Tafamidis Treatment for Patients With Transthyretin Amyloid Cardiomyopathy

N Engl J Med. 2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27.

Abstract

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 .).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Amyloid Neuropathies, Familial / complications
  • Amyloid Neuropathies, Familial / drug therapy*
  • Benzoxazoles / adverse effects
  • Benzoxazoles / therapeutic use*
  • Cardiomyopathies / complications
  • Cardiomyopathies / drug therapy*
  • Disease Progression
  • Double-Blind Method
  • Female
  • Heart Failure / etiology
  • Heart Failure / mortality
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Prealbumin / antagonists & inhibitors*
  • Quality of Life
  • Survival Analysis
  • Walk Test

Substances

  • Benzoxazoles
  • Prealbumin
  • tafamidis

Supplementary concepts

  • Amyloidosis, Hereditary, Transthyretin-Related

Associated data

  • ClinicalTrials.gov/NCT01994889