Outpatient diuretic intensification, NT-proBNP and eGFR as early markers of disease progression in patients with ATTR-CM: a validation study

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a complex heterogenous disease with non-linear progression. Criteria for disease progression based on natriuretic peptides, renal function and diuretic intensification have previously been established at 1 year to track disease evolution, but their utility for earlier prognostication remains unclear. Aim The study aimed to (i) characterise disease progression across TTR genotypes (wild-type, V122I, non-V122I) and disease stages. (ii) Evaluate the ability of the established progression criteria to independently predict prognosis as early as 6 months. Methods Data from 2990 consecutive patients diagnosed with ATTR-CM (2001-2024) at our centre were analyzed. Disease progression was defined using established criteria: NT-proBNP progression (>700 ng/L with >30% increase), outpatient diuretic initiation/intensification (ODI), and renal progression (decline in eGFR >20%). Landmark analysis at 6 months was performed to assess the association of each criteria of progression and all cause-mortality (primary outcome). Results The study population had a mean age of 80.5±9.1 years, with 74.5% wild type ATTR-CM and 82.3% men. Data on disease progression at 6 months was available in 1589 patients for renal progression, 514 patients for NT-proBNP progression, and 1753 patients for ODI. At 6-months, disease progression was more frequent in V122I-associated ATTR-CM (73.3% NT-proBNP progression, 37.5% ODI, 22.2% renal progression) vs wild type ATTR-CM (65.7% NT-proBNP progression, 28.6% ODI, 17.1% renal progression) and non-V122I ATTR-CM (70.2% NT-proBNP progression, 15.7% ODI, 14.4% renal progression). In the landmark analysis at 6 months, with a median follow up of 29 months [IQR 15.5 – 49.0], all criteria of disease progression were significantly associated with all-cause mortality (HR 1.45; 95%CI 1.15-1.83; p=0.02 for NT-proBNP progression; HR 1.52; 95%CI 1.35-1.72; p<0.001 for ODI; HR 1.46; 95%CI 1.26-1.70; p<0.001 for renal progression) (Figure). Findings were consistent across disease stages (P-interaction= 0.57 for NT-proBNP progression, 0.91 for ODI, 0.30 for renal progression) and genotypes (P-interaction= 0.73 for NT-proBNP progression, 0.77 for ODI, 0.71 for renal progression). On multivariable analysis, all 3 criteria of disease progression at 6 months were independently associated with all-cause mortality: HR 1.39; 95%CI 1.07-1.81; p=0.013 for NT-proBNP progression; HR 1.34; 95%CI 1.07-1.66; p=0.009 for ODI; HR 1.45; 95%CI 1.14-1.86; p=0.003 for renal progression. Conclusion In a large population of ATTR-CM patients, the 3 established disease progression criteria confirm more frequent progression in the V122I cohort compared to wild-type and non-V122I ATTR-CM. All 3 established criteria which confirms their utility as early prognostic markers.