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Study Summary

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Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded transthyretin protein in the heart, eventually leading to ventricular stiffness and heart failure. Both the hereditary form (ATTRm) as well as acquired form (ATTRwt) of the disease generally manifest later in life, but carry a poor prognosis after diagnosis, with a median survival of 2-4 years. To date, treatment has been limited to symptom management. Tafamidis stabilizes transthyretin tetramers and is taken by mouth daily; treatment with tafamidis is approved for the treatment of transthyretin familial amyloid polyneuropathy, in which it delays neurologic progression. Its potential to reduce adverse outcomes in amyloid cardiomyopathy was evaluated in a randomized, multicenter, double-blind, placebo-controlled trial of 441 patients with tissue-confirmed TTR cardiac amyloid and clinical heart failure. Of these, 264 patients were randomized to tafamidis (80 mg or 20 mg once daily) and 177 to placebo. Tafamidis was associated with a reduction in all-cause mortality after 18 months of treatment as well as reduction in cardiovascular hospitalizations over 30 months, with hazard ratios of 0.7 (95% CI 0.51-0.96) and 0.68 (95% CI 0.56-0.81), respectively (see accompanying Hurst’s Central Illustration). Treatment with tafamidis was also associated with significantly reduced declines in functional capacity and quality of life after 6 months. Tafamidis exerted very few adverse effects, with more seen in the placebo group. There was no difference in either mortality or hospitalizations with regard to use of either low- or high-dose tafamidis.

Commentary

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Study Strengths: The ATTR-ACT study is the largest randomised clinical trial in patients with transthyretin amyloid cardiomyopathy to date, and the results of this trial offer hope to an entity in which there are no guideline-based recommended treatments. The study’s design and international multicenter structure reduce bias and confounders, and allow for greater external validity. The Finkelstein-Schoenfield method used for primary data analysis increases sensitivity and power in analysis of smaller cohorts while both prioritizing mortality and addressing morbidity by comparing each patient hierarchically within designated strata. Adherence was excellent in both arms, with 97% of treatment doses taken, allowing for accurate assessment of effect.

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Study Weaknesses: The study was designed by and analyzed centrally by the sponsor, which could represent a conflict of interest, though this was mitigated by an independent end-point adjudication committee. Heart transplant, heart/liver transplant, and implantation of mechanical assist devices were treated as death, which might overestimate mortality benefit, but all-cause mortality without treating mechanical assist device or transplant as death showed a hazard ratio of 0.67 (95% CI 0.49-0.94). Generalization of results may be difficult as 90% of studied patients were male and 80% were white, with most being healthier, New York Heart Association (NYHA) class II patients (61.4% in tafamidis group; 57.1% in placebo group). Quantification of prior hospitalizations could have differentiated underlying disease severity.

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Next Steps/Clinical Perspective: Tafamidis is a major step forward in the treatment of cardiac amyloidosis, a disease process with a grim prognosis and for which there are no available therapies to date. This study represents the first trial to show a survival benefit in TTR cardiac amyloidosis. The next step is commercial distribution; tafamidis has already received Fast Track and Breakthrough designations from the FDA. More hospitalizations were seen in NYHA Class III patients on tafamidis, pointing to the greater potential benefit of treatment early in the disease course and underscoring the importance of early diagnosis. This is consistent with mortality benefit after 18 months, implying earlier treatment is needed for true benefit. As this trial demonstrates that tafamidis may be more effective earlier in the course of disease; novel therapies for later-stage cardiac amyloid should be developed and tested.

Trial Reference

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Maurer  MS, Schwartz  JH, Gundapaneni  B et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N. Engl. J. Med. doi: 10.1056/NEJMoa1805689

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