How to monitor disease progression in ATTR amyloid cardiomyopathy: Implications for clinical practice and trial design

Abstract Transthyretin amyloid cardiomyopathy (ATTR-CM) has been traditionally considered a rare and inexorably fatal condition. However, the development of therapies able to slow or halt ATTR-CM progression and increase survival have transformed the management of this condition. As these treatments become more accessible, the need for clinical indicators of disease progression has become increasingly important to guide clinical decision-making and personalise treatment strategies. Changes in widely available parameters have been shown to track disease evolution, which include worsening heart failure symptoms, outpatient diuretic initiation or intensification, decline in the 6-minute walk test, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and structural and functional parameters on cardiac imaging. Given the complexity of ATTR-CM, an integrated, multiparametric approach may provide a more precise assessment of disease trajectories and prognosis. Beyond stabilization and suppression of the circulating transthyretin protein, novel therapeutic approaches, including strategies aimed at clearing amyloid deposits, have shown potential for disease regression, even in patients with advanced involvement. With these advancements, ATTR-CM is shifting from an untreatable disease to a manageable condition where both survival and quality of life can be significantly improved. Future randomised controlled trial of disease-modifying treatments in ATTR-CM might use established criteria of disease progression as surrogate endpoints to have sufficient power and consider endpoints that are still clinically meaningful.