, M., Lanfear, D., & Judge, D. P. (2026). Comparative Effectiveness of TTR Stabilizers for the Treatment of ATTR-CM Using Real-World Evidence. Cardiology and Therapy. https://doi.org/10.1007/s40119-026-00476-2

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00476-2

Keywords: ATTR-CM, acoramidis, tafamidis, TTR stabilizers, diuretic intensification, heart failure hospitalization, real-world evidence, comparative effectiveness, propensity score weighting, claims data, transthyretin amyloidosis, cardiology