Amyloid-specific medication in transthyretin amyloid cardiomyopathy: a systemic review and meta-analysis

Background Transthyretin associated cardiomyopathy (ATTR-CM) is a progressive and ultimately fatal disease. Recently, different ATTR-specific agents have been evaluated in randomised controlled trials. These trials included different patient populations, primary endpoints, and follow-up times, rendering trial comparison challenging. Purpose This systematic review and meta-analysis aimed to harmonise 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. Methods We searched PubMed and Embase for trials published up to February 23rd, 2025. Efficacy outcomes included all-cause death, cardiovascular (CV) hospitalisations, change in 6-minute walk distance (6-MWD) and in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS). Hazard ratios (HR, at 12-months and maximum follow-up), odds ratios (OR, at 12 and 30-months), least squares mean (LSM) differences (at 12 and 30-months) were pooled across trials. Individual time-to-event patient data was extracted from published Kaplan-Meier survival curves. Results We included data from four identified trials (ATTR-ACT, ATTRibute, APOLLO-B, HELIOS-B) and 2,086 patients. Baseline characteristics differed substantially between trials with mean NT-proBNP levels ranging from 3,062pg/mL in ATTR-ACT to 1,911pg/mL in HELIOS-B and mean eGFR levels ranging from 56ml/min/1.73m2 in ATTR-ACT to 69 ml/min/1.73m2 in APOLLO-B. In line with differential baseline risk profiles, mortality rates differed between trials. At 30 months, death rates of the placebo groups were 42.4% vs. 25.7% vs. 17.4% (Chi² and log-rank: p for all intergroup comparisons <0.001; Figure 1) in ATTR-ACT, ATTRibute, and HELIOS-B. At 12 months, ATTR-specific medication showed a trend toward less decline in 6-MWD (LSM change: 12.9 meters; 95% CI -4.1 to 29.8; p=0.14) and was associated with a significantly blunted decline in KCCQ-OS (LSM change: 4.7 points; 95% CI 2.3 to 7.0; p<0.001) compared to placebo. ATTR-specific medication did not improve all-cause mortality compared to placebo after 12 months (OR 1.00; 95% CI 0.69 to 1.44; p=0.98). At 30 months, ATTR-specific medication significantly attenuated the decline in 6-MWD (LSM change: 46.8 meters; 95% CI 18.0 to 75.7; p<0.001) and KCCQ-OS (LSM change: 9.7 points; 95% CI 5.3 to 14.2; p<0.001). Over the maximum follow-up period and at 30-months, respectively, ATTR-specific medication reduced the risk for all-cause mortality by 30% (HR 0.70; 95% CI 0.57 to 0.84; p<0.001) and for CV hospitalisation by 42% (OR 0.58; 95% CI 0.47 to 0.73; p<0.001; Figure 2). Conclusion ATTR-specific medication exhibits early salutary effects on functional capacity and quality of life. These effects translate into reductions in CV hospitalisations and all-cause mortality after continued treatment.