Economic Burden of Overall and Advanced Light Chain Amyloidosis: Results from a Claims Linked Electronic Health Record Database Analysis

Abstract

Background

Real-world data on healthcare resource utilization (HCRU) and costs in light chain amyloidosis (AL) by disease severity are limited. This study evaluates HCRU and costs among patients with AL, particularly those with advanced stages.

Methods

A retrospective analysis of deidentified patient records (January 2016 to March 2022) from Optum’s clinical electronic health record (EHR) database was conducted. Adult patients with ≥2 AL diagnoses or positive mentions of the disease in the physician’s notes (≥30 days apart) were included. Patients with a Mayo disease stage, including those with advanced disease (stages IIIa/IIIb), based on cardiac biomarkers (N-terminal pro-brain natriuretic peptide and troponin T), were identified most proximal to the index date (first-identified AL diagnosis date). Patient records were then linked to payer-agnostic claims. Data, including HCRU and costs, were assessed from the index date until the end of continuous enrollment or death (minimum 30-day follow-up) during the 12-month postindex period.

Results

Among the 85 patients (75% aged ≥60 years; 65% males) included in the study, 60% had at least one condition-related inpatient hospitalization (66.7% with advanced cardiac involvement), 92.9% had an outpatient visit (54.4% with advanced cardiac involvement), 74.1% had an office visit (53.9% with advanced cardiac involvement), and 22.4% had an emergency room visit (68.4% with advanced cardiac involvement) within 12 months after diagnosis. The median (range) per-patient per-month (PPPM) condition-related total, medical, and drug costs for patients with advanced cardiac involvement (n = 47) were $7532 ($3336–$15,097), $2107 ($1079–$4618), and $4613 ($1664–$9488), respectively. The median (range) PPPM condition-related inpatient hospitalization costs for patients with advanced cardiac involvement (n = 34) was $462 ($77–$1839).

Conclusion

This EHR-claims linked database study showed that patients with advanced disease face high economic burden, supporting the continued need for therapeutic advances to help manage this population.

Introduction

Light chain amyloidosis (AL) is a rare, progressive, systemic condition that arises from a plasma cell disorder causing progressive multiorgan dysfunction and contributing to considerable morbidity and mortality.^1,2 Patients with AL have a higher healthcare cost burden, which may further increase in those with advanced disease, as determined by staging based on the presence and extent of cardiac involvement assessed by serum biomarkers indicative of cardiomyopathy.^3–5 The European modification of the Mayo 2004 staging system, which is widely used in AL, uses key cardiac biomarkers––including N-terminal pro-brain natriuretic peptide (NT-proBNP), BNP, troponin T (cTnT), troponin I (cTnI), and high-sensitivity cTnT––to classify the disease into stages I through III (Supplementary Table 1).^5,6 To better differentiate advanced cases, stage III is further subdivided into stage IIIa (NT-proBNP ≤8500 ng/L) and stage IIIb (NT-proBNP >8500 ng/L), which has been historically associated with median overall survivals as short as 21.6 and 4.8 months, respectively.^5–7

Recent advances in treatment options and the prompt initiation of treatment have improved survival rates for most patients with AL.² Despite these advances, patients with stage IIIb disease continue to have a poor prognosis.^2,8 Given the rapid progression of the disease, many clinicians regard treatment as a medical emergency.² Patients face not only significant health challenges but also a considerable economic burden driven by the need for frequent hospital visits, specialized diagnostics, and intensive treatment.³ Overall financial and healthcare resource utilization (HCRU), including hospitalizations and emergency room (ER) visits, have been evaluated in patients with AL.^3,9 We aimed to evaluate economic burden among patients with AL, including those with advanced cardiac involvement (Mayo stages IIIa and IIIb), as defined by the European modification of the Mayo 2004 staging of disease, using real-world data from a US electronic health record (EHR)–claims-linked database.

Methods

Study Design and Data Source

This retrospective cohort study used data from deidentified patient records in the Optum Clinical EHR Database from January 1, 2016, through March 31, 2022. Patients aged ≥18 years with at least two diagnoses of AL (International Classification of Diseases, Tenth Revision [ICD-10] code E85.81) or positive mentions of the disease in physician’s notes at least 30 days apart between January 1, 2017, and March 31, 2021, were included (Supplementary Figure 1). Outcomes were considered “condition-related” if they were associated with a primary or secondary ICD-10 diagnosis code indicating either AL-related conditions (E85.81, E85.4, E85.89, E85.9) or cardiac-related conditions, specifically cardiomyopathy (I42.), cardiomyopathy in diseases classified elsewhere (I43.), or heart failure (I50.*). The index date was defined as the date of the first-identified AL diagnosis. Serum levels of NT-proBNP and cTnT closest to the index date were used to identify patients with advanced disease according to the European modification of the Mayo staging system. Patient records were then linked to payer-agnostic claims. Data were assessed from the index date until the end of continuous enrollment in medical and prescription claims (minimum 30-day follow-up) during a 12-month postindex period or until death (last day) if it occurred within the 12-month postindex period. Economic burden (HCRU and costs) was assessed during the maximum follow-up period postindex while patients had continuous medical and prescription enrollment.

Institutional Review Board (IRB) review was not required for this study because it qualifies as exempt under U.S. federal regulations administered by the Department of Health and Human Services. The analysis used a Health Insurance Portability And Accountability Act (HIPAA)-certified, statistically deidentified database generated through expert determination, and therefore did not constitute human subjects research.

Data access was granted by Optum, which maintains the Clinical EHR and Market Clarity databases in compliance with the HIPAA Privacy Rule. The study involved secondary analysis of existing EHR and claims records only, with no interaction with individuals and no use of identifiable private information.

Patients

Patients were included if they had at least 12 months of continuous coverage before diagnosis and had NT-proBNP and cTnT laboratory values closest to the index date within two weeks of each other. These data were used to identify patients with different disease stages, including those with advanced cardiac involvement (Mayo stages IIIa and IIIb). Patients who died in the same month as their index date were excluded.

Outcomes

Healthcare Resource Utilization

HCRU outcomes, including the average number of all-cause and condition-related inpatient hospitalizations, outpatient visits, office visits, ER visits during the 12-month follow-up period after diagnosis, and inpatient length of stay (LOS), were recorded for all patients and for those with advanced cardiac involvement (Mayo stages IIIa and IIIb).

Cost Analysis

A 12-month follow-up analysis was conducted for all patients and for those with advanced cardiac involvement, examining per-patient per-month (PPPM) and per-visit (HCRU event) all-cause and condition-related total, medical, and drug costs. All-cause drug costs included outpatient pharmacy claims as well as medical claims with a Healthcare Common Procedure Coding System (HCPCS) “J” code or National Drug Codes (NDC). Condition-related costs included costs for drugs of interest that were used to treat AL (Supplementary Box 1). Drug costs were the sum of the outpatient prescription costs with drug costs from the management services file based on HCPCS or NDC. Cost analyses were conducted for the full patient cohort and restricted to those observations with an event cost. Costs were inflation-adjusted to the most recent Medical Consumer Price Index (CPI) of 2023 (https://www.usinflationcalculator.com/). Claims with $0 cost were included, and negative cost claims were proxied as $0 cost claims.

Statistical Analysis

Descriptive statistics, including means, SD, and medians with interquartile ranges for continuous variables were presented for HCRU and healthcare costs.

Results

Study Population

A total of 85 patients with confirmed AL in the US Optum claims-linked EHR database and an identifiable Mayo stage based on cardiac biomarkers, were included in the study (Supplementary Figure 2). Most patients (64 of 85 [75%]) were 60 years and older, and more than half (55 of 85 [65%]) were male (Table 1). A substantial proportion of patients had Medicare insurance (Table 1).

Table 1.

Patient Demographics and Disease Characteristics

	All Patients		Patients with Mayo Stage IIIa		Patients with Mayo Stage IIIb		Patients with Advanced Cardiac Involvement (Mayo Stage IIIa + IIIb)a
	N	%	n	%	n	%	n	%
Total	85	100	20	100	27	100	47	100
Age (y)
40–49	3	4	1	5	0	0	1	2
50–59	18	21	5	25	6	22	11	23
60–69	28	33	7	35	7	26	14	30
70–79	25	29	4	20	9	33	13	28
80+	11	13	3	15	5	19	8	17
Gender
Female	30	35	9	45	10	37	19	40
Male	55	65	11	55	17	63	28	60
Insurance type
Commercial	35	41	10	50	8	30	18	38
Medicare	42	49	8	40	15	56	23	49
Medicaid	5	6	2	10	2	7	4	9
Other	3	4	0	0	2	7	2	4
Race
African American	20	24	6	30	6	22	12	26
Asian	1	1	0	0	0	0	0	0
Caucasian	62	73	13	65	21	78	34	72
Other/unknown	2	2	1	5	0	0	1	2

^aPatients with advanced cardiac involvement included those classified as Mayo stages IIIa and IIIb.

Healthcare Resource Utilization

All-Cause HCRU

Almost three-fourths of patients had at least one all-cause inpatient hospitalization (61 of 85 [71.8%]), 82 of 85 (96.5%) had an outpatient visit, 72 of 85 (84.7%) had an office visit, and 47 of 85 (55.3%) had an ER visit during the 12-month evaluation period after diagnosis (Table 2). Among patients with advanced cardiac involvement, more than half had at least one all-cause inpatient hospitalization (39 of 61 [63.9%]), outpatient visit (45 of 82, 54.9%), office visit (39 of 72 [54.2%]), or ER visit (28 of 47, [59.6%]).

Table 2.

HCRU Analysis from Index Date to 12 Months After Diagnosis, Overall and for Advanced Cardiac Involvement

	Inpatient		Outpatient		Office		Emergency Room
	All-Cause	Condition-Related	All-Cause	Condition-Related	All-Cause	Condition-Related	All-Cause	Condition-Related
All patients, n	61	51	82	79	72	63	47	19
12-month FU, mean (SD)	2.85 (1.90)	2.18 (1.05)	35.80 (48.84)	19.15 (17.59)	22.01 (18.00)	12.49 (12.78)	3.68 (3.32)	1.53 (0.96)
Inpatient LOS (those with an obs), mean (SD)	19.40 (16.50)	15.00 (15.60)	NA	NA	NA	NA	NA	NA
Patients with Mayo stage IIIa, n	16	14	20	20	17	14	10	5
12-month FU, mean (SD)	2.94 (1.88)	2.43 (1.45)	37.50 (29.58)	25.30 (19.25)	21.71 (16.78)	11.00 (14.95)	3.20 (3.36)	1.40 (0.89)
Inpatient LOS (those with an obs), mean (SD)	20.13 (20.91)	16.07 (18.84)	NA	NA	NA	NA	NA	NA
Patients with Mayo stage IIIb, n	23	20	25	23	22	20	18	8
12-month FU, mean (SD)	3.09 (2.19)	2.20 (0.95)	17.12 (11.02)	9.30 (7.05)	15.64 (16.15)	10.05 (11.62)	3.78 (3.49)	2.00 (1.20)
Inpatient LOS (those with an obs), mean (SD)	20.48 (13.58)	13.95 (14.41)	NA	NA	NA	NA	NA	NA
Patients with advanced cardiac involvement (Mayo stage IIIa + IIIb)a, n	39	34	45	43	39	34	28	13
12-month FU, mean (SD)	3.03 (2.05)	2.29 (1.17)	26.18 (23.43)	16.74 (16.09)	18.28 (16.50)	10.44 (12.88)	3.57 (3.39)	1.77 (1.09)
Inpatient LOS (those with an obs), mean (SD)	20.33 (16.71)	14.82 (16.14)	NA	NA	NA	NA	NA	NA

^aPatients with advanced cardiac involvement included those classified as Mayo stages IIIa and IIIb.

Abbreviations: FU, follow-up; HCRU, healthcare resource utilization; LOS, length of stay; NA, not available; obs, observation.

During the 12-month follow-up period, the mean (SD) all-cause inpatient hospitalization was 3.03 (2.05) for patients with advanced cardiac involvement (n = 39) (Table 2). Median (range) values are provided in Supplementary Table 2. The mean (SD) all-cause inpatient LOS for patients across all Mayo stages was 19.44 (16.46) days (Table 2). Among patients with advanced cardiac involvement, the mean (SD) all-cause inpatient LOS was 20.33 (16.71) days.

Condition-Related HCRU

More than half of the patients had at least one condition-related inpatient hospitalization (51 of 85, [60%]), 79 of 85 (92.9%) had an outpatient visit, 63 of 85 (74.1%) had an office visit, and 19 of 85 (22.4%) had an ER visit during the 12 months after diagnosis (Table 2). Among patients with advanced cardiac involvement, more than half had at least one condition-related inpatient hospitalization (34 of 51 [66.7%]), outpatient visit (43 of 79 [54.4%]), office visit (34 of 63 [53.9%]), or ER visit (13 of 19 [68.4%]).

During the 12-month follow-up period, the mean (SD) condition-related inpatient hospitalization was 2.29 (1.17) for patients with advanced cardiac involvement (n = 34) (Table 2). Median (range) values are provided in Supplementary Table 2. The mean (SD) condition-related inpatient LOS for patients across all Mayo stages was 15.00 (15.60) days (Table 2). Among patients with advanced cardiac involvement, the mean (SD) condition-related inpatient LOS was 14.82 (16.14) days.

Cost Analysis

All-Cause Costs

During the 12-month follow-up period, the median (range) all-cause total, medical, and drug costs for all patients with AL were $157,286 ($65,680–$231,120), $71,794 ($35,138–$118,693), and $54,991 ($15,569-$115,000), respectively (Supplementary Table 3). The median (range) PPPM all-cause total, medical, and drug costs for patients with advanced cardiac involvement (n = 47) were $17,149 ($8832–$26,067), $8411 ($4462–$16,804) and $5859 ($2384–$10,740), respectively (Figure 1A).

Figure 1.

Median (Range) All-Cause PPPM (A) Total, Medical, and Drug Costs and (B) Inpatient Hospitalization, Outpatient Visit, Office Visit, and ER Visit Costs Analysis, Overall and for Advanced Cardiac Involvement. *Patients with advanced cardiac involvement included those classified as Mayo stages IIIa and IIIb.

Abbreviations: ER, emergency room; IP, inpatient; PPPM, per-patient per-month; SD, standard deviation.

During the 12-month follow-up period, the median (range) all-cause inpatient hospitalization, outpatient visit, office visit, and ER visit costs were $16,928 ($7819–$50,464), $20,470 ($5819–$95,917), $4757 ($600–$12,159), and $1112 ($708–$4329), respectively (Supplementary Table 4). During the 12-month follow-up period, the median (range) all-cause inpatient hospitalization, outpatient visit, office visit, and ER visit costs for patients with advanced cardiac involvement were $16,380 ($7673–$39,022), $18,426 ($4870–$68,454), $2692 ($690–$13,435), and $1394 ($584–$5473), respectively (Supplementary Table 4). The median (range) PPPM all-cause inpatient hospitalization costs for patients with advanced cardiac involvement (n = 39) were $2110 ($936–$8690; Figure 1B). The median (range) PPPM all-cause outpatient, office, and ER visit costs for patients with advanced cardiac involvement were $2981 ($458–11,639), $415 ($127–$1252), and $230 ($70–$646), respectively (Figure 1B).

The mean (SD) values for total, medical, and drug costs, as well as costs related to inpatient hospitalizations, outpatient visits, office visits, and ER visits are provided in Supplementary Tables 5 and 6, respectively.

Condition-Related Costs

During the 12-month follow-up period, the median (range) condition-related total, medical, and drug costs for all patients with AL were $101,333 ($24,190–$148,649), $21,087 ($6472–$48,330), and $41,288 ($11,489–$106,259), respectively (Supplementary Table 3). Over the 12-month follow-up period, the median (range) condition-related total, medical, and drug costs for patients with advanced cardiac involvement (n = 47) were $59,152 ($18,980–$124,564), $15,199 ($5977–$37,886), and $32,345 ($7186–$82,433), respectively (Supplementary Table 3). The median (range) PPPM condition-related total, medical, and drug costs for patients with advanced cardiac involvement (n = 47) were $7532 ($3336–$15,097), $2107 ($1079–$4618), and $4613 ($1664–$9488), respectively (Figure 2A).

Figure 2.

Median (Range) Condition-Related PPPM (A) Total, Medical, and Drug Costs and (B) Inpatient Hospitalization, Outpatient Visit, Office Visit, and ER Visit Costs Analysis, Overall and for Advanced Cardiac Involvement. *Patients with advanced cardiac involvement included those classified as Mayo stages IIIa and IIIb.

Abbreviations: ER, emergency room; IP, inpatient; PPPM, per-patient per-month.

During the 12-month follow-up period, the median (range) condition-related inpatient hospitalization, outpatient visit, office visit, and ER visit costs for patients across all Mayo stages were $3046 ($932–$16,795), $10,989 ($1782–$67,414), $1428 ($247–$11,252), and $451 ($361–$888), respectively (Supplementary Table 4). During the 12-month follow-up period, the median (range) condition-related inpatient hospitalization, outpatient visit, office visit, and ER visit costs for patients with advanced cardiac involvement were $3034 ($838–$13,884), $9979 ($1856–$43,470), $1052 ($242–$11,252), and $490 ($361–$888), respectively (Supplementary Table 4). The median (range) PPPM condition-related inpatient hospitalization costs for patients with advanced cardiac involvement (n = 34) were $462 ($77–$1839) (Figure 2B). The median (range) PPPM condition-related outpatient, office, and ER visit costs for patients with advanced cardiac involvement were $1567 ($208–$6367), $119 ($42–$937), and $80 ($40–$217), respectively (Figure 2B).

Discussion

This retrospective claims study describes the economic burden (HCRU and costs) associated with cardiac AL in a real-world US setting. In the current study, 60% of patients with AL experienced at least one condition-related hospitalization within one year of diagnosis. This finding is consistent with previous reports showing that approximately 65% of patients with incident AL between 2007 and 2015 experienced at least one hospitalization within the first year of diagnosis.⁹ Our study extends prior reports by providing real-world data on patients with advanced AL, as determined by Mayo stage. Approximately 67% of patients with advanced AL had at least one condition-related hospitalization within one year of diagnosis, exceeding the 45–55% estimated by a panel of experts using a modified Delphi method, underscoring the substantial healthcare burden in this high-risk population.¹⁰ Our analysis showed that patients with AL, including those with advanced disease, had an average LOS of 15 days. This finding is consistent with the LOS of 17 days reported in a previous study of patients with incident AL.⁹ Our findings highlight that a notable proportion of patients with AL, particularly those with advanced disease, experience high healthcare utilization likely driven by the substantial clinical burden associated with the disease.

In addition to hospitalizations, our findings show that approximately 22% of patients with AL required ER visits within one year of diagnosis. This aligns with previously reported trends, in which approximately 38% of patients with incident AL had emergency department visits within one year of diagnosis between 2007 and 2015.⁹ Our study provides real-world evidence on patients with advanced AL, showing that a substantial proportion (68%) required ER visits. The notable proportion of patients with advanced AL requiring ER visits underscores the need for frequent urgent care in this high-risk population.

Our analysis indicates that patients with AL experience a substantial economic burden. The annual median all-cause total, medical, and drug costs were $157,286, $71,794, and $54,991, respectively. As expected due to increased costs over time, these costs are noticeably higher than those reported in a previous study, which found annual median all-cause total and medical costs of $69,494 and $56,991, respectively, among incident patients with AL between 2007 and 2015.⁹ Our study extends prior reports by providing costs for patients with advanced AL. An interim analysis was reported earlier.¹¹ In this analysis, we show the complete results. The median PPPM condition-related total, medical, and drug costs for patients with advanced AL were $7532, $2107, and $4613, respectively. To the best of our knowledge, our study is the first to report PPPM costs for patients with AL, particularly those with advanced disease. These findings emphasize the growing economic burden of treating AL, particularly in its advanced stages.

The annual median all-cause hospitalization and ER visit costs were $16,928 and $1112, respectively. To the best of our knowledge, only one study has reported median hospitalization and emergency department costs for patients with AL. Our hospitalization data are consistent with their data of $14,493.⁹ However, the median costs for ER visits were higher in our study. The annual median condition-related inpatient hospitalization and ER visit costs for patients with AL, particularly those with advanced disease, were $3034 and $490, respectively. Our findings further illustrate the growing economic burden of managing AL. Advanced cardiac involvement likely contributes to the increased costs due to frequent hospitalizations, ER visits, outpatient care, and the need for specialized therapies. This economic impact highlights the necessity for developing strategies to mitigate costs without compromising the quality of care.

Study Limitations

The ICD-10 code used to identify patients with AL (E85.81) was introduced in October 2018. Before that, no specific ICD-10 code was available for AL. The effects of the timing of this change on patient identification in the study are uncertain. Including patients with positive mentions in the EHR database likely increased sensitivity for identifying patients with AL but may have reduced specificity by erroneously including patients with other forms of systemic amyloidosis (eg, transthyretin amyloidosis). Some patients may have been miscoded, either inadvertently or deliberately, to ensure reimbursement for off-label medications. The relatively low number of patients classified as Mayo stage I limits the ability to draw robust conclusions regarding outcomes in early-stage disease. The database includes only US data; therefore, conclusions cannot be drawn about global HCRU and costs among patients with AL. Additional limitations include the generalizability of the results for this select population of linked data and the timing of the data sampling period, which primarily occurred before the approval and widespread adoption of daratumumab as first-line therapy starting in January 2021. Patients who died in the same month as their index date were excluded, which may introduce survival bias; previous reports indicate that approximately 13% of patients with AL amyloidosis die within the first month, particularly among those with advanced cardiac involvement (Mayo stage IIIb).¹² This exclusion likely led to underrepresentation of patients with rapidly progressing or severe disease, potentially underestimating the economic burden among the most critically ill patients.

Conclusions

Patients with AL, particularly those with advanced cardiac involvement, often experience frequent and prolonged hospitalizations, as well as numerous office, outpatient, and ER visits. Managing AL is associated with substantial healthcare costs. Therefore, there is a continued need for therapeutic advances to manage patients with higher levels of disease severity.

Funding Statement

This study was funded by Alexion, AstraZeneca Rare Disease. The funding agreement didn’t impact the author’s independence in designing the study, collecting the data, interpreting the data, writing the manuscript and submitting the manuscript for publication.

Abbreviations

AL, light chain amyloidosis; BNP, brain natriuretic peptide; CPI, Consumer Price Index; EHR, electronic health record; ER, emergency room; HCRU, healthcare resource utilization; HCPCS, Healthcare Common Procedure Coding System; ICD-10, International Classification of Diseases, Tenth Revision; LOS, length of stay; NDC, National Drug Codes; NT-proBNP, N-terminal pro-brain natriuretic peptide; PPPM, per-patient per-month; SD, standard deviation; TnI, troponin I; TnT, troponin T.

Data Sharing Statement

Alexion, AstraZeneca Rare Disease will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods like data de-identification, pseudonymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at https://www.alexionclinicaltrialtransparency.com/data-requests/.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

JT, JC, and PAL are employees of Alexion, AstraZeneca Rare Disease and hold stock in the company. AG is an employee of Optum. The authors report no other conflicts of interest in this work.