Key Information
Source
Science Direct
Year
2024
summary/abstract
Key Words
Transthyretin amyloid cardiomyopathy
tafamidis
real-world
survival
Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the extracellular matrix of the heart, leading to progressive heart failure, arrhythmias and conduction-system disease.1external link, opens in a new tab, 2external link, opens in a new tab, 3external link, opens in a new tab ATTR-CM can be caused by pathogenic variants in the TTR gene (hereditary or variant; ATTRv-CM) or the accumulation of wild-type TTR protein (wild-type; ATTRwt-CM).1external link, opens in a new tab Untreated ATTR-CM has a poor prognosis, with median survival estimates between 2 and 6 years.4external link, opens in a new tab
Tafamidis, a selective TTR stabilizer, is the first disease-modifying therapy for patients with ATTR-CM and has regulatory approval in over 50 countries worldwide. The approval was based on positive findings from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) (NCT01994889), a phase-3 study, conducted from 2013–2018, that investigated the efficacy and safety of tafamidis in patients with ATTRv-CM or ATTRwt-CM.5external link, opens in a new tab Patients in ATTR-ACT were randomized 2:1:2 to tafamidis meglumine 80 mg, tafamidis meglumine 20 mg or placebo for 30 months. Primary results showed a reduction in all-cause mortality (hazard ratio 0.70; 95% confidence interval [CI] 0.51–0.96) and a lower rate of cardiovascular-related hospitalizations (relative risk ratio 0.68; 95% CI 0.56–0.81) with tafamidis vs placebo.5external link, opens in a new tab Follow-up analyses of ATTR-ACT, combined with data from its long-term extension study (NCT02791230), found that patients initially treated with tafamidis in ATTR-ACT had substantially better survival rates than those initially treated with placebo after a median follow-up of ∼ 58 months,6external link, opens in a new tab which highlights the importance of early diagnosis and treatment in patients with ATTR-CM.
The Transthyretin Amyloidosis Outcomes Survey (THAOS) (NCT00628745) was a global, longitudinal, observational, phase 4 study open to patients with ATTR amyloidosis (inclusive of ATTR-CM and transthyretin amyloid polyneuropathy [ATTR-PN]) who were treatment-naïve or receiving tafamidis, as well as asymptomatic participants with pathogenic TTR variants. THAOS was completed on June 16, 2023, and remains the largest and longest transthyretin amyloidosis disease registry to date, enrolling 6718 participants across 33 countries over a 16-year period. The objective of this analysis from THAOS was to examine real-world survival in a tafamidis-treated and tafamidis-untreated ATTR-CM population.
Methods
Study Design and Patients
Full details of study design and eligibility criteria of THAOS have been published.7external link, opens in a new tab All THAOS sites received ethical or institutional review board approval before patient enrollment, and each patient provided written informed consent. The study followed the Good Pharmacoepidemiology Practice guidelines and the principles of the Declaration of Helsinki. Individual study sites entered patients’ data into the THAOS database, which is managed by Pfizer.
This analysis included all patients from THAOS with predominantly cardiac phenotypes at enrollment, which was defined as patients with ATTR-CM without signs and symptoms suggestive of associated ATTR amyloidosis-related neuropathy. Full details of the predominantly cardiac phenotype definition are provided in Supplementary Methods. Patients were categorized as tafamidis-treated if they received tafamidis while enrolled in THAOS, or as tafamidis-untreated if they never received tafamidis while enrolled in THAOS. Patients were not receiving any other investigational treatments for ATTR-CM, and data were censored during any period of time when a patient participated in another clinical trial.
Outcomes and Analysis
The tafamidis-untreated set included all available data from patients enrolled in THAOS who never received tafamidis during THAOS. The tafamidis-treated set included: (1) all available data from enrollment to final discontinuation of tafamidis or end of follow-up in THAOS (whichever was earlier) from patients receiving tafamidis at or prior to enrollment; and (2) all available data from first tafamidis dose to final discontinuation of tafamidis or end of follow-up in THAOS (whichever was earlier) from patients who initiated tafamidis after enrollment. Patients who received any dose of tafamidis were included to provide an accurate representation of the real-world experience of this patient population.
Baseline demographic and clinical characteristics are reported as number (percentage) for categorical data and median (10th and 90th percentiles) for continuous data. Clinical characteristics included TTR genotype, New York Heart Association (NYHA) functional class, left ventricular (LV) septum thickness, LV ejection fraction, modified body mass index; calculated by multiplying body mass index by the serum albumin level to compensate for fluid accumulation), past or current clinical trial participation, diagnostic method, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, estimated glomerular filtration rate, troponin I and T concentration, and National Amyloidosis Centre stage.
Survival was analyzed using the Kaplan-Meier method. Kaplan-Meier curves for the tafamidis-treated and tafamidis-untreated sets are presented up to month 42, and overall survival estimates and 2-sided 95% CIs are provided at months 30 and 42. Patients were censored at last follow-up, the last treatment date (for treated patients), the study discontinuation date, or at enrollment in another clinical trial. Sensitivity analyses were conducted to examine survival in patients with a wild-type or variant TTR genotype, in patients enrolled in THAOS before and after 2019, and in patients treated with tafamidis meglumine 80 mg/free acid 61 mg only. After the study was closed, additional information was received from a single study site in the United States that called into question the tafamidis exposure status of 99 untreated patients with predominantly cardiac phenotypes from that site. We were no longer able to verify whether these patients were treated with tafamidis or not, so an additional sensitivity analysis was conducted to exclude these 99 patients from the untreated cohort.
Safety data were collected prospectively from the time patients began tafamidis while enrolled in THAOS or at the time of the patients’ informed consent if the patients were being treated at enrollment. The safety-data collection period continued through the end of the observation period of the study, which must have included ≥ 28 days after the last administration of tafamidis.
The first patient included in this analysis was enrolled on December 20, 2007, and the final data cutoff date was July 24, 2023.
Results
Baseline Characteristics and Treatment
Of 6718 patients enrolled in THAOS, 1441 had a predominantly cardiac phenotype (tafamidis-treated, n = 587; tafamidis-untreated, n = 854) and were included in this analysis (Supplementary Fig. S1). Patients in this analysis were enrolled in 18 countries (Fig. 1external link, opens in a new tab). In tafamidis-treated and tafamidis-untreated patients, respectively, median age at enrollment was 77.7 and 76.4 years, and 91.8% and 90.0% were male (Table 1external link, opens in a new tab). The largest proportion of tafamidis-treated patients (73.4%) enrolled in THAOS between 2019 and 2023, whereas the largest proportion of tafamidis-untreated patients (54.8%) enrolled between 2013 and 2018. The proportion of patients with a variant TTR genotype (8.2% vs 16.2%) and in NYHA class III (21.1% vs 26.9%) was numerically lower in tafamidis-treated vs tafamidis-untreated patients. The most common TTR variant in both groups was V122I (p. V142I); the proportion of patients with the V122I variant was numerically lower in tafamidis-treated vs tafamidis-untreated patients (3.6% vs 8.1%). In patients with available data, the median LV septal thickness was 17.0 mm in both groups, and the median LV ejection fraction was 50.0% in tafamidis-treated patients and 49.0% in tafamidis-untreated patients. Median NT-proBNP levels were lower in the 157 tafamidis-treated patients vs the 487 tafamidis-untreated patients with available data (1883.0 vs 2498.0 pg/mL). The proportions of patients in National Amyloidosis Centre stage I–III were generally similar between groups, although data were missing for a majority of patients (Supplementary Table S1). Median follow-up time was 2.2 years in the treated group and 2.3 years in the untreated group; 11 and 67 patients, respectively, were lost to follow-up.
DOI
https://doi.org/10.1016/j.cardfail.2024.06.003