When to stop? Real-world decision pathways for transthyretin stabilizer discontinuation in cardiac amyloidosis

Background TTR-stabilization has been proven an effective and well-tolerated treatment for cardiac transthyretin amyloidosis (ATTR-CM) in clinical trials and real-world registries. Considering its cost-intensiveness and the delayed therapeutic effect, physicians have to evaluate the potential prognostic benefit regularly and might consider discontinuation of therapy in selected patients. In Germany, there are no legal restrictions regarding initiation or termination of Tafamidis, making individual treatment decisions challenging. Purpose To evaluate the characteristics of real-world ATTR-CM patients with a recommendation for discontinuation of TTR-stabilization therapy and to analyze the key factors for termination of therapy. Methods Based on clinical registry data from 15 university hospitals in Germany, we included consecutive ATTR-CM patients who had presented to the respective center between January 1st and June 30st 2024. We compared characteristics of patients with newly established diagnosis of ATTR-CM who were considered eligible (Tafamidis YES) or not eligible for Tafamidis (Tafamidis NO) and patients in whom current therapy with Tafamidis was discontinued (Tafamidis STOP). The individual reasons for discontinuing TTR-stabilization were evaluated. Results The Tafamidis STOP group encompassed 28 patients whereas the Tafamidis YES group included 414 patients and Tafamidis NO 99 patients, respectively. Compared to Tafamidis NO, patients in the Tafamidis STOP group had higher NAC stage (p=0.002), higher NT-proBNP (median 6954 vs. 3122pg/ml, p=0.002) and interventricular septum thickness (19 vs. 17mm, p=0.001) but lower left ventricular ejection fraction (LVEF; 48 vs. 53%, p=0.04) while age, NYHA functional class and kidney function were similar. Compared to Tafamidis YES, patients in the Tafamidis STOP group were older (p=0.012), had higher NAC stage, higher NT-proBNP, worse NYHA functional class, more impaired kidney function (all p<0.0001), more comorbidities and lower LVEF (both p<0.05). The main reasons for Tafamidis discontinuation were "frailty/ poor mobility", "limited life expectancy or significant comorbidity", "progression of heart failure" and switch to "palliative care" (figure). In 64% of centers the decision for treatment discontinuation was based on the decision of a specific amyloidosis board, whereas in 36% the treating physician decided whether therapy should be stopped. Conclusions This analysis of contemporary registry data demonstrates that the threshold for Tafamidis discontinuation is high since these patients were in more advanced stages compared to those who were not considered for Tafamidis at initial diagnosis. Most frequent reasons for discontinuation were severely reduced general health status or relevant comorbidity. These data provide novel information about treatment decisions in advanced ATTR-CM disease and may help to implement objective decision pathways about when to stop disease-modifying therapy.