Amyloid-specific medication in transthyretin amyloid cardiomyopathy: a systematic review and meta-analysis of cardiovascular outcome trials

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 inform on the magnitude and timing of treatment efficacy of ATTR-specific medication. We searched PubMed and Embase for trials published up to February 23rd, 2025 (PROSPERO: CRD42025645376). Efficacy outcomes included all-cause death, cardiovascular (CV-)events, change in 6-minute walk distance (6-MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and Kansas-City Cardiomyopathy-Questionnaire-Overall-Score (KCCQ-OS). Outcome metrics were pooled across trials using inverse-variance weighting and a random-effects model. We included data from four identified trials (ATTR-ACT, ATTRibute, APOLLO-B, HELIOS-B) and 2,086 patients. Baseline risk profiles differed substantially highlighted by a decrease in NT-proBNP and eGFR 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-MWD (least squares mean LSM difference: 12.9 meters; 95%CI -4.1 to 29.8) and was associated with a significantly blunted decline in KCCQ-OS (LSM difference: 4.7points; 95%CI 2.3-7.0) and NT-proBNP (geometric mean fold ratio: 0.80; 95%CI 0.74-0.85) compared to placebo. These effects were 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 to placebo. Conversely, over the maximum follow-up period and at 30-months, respectively, ATTR-specific medication reduced the risk for 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). 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. This meta-analysis harmonizes data from all outcome trials assessing disease-specific treatment in cardiac transthyretin amyloidosis to evaluate timing and magnitude of effects of respective treatments on important clinical outcomes. It provides novel evidence that ATTR-targeted medication results in early improvements in cardiac biomarkers, quality of life and functional capacity, which are maintained and enhanced over a period of ≥2.5 years. Early salutary effects translate into reductions in CV-related events and all-cause mortality after continued treatment.