P5401Tafamidis and cardiovascular involvement in hereditary ATTR amyloidosis: a 10-year story

Abstract

Introduction: Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease caused by a mutation in transthyretin gene. Main manifestations of cardiac involvement are conduction disorders and a restrictive cardiomyopathy. Therapeutic options comprehend liver transplantation and, more recently, tafamidis. However, its impact on cardiovascular involvement is still unknown. Purpose: To analyse the clinical course and cardiovascular manifestations of FAP patients that received tafamidis as part of the first clinical trial 10 years ago, all with Val30Met mutation and stage 1. Methods:We retrospectively reviewed the medical records and exams of patients from our centre included in tafamidis clinical trial in 2007. Those randomized to placebo started the drug between 2008 and 2009. Continuous variables were compared using t test and categorical variables using chi-square test or logistic regression. Multivariable analysis was performed using logistic regression; p<0.05 for statistical significance. Results: We analysed data from 74 participants, 45% male, mean age of 36±9 years old when tafamidis was started. Tafamidis was given during 70±43 months and at least 57 patients (77%) experienced worsening of the symptoms during a mean follow-up of 8.1±2.5 years since beginning medication. The drug was stopped in 40 cases (54%), 20 of those underwent liver transplant and 6 enrolled in other clinical trials. An adverse effect of tafamidis was reported in 4, in none of them severe; 6 patients died (all had stopped the drug, 2 had liver transplant). Death significantly related with proBNP levels and age. At baseline, all patients but 1 had preserved left ventricular ejection fraction; 7 had left ventricular hypertrophy; only 1 fulfilled current criteria for diastolic dysfunction; it was undetermined in 5. No clinically significant worsening of echocardiographic parameters was noted, but recent echocardiograms were available in only 49 cases. None had an overt restrictive cardiomyopathy. There was a significant increase in proBNP and troponin T; cardiovascular symptoms were mentioned by 64%. A pacemaker was implanted in 35 patients- only 3 had a general indication for implantation. In just 9 cases more than 1% of pacing was recorded, on average 4 years after the implantation. Conduction abnormalities progressed during follow-up: PR duration increased (163 ms at baseline to 180 ms at 8 years, p<0.001) as well as QRS duration (91 to 102 ms, p<0.001), while Sokolow index decreased (2.2mVto 2.1mV, p<0.001). Conclusions: Patients taking tafamidis experienced few adverse effects, however a significant proportion of patients showed progression of the disease during this long follow-up. Conduction abnormalities continued to evolve, as well as surrogate markers of heart failure, even though this was rarer in this early-onset Val30Met cohort. More studies regarding long-term effects of tafamidis and comparison with other treatment options are needed.