Effect of Tafamidis on Renal Function in Patients With Transthyretin Amyloid Cardiomyopathy in ATTR-ACT.

Background: Chronic kidney disease (CKD) is common among patients with amyloid cardiomyopathy. Tafamidis was approved for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) based on findings from ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy). Objectives: This post hoc analysis evaluated changes in renal function among patients with ATTR-CM in ATTR-ACT. Methods: Patients were randomized to receive tafamidis (20 mg and 80 mg pooled) or placebo for 30 months. The change from baseline in the estimated glomerular filtration rate (eGFR) was compared over time. A composite endpoint of all-cause death, dialysis, kidney transplant, or ≥30% decline in eGFR from baseline was analyzed based on the time to first event. Results: The mean baseline eGFR was 57.5 ± 17.3 and 55.6 ± 16.8 mL/min/1.73 m2 in the tafamidis (n = 264) and placebo (n = 177) groups, respectively. At 30 months, patients treated with tafamidis had a significantly smaller decline in eGFR compared with placebo (least squares mean difference = 3.99 mL/min/1.73 m2; 95% CI: 1.31-6.68; P = 0.004). In patients who completed ATTR-ACT, improvement in CKD staging was more common with tafamidis vs placebo treatment (17.7% vs 7.2%; OR: 2.75; 95% CI: 1.10-6.90; P = 0.034). A lower proportion of tafamidis-treated patients reached the composite renal endpoint (crude rates 34.5% vs 44.1%; HR: 0.73, 95% CI: 0.54-0.99; P = 0.040). Conclusions: Renal function deteriorates over time in patients with ATTR-CM, and tafamidis treatment was associated with a reduction in this deterioration, and a higher incidence of improved eGFR and CKD staging over 30 months compared with placebo. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT] NCT01994889).

Effect of long-term tafamidis treatment on health-related quality of life in patients with transthyretin amyloid cardiomyopathy.

AIMS: To evaluate the effect of long-term tafamidis treatment on health-related quality of life (HRQoL) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension (LTE) study. METHODS AND RESULTS: We examined change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) and clinical summary (KCCQ-CS) scores in patients who received tafamidis meglumine 80 mg for 30 months in ATTR-ACT and tafamidis (meglumine 80 mg or bioequivalent free acid 61 mg) for 30 months in the LTE study, and in patients who received placebo for 30 months in ATTR-ACT and tafamidis for 30 months in the LTE study. In ATTR-ACT, 176 and 177 patients were randomized to tafamidis 80 mg and placebo, respectively. Patients who continuously received tafamidis had a 6- to 7-point reduction in least squares (LS) mean (standard error) KCCQ-OS and KCCQ-CS scores at month 30 (-6.25 [1.53] and -7.48 [1.39]), with little or no further decline over the next 30 months (-5.92 [1.77] and -9.21 [1.88] at month 60). Patients who received placebo in ATTR-ACT had a 20-point reduction in LS mean KCCQ-OS and KCCQ-CS scores at month 30 (-19.60 [1.94] and -19.90 [2.01]), but the decline slowed after initiating tafamidis (-24.70 [3.04] and -25.30 [3.36] at month 60). CONCLUSION: Tafamidis reduced HRQoL decline in patients with ATTR-CM. Patients continuously treated with tafamidis for 60 months demonstrated stabilized HRQoL. In patients who initially received placebo in ATTR-ACT, tafamidis reduced the decline in HRQoL during the LTE study.

Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial.

Importance: Tafamidis 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. Objective: To examine the effect of tafamidis on cardiac function in patients with ATTR-CM. Design, Setting, and Participants: This 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. Intervention: Patients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months. Main Outcomes and Measures: Patients 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. Results: A 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 Relevance: Compared 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 Registration: ClinicalTrials.gov Identifier: NCT01994889.

Tafamidis Efficacy Among Octogenarian Patients in the Phase 3 ATTR-ACT and Ongoing Long-Term Extension Study.

BACKGROUND: Tafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). OBJECTIVES: This study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients. METHODS: Analysis of patients aged <80 and ≥80 years in ATTR-ACT and its ongoing open-label long-term extension (LTE) study, where all patients receive tafamidis. RESULTS: After 30 months in ATTR-ACT, least squares (LS) mean change from baseline in 6-minute walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score were smaller (all P < 0.05) in patients aged ≥80 years treated with tafamidis (n = 51) vs placebo (n = 37). At the LTE study interim analysis, patients aged ≥80 years treated continuously with tafamidis had a smaller decline in KCCQ-OS score (P < 0.05) and trended toward longer median survival (45 vs 27 months; all-cause mortality HR: 0.6828 [95% CI: 0.4048-1.1517]; P = 0.1526) than those initially treated with placebo in ATTR-ACT. Similar efficacy was observed in patients aged <80 years in ATTR-ACT, including smaller LS mean change from baseline in 6MWT distance, NT-proBNP concentration, and KCCQ-OS score, and lower rate of cardiovascular-related hospitalizations with tafamidis (n = 125) vs placebo (n = 140). In the LTE study, patients aged <80 years treated continuously with tafamidis had a longer median survival (80 vs 41 months; HR = 0.4513 [95% CI: 0.3176-0.6413]; P < 0.0001) and a smaller decline in KCCQ-OS score than those initially treated with placebo. CONCLUSIONS: The findings demonstrate tafamidis efficacy for patients with ATTR-CM both in those aged <80 and those aged ≥80 years. (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]; NCT01994889/Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy; NCT02791230).

Improved long-term survival with tafamidis treatment in patients with transthyretin amyloid cardiomyopathy and severe heart failure symptoms.

AIM: The value of disease-modifying therapies (such as tafamidis) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and severe heart failure symptoms has been debated. This study assessed long-term all-cause survival in patients with New York Heart Association (NYHA) class III symptoms in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) long-term extension (LTE) study. METHODS AND RESULTS: At the baseline of ATTR-ACT, 55/176 (31.3%) patients receiving tafamidis 80 mg and 63/177 (35.6%) receiving placebo had NYHA class III symptoms. After 30 months of treatment, patients could join an ongoing LTE study to receive open-label tafamidis. In an interim analysis of the LTE study (August 2021), all-cause mortality was lower among patients with NYHA class III symptoms who received continuous tafamidis in ATTR-ACT and the LTE study (hazard ratio 0.64; 95% confidence interval 0.41-0.99; median follow-up: 60 months), as compared with those who received placebo in ATTR-ACT and tafamidis in the LTE study (median follow-up: 56 months). Similar findings were observed in patients with NYHA class I/II symptoms at baseline (0.50; 0.35-0.73; tafamidis 80 mg n = 121; placebo n = 114; median follow-up of 61 and 60 months, respectively). CONCLUSION: We observed reduced all-cause mortality with continuous tafamidis treatment compared with delayed tafamidis treatment (placebo then tafamidis) in patients with NYHA class III symptoms at baseline over a median follow-up of ∼5 years. These findings demonstrate the value of tafamidis treatment in patients with ATTR-CM and severe heart failure symptoms, and emphasize the importance of early treatment. CLINICAL TRIAL REGISTRATIONS: ClinicalTrials.gov NCT01994889 and NCT02791230.

Long-term survival in people with transthyretin amyloid cardiomyopathy who took tafamidis: A Plain Language Summary.

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. WHAT DID RESEARCHERS FIND OUT?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. WHAT DO THE RESULTS MEAN?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration: NCT02791230 (ClinicalTrials.gov).

How did transthyretin amyloid cardiomyopathy progress in patients who took placebo in the study ATTR-ACT? A plain language summary.

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations). IMPORTANT INFORMATION ABOUT ATTR-ACT: In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo. WHAT ELSE DID RESEARCHERS FIND OUT IN ATTR-ACT?: As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time. WHY ARE THESE RESULTS IMPORTANT?: By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889.

Tafamidis and quality of life in people with transthyretin amyloid cardiomyopathy in the study ATTR-ACT: A plain language summary.

This plain language summary describes the results of a study called ATTR-ACT, which was published in the American Journal of Cardiology. In ATTR-ACT, researchers looked at the effects of tafamidis treatment in people with transthyretin amyloid cardiomyopathy (called ATTR-CM for short). Tafamidis is currently available in the USA and other countries as an oral treatment for adults with ATTR-CM. In ATTR-ACT, 441 people with ATTR-CM from 13 different countries took either tafamidis or placebo by mouth for 30 months. First, researchers looked at the effects of tafamidis on the risk of death and hospitalization due to heart problems between the start and the end of the study; they found that these risks were about one-third lower with tafamidis compared with placebo. As described in this summary, researchers also looked at the effects of tafamidis on people's heart failure symptoms, quality of life, and general health over the 30-month study. People who took part in ATTR-ACT rated these effects using questionnaires filled out before, during, and after the study. More people who took tafamidis saw improvement or no change in their heart failure symptoms and quality of life than people who took placebo. In addition, compared with people taking placebo, people taking tafamidis had less worsening of their general health during the study. These results show the benefits of tafamidis in reducing the declines in quality of life and health that often occur with this debilitating disease. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov).

Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Tafamidis 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). METHODS: Patients 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. RESULTS: Median 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). CONCLUSIONS: In 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.

Natural history and progression of transthyretin amyloid cardiomyopathy: insights from ATTR-ACT.

AIMS: Transthyretin 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 RESULTS: Changes 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. CONCLUSIONS: Patients 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.

Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]).

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.

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.

Efficacy of Tafamidis in Patients With Hereditary and Wild-Type Transthyretin Amyloid Cardiomyopathy: Further Analyses From ATTR-ACT.

OBJECTIVES: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between variant transthyretin amyloidosis (ATTRv) and wild-type transthyretin (ATTRwt). BACKGROUND: ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt. METHODS: In pre-specified analyses from ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), baseline characteristics, all-cause mortality, and change from baseline to month 30 in 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary score were compared in patients with ATTRwt and ATTRv. RESULTS: There were 335 patients with ATTRwt (201 tafamidis, 134 placebo) and 106 with ATTRv (63 tafamidis, 43 placebo) enrolled in ATTR-ACT. Patients with ATTRwt (vs. ATTRv) had less advanced disease at baseline and a lower rate of disease progression over the study. The reduction in all-cause mortality with tafamidis compared with placebo was not different between ATTRwt (hazard ratio: 0.706 [95% confidence interval (CI): 0.474 to 1.052]; p = 0.0875) and ATTRv (hazard ratio: 0.690 [95% CI: 0.408 to 1.167]; p = 0.1667). Tafamidis was associated with a similar reduction (vs. placebo) in the decline in 6-min walk test distance in ATTRwt (mean ± SE difference from placebo, 77.14 ± 10.78; p < 0.0001) and ATTRv (79.61 ± 29.83 m; p = 0.008); and Kansas City Cardiomyopathy Questionnaire Overall Summary score in ATTRwt (12.72 ± 2.10; p < 0.0001) and ATTRv (18.18 ± 7.75; p = 0.019). CONCLUSIONS: Pre-specified analyses from ATTR-ACT confirm the poor prognosis of untreated ATTRv-related cardiomyopathy compared with ATTRwt, but show the reduction in mortality and functional decline with tafamidis treatment is similar in both disease subtypes. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889).

Impact of Tafamidis on Health-Related Quality of Life in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease; further analysis of patient-reported quality of life will provide additional data on the efficacy of tafamidis. In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, 441 adult patients with ATTR-CM were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (80 mg and 20 mg) compared with placebo. Change in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) domain scores, EQ-5D-3L scores, and patient global assessment, were prespecified exploratory end points. A greater proportion of patients improved KCCQ-OS score at month 30 with tafamidis (41.8%) versus placebo (21.4%). Tafamidis significantly reduced the decline in all 4 KCCQ-OS domains (p <0.0001 for all), and in EQ-5D-3L utility (0.09 [confidence interval 0.05 to 0.12]; p <0.0001) and EQ visual analog scale (9.11 [confidence interval 5.39 to 12.83]; p <0.0001) scores at month 30 versus placebo. A larger proportion of tafamidis-treated patients reported their patient global assessment improved at month 30 (42.3% vs 23.8% with placebo). In conclusion, tafamidis effectively reduced the decline in patient-reported outcomes, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.

A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy.

Background: Tafamidis is approved in over 40 countries to delay neurologic progression in patients with transthyretin amyloid polyneuropathy (ATTR-PN). A comprehensive, integrated analysis of safety data from interventional, observational and surveillance studies of tafamidis in ATTR-PN patients was conducted. Methods: Safety data from all sponsored, completed, or ongoing, Phase 2/3 studies of tafamidis in ATTR-PN patients as of 3 January 2017 were pooled. Also assessed were safety data from the ongoing Transthyretin Amyloidosis Outcomes Survey (THAOS) as of 3 January 2017 and post-marketing surveillance reports as of 31 March 2017. Results: There were 137 patients in Phase 2/3 studies (mean duration of tafamidis exposure, 44.2 months), with 134 (97.8%) experiencing ≥1 treatment-emergent adverse event (TEAE) and 46 (33.6%) ≥1 treatment-emergent serious adverse event (TESAE). The most common TEAEs were diarrhoea (26.3%), urinary tract infection (UTI; 25.5%) and influenza (21.2%). In THAOS, 661 subjects had tafamidis exposure (mean duration, 27.6 months), with 250 (37.8%) experiencing ≥1 TEAE and 96 (14.5%) ≥1 TESAE. The most common TEAE was UTI (6.1%). Post-marketing surveillance reports generally reflected the known safety profile of tafamidis. Conclusions: This analysis did not reveal any significant new safety findings; tafamidis was generally safe and well tolerated in ATTR-PN patients. ClinicalTrials.gov: NCT00409175, NCT00791492, NCT00630864, NCT01435655, NCT00925002, and NCT00628745.

Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

BACKGROUND: Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN. METHODS: A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment. RESULTS: The T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p < 0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p = 0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale. CONCLUSIONS: This analysis of patients with Val30Met ATTR-PN demonstrates that neurologic disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN. TRIAL REGISTRATION: NCT00409175 , NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. METHODS: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. RESULTS: In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy.

BACKGROUND: Transthyretin 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. METHODS: In 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. RESULTS: Patients 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). CONCLUSIONS: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00694161.