Misdiagnosis rates in ATTR-CM patients and associated symptoms

Abstract Background Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a rare, progressive cardiac condition caused by the accumulation of misfolded transthyretin protein in the heart. Due to its non-specific symptoms, ATTR-CM is often misdiagnosed, leading to delayed treatment. Purpose This study sought to characterize the diagnostic journey of ATTR-CM patients, including misdiagnosis rates, associated symptoms, and time from symptom onset to correct diagnosis in order to identify potential areas for improving diagnostic accuracy and efficiency. Methods A multi-center online medical chart review of patients was carried out. Cardiologists and cardiology-focused internists from EU4 hospitals and private practices were recruited and screened for ATTR-CM patient management. Data from three waves of the study (Q2, Q3 & Q4 2024) collected an aggregate total of 1,935 patient records across France (443), Germany (508), Italy (477) and Spain (507) from the recruited physicians. Misdiagnosis rates and the most common incorrect diagnoses were identified. Symptoms presented before diagnosis were compared between misdiagnosed and correctly diagnosed patients. NYHA class at diagnosis and time from first symptoms to diagnosis were also analyzed. Results Analysis of 1,935 ATTR-CM patient records revealed a misdiagnosis rate of 26% (n=497). Hypertrophic cardiomyopathy (53%) and ischemic heart disease (20%) were the most common misdiagnoses among this patient subset. Of the symptoms experienced prior to diagnosis among all reported patients, previously misdiagnosed patients exhibited significantly higher rates (p<0.01) of intolerance to standard heart failure therapies (39% vs 21%), multiple hospitalizations for heart failure (38% vs 21%), exercise intolerance (71% vs 58%), peripheral oedema (51% vs 38%), shortness of breath (85% vs 75%), fatigue (66% vs 56%), and lumbar spinal stenosis (12% vs 7%) compared to correctly diagnosed patients (Figure 1). At diagnosis, the misdiagnosed patients were more likely to be in NYHA class 3 (53% vs 43%, p<0.01), while correctly diagnosed patients were more frequently diagnosed at NYHA class 1 or 2 (Figure 2). Time from symptom onset to diagnosis was prolonged in the misdiagnosed patients, with 42% diagnosed after more than 12 months compared to 17% of correctly diagnosed patients (Figure 3). Conclusion The high misdiagnosis rate, prolonged time from symptom onset to diagnosis, and advanced disease stages at diagnosis observed in this study underscores the critical need for improved diagnostic accuracy in ATTR-CM. Given the non-specific nature of predominant symptoms, clinicians should maintain a high index of suspicion for ATTR-CM in patients presenting with heart failure symptoms. Future research is warranted and can focus on validating these findings and developing targeted interventions to reduce misdiagnosis and improve patient outcomes in ATTR-CM.Figure 1 - Symptoms prior to diagnosis Figures 2 & 3 - Disease outcomes