Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.
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ABSTRACT: Aims
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.Methods and results
In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.Conclusion
Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose.Clinical trial registration
ClinicalTrials.gov NCT01994889; NCT02791230.
SUBMITTER: Damy T
PROVIDER: S-EPMC8048553 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimThe Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed that tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to estimate the impact of tafamidis on survival and quality-adjusted life-years (QALYs).Methods and resultsA multi-state, cohort, Markov model was developed to simulate the disease course of ATTR-CM throughout a lifetime. For survival extrapolation, survival curves were fitted by treatment arm and New York Heart Association (NYHA) Class I/II (68% of patients) and NYHA Class III (32% of patients) cohorts using the individual patient-level data from both the ATTR-ACT and the corresponding long-term extension study. Univariate and multivariate sensitivity analyses were conducted. The predicted mean survival for the total population (NYHA Class I/II + III) was 6.73 years for tafamidis and 2.85 years for the standard of care (SoC), resulting in an incremental mean survival of 3.88 years [95% confidence interval (CI) 1.32-5.66]. Of the 6.73 life-years, patients on tafamidis spend, on average, 4.82 years in NYHA Class I/II, while patients on SoC spend an average of 1.60 life-years in these classes. The combination of longer survival in lower NYHA classes produced a QALY gain of 5.39 for tafamidis and 2.11 for SoC, resulting in 3.29 incremental QALYs (95% CI 1.21-4.74) in favour of tafamidis.ConclusionBased on the disease simulation model results, tafamidis is expected to more than double the life expectancy and QALYs of ATTR-CM patients compared to SoC. Longer-term follow-up data from the ATTR-ACT extension study will further inform these findings.Clinical trials.gov identifierNCT01994889 (date of registration: 26 November 2013).
| S-EPMC9382662 | biostudies-literature
Project description:ImportanceTafamidis has been shown to improve survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo. However, its effect on cardiac function has not been fully characterized.ObjectiveTo examine the effect of tafamidis on cardiac function in patients with ATTR-CM.Design, setting, and participantsThis was an exploratory, post hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, international, double-blind, placebo-controlled phase 3 randomized clinical trial conducted from December 2013 to February 2018. The ATTR-ACT included 48 sites in 13 counties and enrolled patients aged 18 to 90 years with ATTR-CM. Data were analyzed from July 2018 to September 2023.InterventionPatients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months.Main outcomes and measuresPatients were categorized based on left ventricular (LV) ejection fraction at enrollment as having heart failure with preserved ejection fraction (≥50%), mildly reduced ejection fraction (41% to 49%), or reduced ejection fraction (≤40%). Changes from baseline to month 30 in LV ejection fraction, LV stroke volume, LV global longitudinal strain, and the ratio of early mitral inflow velocity to septal and lateral early diastolic mitral annular velocity (E/e') were compared in patients receiving tafamidis, 80 mg, vs placebo.ResultsA total of 441 patients were randomized in ATTR-ACT, and 436 patients had available echocardiographic data. Of 436 included patients, 393 (90.1%) were male, and the mean (SD) age was 74 (7) years. A total of 220 (50.5%), 119 (27.3%), and 97 (22.2%) had heart failure with preserved, mildly reduced, and reduced LV ejection fraction, respectively. Over 30 months, there was less pronounced worsening in 4 of the echocardiographic measures in patients receiving tafamidis, 80 mg (n = 176), vs placebo (n = 177) (least squares mean difference: LV stroke volume, 7.02 mL; 95% CI, 2.55-11.49; P = .002; LV global longitudinal strain, -1.02%; 95% CI, -1.73 to -0.31; P = .005; septal E/e', -3.11; 95% CI, -5.50 to -0.72; P = .01; lateral E/e', -2.35; 95% CI, -4.01 to -0.69; P = .006).Conclusions and relevanceCompared with placebo, tafamidis, 80 mg, attenuated the decline of LV systolic and diastolic function over 30 months in patients with ATTR-CM. Approximately half of patients had mildly reduced or reduced LV ejection fraction at enrollment, suggesting that ATTR-CM should be considered as a possible diagnosis in patients with heart failure regardless of underlying LV ejection fraction.Trial registrationClinicalTrials.gov Identifier: NCT01994889.
| S-EPMC10652219 | biostudies-literature
Project description:AimsTransthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disorder that remains underdiagnosed. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) was the first large clinical trial to include both wild-type (ATTRwt) and hereditary (ATTRv) patients. A description of the natural history of ATTR-CM, utilizing data from placebo-treated patients in ATTR-ACT, will provide a greater understanding of presentation and progression of ATTR-CM and may aid in disease awareness, earlier diagnosis and treatment monitoring.Methods and resultsChanges in clinical endpoints (mortality, cardiovascular [CV]-related hospitalizations, 6-min walk test [6MWT] distance and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) from baseline to Month 30 in the 177 patients (134 ATTRwt, 43 ATTRv) who received placebo in ATTR-ACT were assessed. ATTRwt patients tended to have less severe disease at baseline. Over the duration of ATTR-ACT, there were 76 (42.9%) all-cause deaths, and 107 (60.5%) patients had a CV-related hospitalization. There was a lower proportion of all-cause deaths in ATTRwt (49, 36.6%) than ATTRv (27, 62.8%). There was a similar, steady decline in mean (SD) 6MWT distance from baseline to Month 30 in ATTRwt (93.9 [93.7] m) and ATTRv (89.1 [107.2] m) patients. The decline in mean (SD) KCCQ-OS score was less severe in ATTRwt (13.8 [20.7]) than ATTRv (21.0 [26.4]) patients.ConclusionsPatients with ATTR-CM experience a severe, progressive disease. In ATTR-ACT, placebo-treated patients with ATTRv, compared with ATTRwt, had more severe disease at baseline, and their disease progressed more rapidly as shown by mortality, hospitalizations and quality of life over time.
| S-EPMC8497209 | biostudies-literature
Project description:BackgroundTafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).MethodsPatients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE.ResultsMedian follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06).ConclusionsIn the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.
| S-EPMC8763250 | biostudies-literature
Project description:In May 2019, the U.S. Food and Drug Administration approved tafamidis as the first conservative management of transthyretin amyloid cardiomyopathy (ATTR-CM). Our aim in conducting this systematic review and meta-analysis was to assess the efficacy of tafamidis on patients with ATTR-CM. For that purpose, we thoroughly searched PubMed, ScienceDirect, and Clinical trails.gov by using the appropriate search strategy and following predefined inclusion and exclusion criteria, which retrieved 235 articles initially. Of which two randomized controlled trials (RCTs) and one observational study matched our inclusion criteria. A total of 876 patients are included in this analysis. Based on results, tafamidis significantly reduced cardiovascular (CV) mortality in the ATTR-ACT trial and Ochi et al. (OR 0.58; 95% CI: [0.41-0.83], P=0.003, I 2=87%). A subgroup analysis was conducted for CV mortality due to heart failure (OR 0.89; 95% CI: [0.63-1.25], P=0.50, I 2=93%). The results exhibit that tafamidis reduced all causes of mortality (OR 0.45; 95% CI: [0.32-0.64], P≤0.00001, I 2=22%). Furthermore, mortality remained statistically insignificant in patients with heart transplants (OR 1.18; 95% CI: [0.52-2.70], P=0.70, I 2=0%) and patients with cardiac mechanical assist devices (OR 4.15; 95% CI: [0.48-35.66], P=0.20, I 2=0%). This meta-analysis suggests that tafamidis is a safe and efficient drug to use in patients with ATTR-CM and can possess the potential to be a milestone in enhancing the conservative management of the patients.
| S-EPMC10783421 | biostudies-literature
Project description:IntroductionIn the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT; ClinicalTrials.gov number NCT01994889), tafamidis reduced the risk of all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) by 30% versus placebo. Median overall survival was not achieved in either treatment arm (57.1 and 70.5% of patients in the placebo and tafamidis groups, respectively, survived at 30 months), limiting assessment of the potential survival benefits of treatment.MethodsA survival extrapolation analysis was conducted following technical support guidelines from the National Institute for Health and Care Excellence. Multiple models (i.e., exponential, Weibull, gamma, log-logistic, log-normal, Gompertz, generalized gamma, and generalized F) were applied to systematically fit different candidate curves to existing patient-level data from the 30-month treatment period in ATTR-ACT. The relative goodness-of-fit for each candidate curve was then tested by Akaike's and Bayesian information criteria to select a single model that was fitted to the placebo and pooled tafamidis treatment arms.ResultsA gamma distribution was selected as best fitting model and fitted to both treatment arms. The resulting estimated median overall survival was 35.16 months for placebo and 52.64 months for tafamidis (difference 17.48 months).ConclusionsThis extrapolation of survival data from ATTR-ACT further supports the efficacy of tafamidis in patients with ATTR-CM. Owing to the limitations of this analysis, these survival estimates should be interpreted with caution; however, they are consistent with recently presented findings from a combined analysis of data from ATTR-ACT and interim data from an ongoing long-term extension study (median follow-up 36 months; ClinicalTrials.gov number NCT02791230).Trial registrationClinicalTrials.gov: NCT01994889.
| S-EPMC7584686 | biostudies-literature
Project description:BackgroundIn patients with transthyretin amyloid cardiomyopathy, tafamidis reduces all-cause mortality and cardiovascular hospitalizations and slows decline in quality of life compared with placebo. In May 2019, tafamidis received expedited approval from the US Food and Drug Administration as a breakthrough drug for a rare disease. However, at $225 000 per year, it is the most expensive cardiovascular drug ever launched in the United States, and its long-term cost-effectiveness and budget impact are uncertain. We therefore aimed to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending.MethodsWe developed a Markov model of patients with wild-type or variant transthyretin amyloid cardiomyopathy and heart failure (mean age, 74.5 years) using inputs from the ATTR-ACT trial (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. We compared no disease-specific treatment ("usual care") with tafamidis therapy. The model reproduced 30-month survival, quality of life, and cardiovascular hospitalization rates observed in ATTR-ACT; future projections used a parametric survival model in the control arm, with constant hazards reduction in the tafamidis arm. We discounted future costs and quality-adjusted life-years by 3% annually and examined key parameter uncertainty using deterministic and probabilistic sensitivity analyses. The main outcomes were lifetime incremental cost-effectiveness ratio and annual budget impact, assessed from the US healthcare sector perspective. This study was independent of the ATTR-ACT trial sponsor.ResultsCompared with usual care, tafamidis was projected to add 1.29 (95% uncertainty interval, 0.47-1.75) quality-adjusted life-years at an incremental cost of $1 135 000 (872 000-1 377 000), resulting in an incremental cost-effectiveness ratio of $880 000 (697 000-1 564 000) per quality-adjusted life-year gained. Assuming a threshold of $100 000 per quality-adjusted life-year gained and current drug price, tafamidis was cost-effective in 0% of 10 000 probabilistic simulations. A 92.6% price reduction from $225 000 to $16 563 would be necessary to make tafamidis cost-effective at $100 000/quality-adjusted life-year. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with transthyretin amyloid cardiomyopathy in the United States with tafamidis (n=120 000) was estimated to increase annual healthcare spending by $32.3 billion.ConclusionsTreatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. On the basis of recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.
| S-EPMC7156331 | biostudies-literature
Project description:BackgroundTransthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic stabilizer of TTR that inhibits misfolding and amyloid formation.MethodsIn this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis.ResultsPatients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients (P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification (P = .0262).ConclusionsThese results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation.Trial registrationClinicalTrials.gov, NCT00694161.
| S-EPMC5606341 | biostudies-literature
Project description:AimsTafamidis treatment positively affects left ventricular (LV) structure and function and improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). We aimed to investigate the relationship between treatment response and cardiac amyloid burden identified by serial quantitative 99mTc-DPD SPECT/CT. We furthermore aimed to identify nuclear imaging biomarkers that could be used to quantify and monitor response to tafamidis therapy.Methods and resultsForty wild-type ATTR-CM patients who underwent 99mTc-DPD scintigraphy and SPECT/CT imaging at baseline and after treatment with tafamidis 61 mg once daily [median, 9.0 months (interquartile range 7.0-10.0)] were divided into two cohorts based on the median (-32.3%) of the longitudinal percent change in standardized uptake value (SUV) retention index. ATTR-CM patients with a reduction greater than or equal to the median (n = 20) had a significant decrease in SUV retention index (P < 0.001) at follow-up, which translated into significant benefits in serum N-terminal prohormone of brain natriuretic peptide levels (P = 0.006), left atrial volume index (P = 0.038), as well as LV [LV global longitudinal strain: P = 0.028, LV ejection fraction (EF): P = 0.027, LV cardiac index (CI): P = 0.034] and right ventricular (RV) [RVEF: P = 0.025, RVCI: P = 0.048] functions compared with patients with a decrease less than the median (n = 20).ConclusionTreatment with tafamidis in ATTR-CM patients results in a significant reduction in SUV retention index, associated with significant benefits for LV and RV function and cardiac biomarkers. Serial quantitative 99mTc-DPD SPECT/CT imaging with SUV may be a valid tool to quantify and monitor response to tafamidis treatment in affected patients.Translational perspective99mTc-DPD SPECT/CT imaging with determination of SUV retention index as part of a routine annual examination can provide evidence of treatment response in ATTR-CM patients receiving disease-modifying therapy. Further long-term studies with 99mTc-DPD SPECT/CT imaging may help to evaluate the relationship between tafamidis-induced reduction in SUV retention index and outcome in patients with ATTR-CM and will demonstrate whether highly disease-specific 99mTc-DPD SPECT/CT imaging is more sensitive than routine diagnostic monitoring.
| S-EPMC10364619 | biostudies-literature
Project description:BackgroundPatients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience infiltrative cardiomyopathy and heart failure symptoms requiring costly hospitalizations. The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the efficacy of tafamidis on the frequency of cardiovascular (CV)-related hospitalizations in patients with ATTR-CM.PurposeAs length of stay can affect the total hospitalization burden, our study aimed to better understand the impact of tafamidis on the number of CV-related hospital days avoided in the management of ATTR-CM patients.MethodsData from ATTR-ACT were used to calculate the total burden of CV-related hospitalization (days) by treatment arm in this post hoc analysis.ResultsIn the total trial population, patients receiving tafamidis had significantly fewer CV-related hospitalizations per year (relative risk reduction [RRR] 0.68; 0.4750 vs. 0.7025, p < 0.0001) and a shorter mean length of stay per CV-related hospitalization event (8.6250 vs. 9.5625 days) than patients receiving placebo. Taken together, tafamidis prevented 2.62 CV-related hospitalization days per patient per year. A subgroup analysis showed that with earlier treatment initiation of tafamidis, the annual number of CV-related hospitalizations was significantly lowered by 52% compared with placebo (RRR 0.48; 0.3378 vs. 0.7091, p < 0.0001). With 1.14 fewer days per hospitalization, tafamidis reduced the annual number of CV-related hospitalization days by 3.96 days per New York Heart Association class I/II patient.ConclusionsIn patients with ATTR-CM, tafamidis was associated with a lower rate of CV-related hospitalizations and shorter length of hospital stay. Timely diagnosis and treatment with tafamidis could further decrease the total number of CV-related hospitalization days per year.ClinicaltrialsGov identifierNCT01994889.
| S-EPMC9270297 | biostudies-literature