Transthyretin amyloid cardiomyopathy (ATTR-CM) is a systemic amyloidosis characterized by misfolding of the transthyretin (TTR) protein, resulting in the formation and deposition of insoluble amyloid fibrils in the interstitial space of the myocardium and other organs (1). This progressive, debilitating disease may stem from either mutations in the TTR gene (variant/hereditary ATTR-CM) or from a genetically normal, aging-related process [wild-type ATTR-CM (ATTRwt-CM)] (2). The clinical manifestations of ATTR-CM can extend across cardiac and noncardiac systems and can often overlap with signs/symptoms of more prevalent cardiac conditions, such as hypertensive heart disease, aortic stenosis, and hypertrophic cardiomyopathy (3), which can be an obstacle to achieving an accurate diagnosis. Fewer than half of patients with the disease receive an ATTR-CM diagnosis within 6 months of symptom onset (4). And misdiagnosis or delayed diagnosis can lead to continued amyloid deposition and worsening prognosis (5, 6).

Important advances in ATTR-CM diagnosis have been achieved in recent years, due in part to the increased recognition of the clinical clues associated with ATTR-CM, its prevalence among older adults with heart failure, and the availability of a readily accessible and accurate noninvasive diagnostic approach to the disease. Beginning in 2016, a noninvasive pathway has been widely accepted for confirming a diagnosis of ATTR-CM in most patients, which requires a combination approach of bone scintigraphy and serum and urine studies to rule out the presence of a monoclonal protein (1, 5, 7, 8). However, concerns have been raised that some patients may receive a diagnosis of ATTR-CM based on incomplete evaluations rather than evaluations based on established consensus recommendations (9).

In the current study, conducted using a cohort of US Medicare Fee-for-Service (FFS) patients diagnosed with ATTR-CM, we explored the frequency and cadence of diagnostic testing that patients with ATTRwt-CM underwent in the 2 years prior to their diagnosis. In addition, we assessed the clinical comorbid conditions of patients with ATTR-CM in the prediagnosis period to help characterize the population. A plain language summary of this original research is included in the Supplementary Materials.

Based on the Medicare claims data analyzed in this study, although the incidence of ATTRwt-CM diagnosis nearly tripled from 2018 to 2022, only a small minority of patients received an ATTRwt-CM diagnosis during this time based on consensus-recommended pathways (9). The proportion of patients diagnosed with ATTRwt-CM who underwent ^99mTc-PYP scintigraphy increased from approximately 30% in 2018 to nearly 50% in 2020 to 2022; however, this imaging was conducted in combination with complete monoclonal protein testing in no more than 16% of patients per year during this period. This increase in PYP utilization is likely driven by multiple factors: greater awareness of ATTR-CM following the FDA approval of tafamidis in 2019, as well as increased education and dissemination of diagnostic algorithms (5). Given that cardiac biopsy was performed in only 5% of patients with ATTRwt-CM in 2022, an ATTRwt-CM diagnosis appears to have been reached based on accepted guidelines in only one in five Medicare patients with the disorder. While access to these diagnostic tools for Medicare patients may vary by region, the national increase in scan use observed in our data suggests that these services have become more routinely accessible over time. The availability of approved therapies may have also contributed to more widespread adoption of diagnostic imaging in clinical practice.

Accepted diagnostic tools, i.e., ^99mTc-PYP scintigraphy (irrespective of monoclonal testing) and cardiac biopsy, were used in only 44% to 54% of patients with an ATTRwt-CM diagnosis between 2018 and 2022. We could not determine the basis for the diagnosis in the remaining patients, but these findings suggest a need for additional research and education regarding current diagnostic algorithms for ATTR-CM, to ensure appropriate and timely diagnosis and initiation of treatment for optimal outcomes.

Our findings also suggest insufficient understanding of the role of comprehensive monoclonal protein testing with cardiac scintigraphy in establishing a diagnosis of ATTR-CM. Among all the Medicare patients included in our study, a complete monoclonal protein screen was performed with ^99mTc-PYP scintigraphy in only 16% of those diagnosed with ATTRwt-CM by the end of the study period. While monoclonal protein testing was incomplete in nearly 25% of patients in 2022, it was not conducted at all in almost 10%. Although cardiac scintigraphy is increasingly recognized as a cornerstone of noninvasive ATTR-CM diagnosis, cardiac uptake supporting a diagnosis of ATTR-CM (grade 2 or 3 uptake) may occur in 10% of patients with AL amyloidosis, with grade 1 uptake occurring in an additional 29% (10). Given that serum kappa and lambda-free light chain assays in combination with serum and urine immunofixation electrophoresis have >99% sensitivity for detecting AL amyloidosis (11–13), a complete monoclonal protein screen is an indispensable component of the nonbiopsy ATTR-CM diagnostic pathway (7). Notably, 16% of patients presented with periorbital purpura, a condition that can precede a diagnosis of amyloidosis (14–16).

Strengths of our study include the provision of insights into how patients with ATTRwt-CM are diagnosed in the real-world setting. Similar research was conducted by Bourque et al. using administrative claims from a Medicare FFS population (17) but was limited to a 2-year period ending in 2019; thus, examination of more recent patterns in diagnostic testing for ATTR-CM is needed, particularly given the growth of ^99mTc-PYP scintigraphy as an accepted diagnostic tool in recent years. Secondary findings of our study have also allowed examination of the “real-world” demographics and comorbidities of a sizable population of patients with ATTRwt-CM. In addition, by limiting the population to patients with continuous Medicare A, B, and D coverage with full medical and drug coverage for at least 2 years prior to ATTRwt-CM diagnosis, it is likely that the vast majority of diagnostic laboratory and imaging studies and medication prescriptions were captured in the dataset.

Our study's limitations are primarily related to the use of administrative claims data. Claims data do not provide detailed clinical information and may contain inaccuracies in coding diagnoses, procedures, pharmacy claims, and other undetected confounders. Because ATTR-CM is uncommon, the disease and its subclassifications (wild type and variant) may not be well captured in administrative claims. Miscoding is also possible when using ICD-10-CM diagnosis and procedure codes to identify ATTR-CM diagnoses. For example, patients with AL amyloidosis may have been labeled as “other amyloidosis” or “ATTR amyloidosis”. However, to reduce the likelihood that patients with AL amyloidosis would be inadvertently included in the study, we excluded all patients with a concomitant diagnosis of plasma cell dyscrasia and who had received chemotherapy/immunotherapy commonly used to treat plasma cell dyscrasias. No data on biopsies following PYP test results are available in this dataset. In addition, the lack of a code for hereditary/variant disease may have resulted in patients with this subtype being included in the ATTRwt-CM cohort. Because only data from individuals with Medicare FFS health coverage were analyzed in this study, results may not be generalizable to patients with commercial health insurance or no health insurance coverage. Finally, because diagnostic testing patterns were examined only in patients who had been diagnosed with ATTR-CM, and not in patients who could have had ATTR-CM, the results of this study may not provide the full picture of the testing conducted in the underlying population.

Based on administrative claims data from 2018 to 2022, most Medicare patients with ATTRwt-CM did not receive a diagnosis based on accepted noninvasive diagnostic pathways. Improved understanding of these pathways, particularly pertaining to the requisite use of comprehensive monoclonal protein screens in combination with cardiac screening, is needed to improve ATTR-CM diagnosis in the clinical practice setting.