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Published on: June 9, 2018
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy
Mathew S Maurer1, Jeffrey H Schwartz1, Balarama Gundapaneni1
1From the Columbia University Vagelos College of Physicians and Surgeons (M.S.M.) and Pfizer (J.H.S., A.I.B., P.H., J.S., M.B.S.), New York; Syneos Health, Raleigh, NC (B.G.); University College London and St. Bartholomew's Hospital, London (P.M.E.); the Amyloidosis Center, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, and the University of Pavia, Pavia (G.M.), and the Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna (C.R.) - both in Italy; the Amyloidosis Center (CEPARM), Federal University of Rio de Janeiro, Rio de Janeiro (M.W-C.); the Amyloidosis Center, Medical University of Heidelberg, Heidelberg, Germany (A.V.K.); the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (M.G.); Stanford University School of Medicine, Stanford, CA (R.W.); the French Referral Center for Cardiac Amyloidosis, Amyloidosis Mondor Network, GRC Amyloid Research Institute and Department of Cardiology, Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor, and INSERM Unité 955, Clinical Investigation Center 006, and DHU ATVB, Creteil, France (T.D.); Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.M.D.); the Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (S.J.S.); Cleveland Clinic, Cleveland (M.H.); the Medical University of South Carolina, Charleston (D.P.J.); and Pfizer, Groton, CT (T.A.P., S.R., M.S.).
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 .).
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