Which patients did recent trials in transthyretin amyloid cardiomyopathy select? -Insights from a prospective patient registry

IntroductionSeveral randomized, double-blind, placebo-controlled phase III trials (RCT) explore disease-modifying therapeutics in transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is currently unclear whether patients eligible to participate in the RCT are representative of real-world patients. MethodsATTR-CM patients presenting to a tertiary referral center for cardiac amyloidosis at the Medical University of Vienna between March 2012 and May 2024 were included in a prospective cardiac amyloidosis registry. Inclusion and exclusion criteria of the ATTRACT, ATTRIBUTE, HELIOS-B, CARDIO-TTRANSFROM, and the DEPLETTR-CM trial were applied, and the baseline characteristics of the hypothetical trial cohorts as well as their survival were compared. ResultsA total of 353 patients (80.3 years, IQR: 75.5 - 84.2, 17.6% female) were included, out of which 192 patients would have been eligible to participate in ATTRIBUTE, ATTRACT would have recruited 163 patients, HELIOS-B 105 patients, CARDIO-TTRANSFROM 80 subjects, and 71 patients would have been eligible for DEPLETTR-CM. Patients included in ATTRIBUTE, ATTRACT, HELIOS-B, and CARDIO-TTRANSFORM demonstrated only minor differences regarding baseline characteristics, both among each other and compared to the real-world cohort. However, patients eligible for the DEPLETTR-CM trial exhibited both more severely elevated biomarkers of heart failure (NT-proBNP: 2590pg/mL, IQR: 1614-4423, vs. 2339pg/mL, IQR: 1154-4250; p<0.001) as well more advanced disease assessed utilizing the New York Heart Association and National Amyloidosis Centre stage (p<0.001, respectively). Concerning all-cause mortality, patients who could have been included in DEPLETTR-CM also showed significantly worse survival. At the same time, no significant differences were observed between the real-world cohort and the other patient cohorts. ConclusionsWhen applied to our real-world ATTR-CM cohort, recent RCT inclusion and exclusion criteria would have selected patients comparable to the real-world cohort. Only the DEPLETTR-CM trial would have selected patients with more advanced disease and worse prognosis in our cohort. Clinical perspectiveO_ST_ABSWhats new?C_ST_ABSO_LIThis is the first study to assess whether patient cohorts in recent ATTR-CM trials represent real-world ATTR-CM patients. C_LIO_LIWhile this analysis suggests that ATTRACT, ATTRIBUTE, HELIOS-B, and CARDIO-TTRANSFROM would have included a somewhat representative patient sample, DEPLETTR-CM includes patients with more advanced disease. C_LIO_LIFemales may have been underrepresented in recent ATTR-CM trials. C_LI What are the clinical implications?O_LIThese results may aid the interpretation of the trial results. C_LIO_LIThis may be especially useful as currently there are no trials directly comparing ATTR-CM disease-modifying therapeutics. C_LIO_LIFinally, this analysis should support the design of future trials to be more representative of real- world ATTR-CM patients and more inclusive with regard to women and patients in very early disease stages. C_LI