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

Objectives: To assess natural history and treatment effect on survival among transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) Val30Met patients. Methods: Multi-institutional, hospital-based study of TTR-FAP Val30Met patients prospectively followed-up until December 2016, grouped into untreated (n = 1,771), liver transplant (LTx) (n = 957) or tafamidis-treated (n = 432) cohorts. Standardized mortality ratios (SMR), Kaplan-Meier and Cox methods were used to estimate excess mortality, survival probabilities and adjusted hazard ratios (HR) for all-cause mortality, respectively. Results: Disease-modifying treatments decreased TTR-FAP excess mortality from ten to four (SMR 3.92, 95% 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 (<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), tafamidis reduced mortality risk by 82% compared with untreated patients (HR 0.18, 95% CI 0.06-0.49, p = 0.001).
Conclusions: 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.