The six-minute walk test in transthyretin cardiac amyloidosis - prognostic utility put to the real-world test

Abstract Background The six-minute walk test (6MWT) has been identified as a predictor of adverse outcome in transthyretin amyloid cardiomyopathy (ATTR-CM). However, the real-world applicability of these findings remains uncertain as only therapy-naïve patients were included in the primary analysis. This study therefore aims to confirm the association of the 6MWT distance (6MWD) with all-cause mortality in patients receiving disease-modifying therapy. Methods Consecutive patients presenting to a medical university tertiary referral centre for cardiac amyloidosis between March 2012 and July 2024 were included into a prospective patient registry. ATTR-CM patients who completed a 6MWT at baseline were included in the present analysis. Association with the primary endpoint of all-cause mortality was assessed utilising Cox regression analysis and the log-rank test. Results A total of 252 patients 79.8 years, interquartile range (IQR): 75.4 – 83.7, 83.7% male were included. After a median of 21.7 (12.7 – 34.1) months, 61 (24.2%) patients deceased. A 6MWD of 350 meters was associated with worse survival hazard ratio (HR): 3.29, 95%-confidence interval (CI): 1.94 – 5.55, p 0.001, even after adjustment for National Amyloidosis Centre stage (HR: 2.30, 95%-CI: 1.29 – 4.10, p = 0.005). The Δ 6MWD thresholds of -35 meters / -5% were only associated with the primary endpoint after adjustment for change in treatment status, but not in univariate analysis. Conclusions The 6MWD is independently associated with mortality in ATTR-CM irrespective of treatment status. A baseline 6MWD of 350 meters is associated with a ~3-fold risk for all-cause mortality. However, our results suggest that the Δ 6MWD should only be used in patients on stable background therapy.