Drugs for transthyretin amyloidosis under the microscope: Survival, safety, and a meta-analysis with certainty of evidence assessment

Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by the deposition of misfolded transthyretin (TTR) fibrils in organs and tissues, with incidence and prevalence rapidly increasing worldwide. Current therapeutic strategies fall into two main classes: TTR stabilizers and TTR gene silencers. To date, no comprehensive reviews cover all the available pharmacological treatments for ATTR, both approved and off-label. In addition, previous meta-analyses have often excluded real-world data and have not evaluated safety outcomes. In this Grading of Recommendations Assessment Development and Evaluation (GRADE)-assessed meta-analysis, interventional and observational studies were searched in four databases (MEDLINE, Scopus, Embase, and CENTRAL), and 28 studies were included. The use of TTR stabilizers and gene silencers significantly reduced the risk of all-cause mortality compared with placebo (relative risk, RR: 0.70 [95 % Confidence Interval, CI: 0.60–0.83]) in patients with cardiomyopathy, with no differences between drug classes. In observational studies, TTR stabilizers were associated with an even greater reduction in mortality risk (RR: 0.23 [95 % CI: 0.12–0.44] and an approximately 37 % increase in overall survival probability compared with unexposed patients, estimated using individual patient data from Kaplan-Meier (IPDfromKM) method. These pharmacological treatments also improved nutritional status and quality of life. Overall, they were safe and well tolerated, with no increased risk of adverse events (AEs) or treatment discontinuation due to AEs. In conclusion, this is the first meta-analysis integrating both clinical and real-world data to evaluate efficacy and safety of all available drugs for ATTR, including off-label use. This approach facilitates healthcare decision-making and paves the way for future research.