Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy

Objective To assess the natural history and treatment effect on survival among patients with transthyretinassociated familial amyloid polyneuropathy (TTR-FAP) stage 1 Va130Met. Methods Multi-institutional, hospital-based study of patients with TTR-FAP Val30Met prospectively followed up until December 2016, grouped into untreated (n = 1,771), liver transplant (LTx)treated (n = 957), or tafamidis-treated (n 432) cohorts. Standardized mortality ratios, Kaplan Meier, and Cox methods were used to estimate excess mortality, survival, and adjusted hazard ratios (HRs) for all-cause mortality. Results Disease-modifying treatments decreased TTR-FAP excess mortality from 10 to 4 (standardized mortality ratio 3.92, 95% confidence interval [CI] 2.64-5.59). Median overall survival of untreated and LTx-treated cohorts was 11.61 (95% CI 11.14-11.87) and 24.73 years (95% CI 22.90-27.09), respectively, and was not reached in the tafamidis-treated cohort (maximum follow-up, 10 years). Both disease-modifying treatments improved survival. Among early-onset patients (younger than 50 years of age), tafamidis reduced the mortality risk compared with untreated patients by 91% (HR 0.09, 95% CI 0.03-0.25, p < 0.001) and with LTx-treated patients by 63% (HR 0.37, 95% CI 0.14-1.00, p = 0.050). Previous tafamidis treatment did not affect mortality risk after LTx (HR 0.83, 95% CI 0.25-2.78, p = 0.763). Among late-onset patients (50 years and older), tafamidis reduced mortality risk by 82% compared with untreated patients (HR 0.18, 95% CI 0.06-0.49, p = 0.001). Conclusion LTx and tafamidis convey substantial survival benefits, but TTR-FAP mortality remains higher than in the general population. These results strongly reinforce the importance of timely diagnosis and earlier treatment, boosting the pursuit for an increased life expectancy. Classification of evidence This study provides Class III evidence that for patients with stage 1 Va130Met TTR-FAP, LTx and tafamidis increase survival.