In this randomized, controlled, phase 3 trial of tafamidis for transthyretin amyloid cardiomyopathy, tafamidis was associated with lower all-cause mortality and lower rates of cardiovascular-related ...hospitalizations and decline in functional capacity and quality of life.
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.
Background: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the effectiveness of tafamidis for the treatment of patients with transthyretin amyloid cardiomyopathy ...(ATTR-CM). Tafamidis reduced mortality in all subgroups of patients studied. Tafamidis also reduced observed frequency of cardiovascular (CV)-related hospitalizations in all subgroups except those who were New York Heart Association (NYHA) class III at baseline who, paradoxically, had a higher frequency of CV-related hospitalizations than placebo. Given the greater mortality rate with placebo, this analysis assessed the impact of the confounding effect of death on the frequency of CV-related hospitalization in ATTR-ACT. Methods: In ATTR-ACT, patients with ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. Post hoc analyses first defined and compared the effect of tafamidis treatment in the subset of NYHA class III patients from each treatment arm alive at month 30. The impact of a potential survivor bias was then adjusted for using principal stratification, estimating the frequency of CV-related hospitalization in NYHA class III patients who would have survived regardless of assigned treatment group (defined as the survivor average causal effect SACE). Results: In the subset of NYHA class III patients alive at month 30, tafamidis reduced the relative risk of CV-related hospitalization versus placebo (relative risk: 0.95 95% CI: 0.55–1.65). In the principal stratification analyses of those patients who would survive to 30 months regardless of treatment, tafamidis treatment was associated with a 24% lower risk of CV-related hospitalization (relative risk: 0.76 95% CI: 0.45–1.24). Similarly, there was a larger reduction in CV-related hospitalization frequency with tafamidis in NYHA class I or II patients in the SACE than was initially observed in ATTR-ACT. Conclusions: Initial data from ATTR-ACT likely underestimated the effect of tafamidis on CV-related hospitalizations due to the confounding effect of death. When SACE was used to adjust for survivor bias, there was a 24% reduction in the frequency of CV-related hospitalization in NYHA class III patients treated with tafamidis.
Background: The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy.
Methods: A prospectively ...planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirty-seven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years.
Results: Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures.
Conclusions: These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis.ClinicalTrials.gov: NCT00925002
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).
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.
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;
<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;
=0.05) and wild-type transthyretin amyloidosis (0.61 0.43-0.87;
=0.006); and baseline New York Heart Association class I and II (0.56 0.38-0.82;
=0.003) and class III (0.65 0.41-1.01;
=0.06).
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.
To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula ...associated with vision loss not due to ischemia.
Randomized (1:1), sham-controlled, multicenter, parallel-group trial.
Subjects with DME.
Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria.
The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout.
In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio OR, 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 23.3% vs 53/127 41.7%, respectively, P = 0.002; week 102, 27/107 25.2% vs 45/100 45.0%, respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups.
Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population.
Proprietary or commercial disclosure may be found after the references.
Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic ...presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994889.
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.
PDF
