Specific Therapy for Transthyretin Cardiac Amyloidosis: A Systematic Literature Review and Evidence‐Based Recommendations

Abstract

Background The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and Results A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English‐language randomized controlled trials (RCTs), non‐RCTs, or observational studies, which included adult patients with variant/wild‐type transthyretin‐CA, assessed specific therapies for transthyretin‐CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non‐RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non‐RCTs (18 publications). Tafamidis was shown to significantly improve all‐cause mortality and cardiovascular hospitalizations and reduce worsening in 6‐minute walk test, Kansas City Cardiomyopathy Questionnaire—Overall Summary score, and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) in variant/wild‐type transthyretin‐CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyretin‐CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1‐month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single‐arm small non‐RCTs existed for diflunisal, epigallocatechin‐3‐gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid. Conclusions This systematic review of the literature supports the use of tafamidis in wild‐type and variant transthyretin‐CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.

Disease Modifying Therapies for Transthyretin Amyloid Cardiomyopathy

“…Furthermore, it is necessary to assess whether the association of treatments with distinct mechanisms of action could improve the outcome of ATTR-CA. 5 As demonstrated, this is a growing research field with many RCTs currently ongoing, and their results will likely shift the paradigm of treatment of ATTR-CA. Our main goal continues to be finding the best therapy or combination of therapies for each patient with ATTR-CA by optimizing the efficacy and minimizing the side effects.…”

“…In patients with ATTR-CA, either ATTRv or ATTRwt, tafamidis is considered the agent of choice due to the proven clinical benefit in cardiovascular outcomes. 5 Tafamidis is a kinetic TTR stabilizer that binds to the unoccupied thyroxine binding sites of tetrameric TTR and blocks the amyloidogenic cascade. 6 It was first adopted for treatment of symptomatic ATTRv polyneuropathy, and it is the only therapy approved with effectiveness to treat ATTR-CA.…”

“…6 It was first adopted for treatment of symptomatic ATTRv polyneuropathy, and it is the only therapy approved with effectiveness to treat ATTR-CA. 5 This recommendation is essentially based on the results of a large, well-designed phase III randomized clinical trial (RCT), ATTR-ACT. 7 In this study, tafamidis (20 and 80 mg, pooled) showed a decline in all-cause mortality and cardiovascular-related hospitalization, decreased DOI: https://doi.org/10.36660/abchf.20210034 decline in 6-minute walk test, slower deterioration in quality of life, and a minor increase of NT-proBNP in patients with biopsyproven ATTRwt or ATTRv CA with heart failure and NYHA class I to III at 30 months.…”

“…8 Other drugs with the capacity to stabilization of TTR have been tested, but, differently from tafamidis, they have not been approved for ATTR-CA treatment yet. 5 Diflunisal is a nonsteroidal anti-inflammatory (NSAID) drug with TTR-stabilizing attributes. Studies on diflunisal are all noncomparative, small non-RCTs, including almost exclusively patients with ATTRv, with exploratory cardiovascular endpoints limited to cardiovascular biomarkers and echocardiographic parameters.…”

Brazilian consensus for diagnosis, management and treatment of hereditary transthyretin amyloidosis with peripheral neuropathy: second edition

“…The reader is referred to excellent reviews elsewhere. 63,[82][83][84][85] Neurologists, cardiologists, internists, nephrologists, ophthalmologists, general practitioners, neurogeneticists, mental health providers, nutritionists, nurses, and physical therapists need to work together to improve patient care and quality of life.…”