Highlights
In a large Medicare fee-for-service cohort, transthyretin cardiac amyloidosis (ATTR-CM) was typically diagnosed long after the first heart failure (HF) diagnosis, with a median delay of 494 days.
Among patients who had already started a loop diuretic before ATTR-CM recognition, the median interval from first loop prescription to diagnosis was even longer at 840 days, suggesting prolonged symptomatic treatment before the underlying cause was identified.
Female sex and several common comorbidities linked to dyspnea or alternative explanations for HF symptoms, including aortic stenosis, coronary artery disease, diabetes, hypertension, and chronic obstructive pulmonary disease, were associated with greater odds of delayed diagnosis.
Older age, atrial fibrillation, and carpal tunnel syndrome were associated with lower odds of delay, consistent with the idea that classic “red flags” may prompt earlier suspicion of ATTR-CM.
Background
ATTR-CM is an infiltrative cardiomyopathy caused by deposition of misfolded transthyretin protein in the myocardium. It is increasingly recognized as an important and treatable cause of HF in older adults, particularly those with preserved ejection fraction, aortic stenosis, atrial fibrillation, neuropathy, or extracardiac amyloid clues such as carpal tunnel syndrome.
Despite growing awareness, diagnosis is often late. This matters clinically because the disease progresses silently, and treatment benefit is generally greatest before severe functional decline, advanced ventricular remodeling, and recurrent HF hospitalizations occur. In practice, many patients are initially labeled as having “ordinary” HF, hypertensive heart disease, COPD-related dyspnea, ischemic cardiomyopathy, or valve disease. Those competing explanations can delay the diagnostic workup needed to identify ATTR-CM.
The present study directly addresses a key implementation problem: how long do Medicare beneficiaries wait between incident HF and confirmed ATTR-CM diagnosis, and who is most likely to experience delay?
Study design
This was a retrospective cohort study using US Medicare fee-for-service claims data from January 2016 through December 2022. Data were analyzed between November 2024 and July 2025.
The cohort included 7,770 Medicare beneficiaries with HF and ATTR-CM. ATTR-CM diagnosis was assessed relative to the first recorded HF diagnosis, including cases in which ATTR-CM occurred after HF or within 1 year before HF diagnosis. The primary outcome was time from first HF diagnosis to first ATTR-CM diagnosis. Delayed diagnosis was defined as more than 6 months between these two events.
Investigators used multivariable logistic regression to examine demographic, clinical, and socioeconomic factors associated with delayed diagnosis. The study is best interpreted as a health-services analysis of real-world diagnostic timing rather than a causal analysis of disease biology.
Key findings
The median age at ATTR-CM diagnosis was 81 years, with an interquartile range of 76 to 86 years. Men comprised 5,995 patients, or 77% of the cohort, reflecting the well-known male predominance of diagnosed ATTR-CM in older populations.
The central finding was the substantial diagnostic lag. The median time from HF diagnosis to ATTR-CM diagnosis was 494 days, with a very wide interquartile range of 63 to 1,340 days. In other words, for many patients, almost 2 years passed before the amyloid diagnosis was established, and for a substantial subset the delay was considerably longer.
The delay was even more striking among the 6,175 patients who had received a loop diuretic before ATTR-CM diagnosis. In that subgroup, the median time from the first loop diuretic prescription to ATTR-CM diagnosis was 840 days (interquartile range, 252 to 1,768 days). This suggests that many patients were treated symptomatically for congestion for a prolonged period before clinicians identified the infiltrative cardiomyopathy driving the HF syndrome.
Several patient characteristics were independently associated with delayed diagnosis. The strongest findings are summarized below.
| Factor | Association with delayed ATTR-CM diagnosis | Adjusted OR (95% CI) | |
|---|---|---|---|
| Older age | Lower odds of delay | 0.68 (0.63-0.74) | |
| Atrial fibrillation | Lower odds of delay | 0.39 (0.33-0.49) | |
| Carpal tunnel syndrome | Lower odds of delay | 0.85 (0.74-0.97) | |
| Female sex | Higher odds of delay | 1.28 (1.13-1.45) | |
| Aortic stenosis | Higher odds of delay | 1.39 (1.20-1.62) | |
| COPD | Higher odds of delay | 1.18 (1.03-1.34) | |
| Coronary artery disease | Higher odds of delay | 1.26 (1.13-1.40) | |
| Diabetes | Higher odds of delay | 1.21 (1.07-1.37) | |
| Hypertension | Higher odds of delay | 1.28 (1.13-1.45) |
These results are clinically intuitive. Atrial fibrillation and carpal tunnel syndrome are well-known ATTR-CM clues and may trigger more targeted evaluation, shortening the time to diagnosis. In contrast, aortic stenosis, coronary artery disease, COPD, diabetes, and hypertension are common competing diagnoses that can plausibly explain dyspnea, exercise intolerance, edema, or abnormal cardiac testing. When such conditions are present, ATTR-CM may remain lower on the differential diagnosis list.
The association with female sex deserves special attention. ATTR-CM has historically been underrecognized in women, in part because the phenotype is often thought of as a disease of older men. Women may therefore be more likely to experience diagnostic anchoring on other causes of HF symptoms, contributing to delay.
Expert commentary
This study reinforces a major theme in contemporary amyloidosis care: recognition often lags behind disease burden. The problem is not simply that ATTR-CM is rare; rather, it is a disease whose symptoms overlap with many common conditions encountered in primary care, cardiology, and general internal medicine. As a result, diagnosis depends heavily on clinician suspicion.
The findings also fit with current expert guidance, which emphasizes early consideration of ATTR-CM in older patients with HF, increased ventricular wall thickness, HF with preserved ejection fraction, unexplained elevated natriuretic peptides, atrial fibrillation, carpal tunnel syndrome, lumbar spinal stenosis, or discordance between symptoms and standard HF explanations. The present analysis suggests that, in real-world practice, those red flags are not being applied consistently enough.
From a systems perspective, the study raises an important question: where should ATTR-CM case-finding be embedded? Potential touchpoints include echocardiography laboratories, HF clinics, valve clinics, electrophysiology practices, and post-carpal-tunnel or post-aortic-stenosis pathways. Automated prompts or referral algorithms may be especially useful for patients with recurrent congestion, preserved ejection fraction, or multiple “explanatory” comorbidities.
There are also important limitations. Claims-based studies identify coded diagnoses, not adjudicated clinical phenotypes. The authors could not directly measure symptom onset, imaging findings, biomarkers, biopsy results, or whether patients had wild-type versus hereditary ATTR. Coding may also miss cases or misclassify timing, and the analysis was limited to Medicare fee-for-service beneficiaries, reducing generalizability to younger adults and Medicare Advantage enrollees. In addition, the study cannot prove that the listed comorbidities cause delay; they may simply mark a more complex clinical picture in which amyloidosis is harder to recognize.
Even with these caveats, the message is robust: the diagnostic interval remains too long for a progressive cardiomyopathy in which earlier identification could alter management. The data support a lower threshold for ATTR-CM evaluation in patients who have HF plus seemingly “sufficient” alternative diagnoses but an atypical course, recurrent diuretic need, or extracardiac clues.
Clinical implications
For clinicians, this study argues for a more deliberate amyloidosis screen in older adults with HF, especially when the following are present:
• Persistent congestion despite escalating diuretics
• HF that seems disproportionate to coronary disease or hypertension burden
• Atrial fibrillation, conduction disease, or low-voltage ECG findings
• Carpal tunnel syndrome or other extracardiac amyloid manifestations
• Coexisting aortic stenosis, COPD, diabetes, or hypertension that may obscure the diagnosis
For health systems, the main implication is that ATTR-CM should be treated as a time-sensitive diagnosis. A delay of more than a year after HF recognition is not a benign administrative lag; it likely represents missed opportunities for disease-specific therapy, advanced HF planning, and appropriate counseling.
Conclusion
Among Medicare beneficiaries with HF and ATTR-CM, diagnosis was often delayed by many months and sometimes by years. Delays were more likely in women and in patients with common comorbidities that can mask the amyloid phenotype, while older age, atrial fibrillation, and carpal tunnel syndrome were associated with earlier recognition. The study underscores a practical point for cardiology and general medicine: ATTR-CM should remain high on the differential diagnosis in older patients with HF, particularly when the clinical picture is complex or the response to standard therapy is incomplete.
Funding and trial registration
Funding was not specified in the provided abstract. As a retrospective claims-based cohort study, clinicaltrials.gov registration is not applicable.
References
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