A Systematic Review of Representation in Clinical Trials for Transthyretin Associated Cardiac Amyloidosis: Where Demographics Diverge from Disease

Abstract Background Underrepresentation of minority groups in clinical trials worsens health disparities and reduces generalizability of results. Transthyretin-associated cardiac amyloidosis (ATTR), is a condition that disproportionately impacts some racial and ethnic groups yet the extent to which trial enrollment reflects disease burden remains unclear. Misalignment between disease prevalence and trial representation may delay treatment development and increase the economic burden of late diagnosis and mismanagement. Methods This was a systematic review of US-based ATTR clinical trials found on clinicaltrials.gov up to 2025 (search date February 12, 2025). Only completed trials with publicly available results were included. Demographic data were extracted at the trial level. An enrollment fraction (where EF = observed enrollment ÷ expected enrollment based on Cardiac Amyloidosis Registry Study (CARS) prevalence; adequacy defined EF ≥ 0.75) was calculated for each group. Results Of the 264 clinical trials on ATTR identified, 16 met inclusion criteria. African Americans/Individuals of African descent had EFs below the adequate ratio of 0.75 in all phases of the trials reviewed compared to their Asian or White counterparts. Despite the FDA Final Rule in 2017, our study showed that there was increased study demographic reporting (60% to 85.7%), but a paradoxical decline for Black participants (EF 0.29 to 0.12, p < 0.001) and other minority participants. Conclusions Black individuals remain substantially underrepresented in U.S. ATTR-CM clinical trials despite improved demographic reporting after the 2017 Final Rule. Actionable strategies, community engagement, trial-site diversification, enrollment targets, and sponsor accountability are needed to improve representativeness and expand access.