Amyloid-Specific Medication in Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis of Cardiovascular Outcome trials

Background The introduction of disease-specific medication has revolutionized the management of transthyretin-associated cardiomyopathy (ATTR-CM). However, dedicated trials included different patient populations, primary endpoints, and follow-up periods, rendering study comparison challenging. This systematic review and meta-analysis aimed to harmonize data from all phase 3 placebo-controlled drug trials in ATTR-CM to elucidate the magnitude and timing of treatment efficacy of ATTR-specific medication. Methods We searched PubMed and Embase for trials published up to February 23, 2025 (PROSPERO: CRD42025645376). Efficacy outcomes included all-cause death, cardiovascular (CV) events, change in 6-minute walk distance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and Kansas City Cardiomyopathy Questionnaire Overall Score. Outcome metrics were pooled across trials using inverse-variance weighting and a random-effects model. Results We included data from 4 identified trials (ATTR-ACT, ATTRibute, APOLLO-B, and HELIOS-B) and 2086 patients. Baseline risk profiles differed substantially, highlighted by a decrease in NT-proBNP and estimated glomerular filtration rate levels from earlier to later trials, likely resulting in different death rates of the respective placebo groups. At 12 months, ATTR-specific medication showed a trend toward less decline in 6-minute walk distance (least squares mean difference: 12.9 meters; 95% confidence interval [CI] −4.1 to 29.8) and was associated with a significantly blunted decline in Kansas City Cardiomyopathy Questionnaire Overall Score (least squares mean difference: 4.7 points; 95% CI 2.3−7.0) and NT-proBNP (geometric mean fold ratio 0.80; 95% CI 0.74−0.85) compared with placebo. These effects are consolidated with continued treatment. At 12-months, ATTR-specific medication did not improve all-cause mortality (OR 1.00; 95% CI 0.69−1.44) compared with placebo. Conversely, over the maximum follow-up period and at 30 months, respectively, ATTR-specific medication reduced the risk of all-cause mortality by 28% (HR 0.72; 95% CI 0.59−0.87) and for CV events by 42% (OR 0.58; 95%CI 0.47−0.73). Conclusions ATTR-specific medication exhibits early salutary effects on blood biomarkers, functional capacity and quality of life. These effects translate into reductions in CV events and all-cause mortality after continued treatment.