Abstract
Background
Transthyretin amyloid cardiomyopathy (ATTR-CA) is a progressive, fatal disease that often presents as heart failure with preserved ejection fraction (HFpEF). To date, scarce evidence about the economic burden of ATTR-CA has been published. This study compared the economic impact of HFpEF in patients with and without ATTR-CA in Spain.
Methods
The PRACTICA study was a cross-sectional, multicenter, nationwide study in twenty sites in Spain. A total of 387 consecutive ambulatory or hospitalized patients aged ≥ 50 years with HFpEF and LVH ≥ 12 mm were included and screened for ATTR-CA. Healthcare resource utilization (HRU), except specific pharmacologic treatments, non-HRU and its associated average cost per-patient per-year were assessed in year 2021 for ATTR-CA and non-ATTR-CA patients.
Results
Patients were classified as: ATTR-CA (n = 65), non-ATTR-CA (n = 306) and inconclusive (n = 16). Mean total cost per-patient per-year was higher in ATTR-CA patients: €3,407 (Min-Max: €1,067-€6,473) in ATTR-CA, €3,203 (€1,168-€5,646) in non-ATTR-CA and €2,920 (€1,165-€5,080) in inconclusive patients (p < 0.001, Kruskal-Wallis). Determinants of differential cost favoring ATTR-CA were hospitalizations, genetic testing, implantable cardiac defibrillator, and scintigraphy. No statistical differences were observed between patients with and without ATTR-CA in non-healthcare resources paid by patients themselves, although inconclusive patients showed significantly higher home adaptation (shower, bed rail) and crutch utilization (p = 0.031, Kruskal-Wallis).
Conclusions
This is the first multicenter nationwide study assessing the economic impact on Spanish society of ATTR-CA patients with HFpEF and LVH ≥ 12 mm. The cost was substantial, with negative implications particularly for the Spanish National Health System.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10198-025-01847-7.
Keywords: Transthyretin amyloidosis with cardiomyopathy, Cost analysis, Healthcare resource utilization, Heart failure, Preserved ejection fraction, Cost comparison
Introduction
The term amyloidosis describes a group of diseases whose main finding is extracellular accumulation of fibrillary proteins that lead to loss of normal tissue architecture [1, 2]. Amyloidosis may be systemic or localized and is currently classified according to the type of precursor protein [1, 3]. Despite the intrinsic pathogenic heterogeneity of cardiac amyloidosis in general, most available clinical/instrumental studies address the disease as a single entity [4, 5]. Correct recognition of cardiac amyloidosis and its various types remains a challenge, and the condition may be vastly underdiagnosed [5, 6]. Historically, light-chain (AL) amyloidosis was considered the most frequent form; however, recent evidence has revealed transthyretin (TTR) amyloidosis to be more prevalent [5–8]. Transthyretin cardiac amyloidosis (ATTR-CA) is caused by the accumulation of transthyretin amyloid fibers in the myocardium, causing cardiomyopathy, heart failure (HF) and, ultimately, death [2, 3]. Two forms of ATTR-CA have been described, a genetic (hereditary) form (ATTRv-CA) and a wild-type (sporadic) form (ATTRwt-CA), with the wild-type form being more frequent [3, 4, 6, 9]. ATTR-CA mirrors other, more common forms of left ventricular hypertrophy (LVH) such as hypertensive heart disease, or even heart failure with preserved ejection fraction (HFpEF).
HFpEF is expected to increase considerably in the coming years due to population aging [7, 8]. However, HFpEF is a frequent manifestation of several underlying myocardial diseases, including ATTR-CA [2, 5–7]. Advances in disease awareness and diagnostic procedures show the proportion of HFpEF patients with a formal diagnosis of TTR amyloidosis has increased significantly [6, 8, 10]. Identifying the etiology underlying HFpEF is a crucial step towards improved patient management, as patient management will vary depending on the etiology [5, 6, 8]. Even though awareness among heart specialists has increased in recent years, ATTR-CA is frequently misdiagnosed, which, in turn, delays correct diagnosis several years [10]. As the disease progresses, patients become unable to carry out their daily lives, increased care is required, and a meaningful decline in health-related quality of life (HRQoL) and work productivity, in active workers, occurs [11].
Given the known substantial patient and economic burden of ATTR-CA and the availability of treatment options, it has become increasingly important to understand differences in patient burden and overall cost of HFpEF depending on the underlying etiology [12]. To date, scarce evidence about the economic burden of ATTR-CA has been published [12, 13], although some evidence on cost of illness is available in relation to the neuropathic version of this health condition [14–16]. This research was a secondary objective of the national PRACTICA study, whose main goal was to ascertain the prevalence of ATTR-CA in patients ≥ 50 years with HFpEF and LVH ≥ 12 mm in Spain [17]. Secondarily, this study estimated the use and annual costs of healthcare and non-healthcare resource utilization in patients with HFpEF according to their ATTR-CA status from a societal perspective in Spain.
Methods
Study design and data source
The cost comparison analysis included here was conducted as a secondary objective of the published PRACTICA study (“PRevalencia de Amiloidosis Cardiaca por TranstIretina en pacientes con Insuficiencia CArdiaca con fracción de eyección preservada”) [17]. The PRACTICA study was designed as a multicenter, cross-sectional, non-interventional prevalence study that was carried out in twenty tertiary hospitals all over Spain (Pfizer protocol number B3461067). Its secondary objectives included the estimation of cost of HFpEF, comparing patients with and without ATTR-CA. The economic evaluation was carried out following national and international recommendations for evaluations of this type [18–20], and included the societal perspective in Spain, which comprises the patient and the Spanish National Health System (NHS) perspectives. Sources of data were hospital and outpatient medical records to characterize samples according to ATTR-CA status. All patients provided written informed consent prior to study enrollment. The study protocol was submitted and approved by the Clinical Research Ethic Committee of the Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain (date of approval: January 31 st, 2019).
In enrolled patients, screening for cardiac amyloidosis was carried out according to clinical practice in each center. Bone scintigraphy was analyzed locally and centrally; centralized results were established as valid to decrease inter-rater bias. Patients underwent monoclonal protein studies (serum chain assay and immunofixation electrophoresis of blood and urine) to rule out AL amyloidosis, as well as genetic testing following European and Spanish recommendations for the diagnosis of ATTR-CA at the time of the study [6, 21, 22]. Biopsy was performed when required and following routine clinical practice. A patient was considered to have ATTR-CA when they presented a Perugini grade of 2 or 3 in scintigraphy and hematological testing showed absence of the monoclonal component. In the absence of confirmatory biopsy, patients with grade 2–3 cardiac uptake and monoclonal protein abnormalities were classified as inconclusive patients; if biopsy demonstrated TTR deposition, ATTR-CA was diagnosed. Those patients in which ATTR-CA was ruled out were considered non-ATTR-CA patients.
Study sample
The sample in this study consists of patients who met the following inclusion criteria: men and women ≥ 50 years of age, diagnosis of HFpEF according to the criteria of the European Society of Cardiology at the time of the study [22], at least one previous admission for heart failure (HF) in the last 24 months, echocardiogram evidence of LVH ≥ 12 mm and a signed informed consent indicating that the patient (or their legal representative) has been informed of all relevant aspects of the study. Exclusion criteria: presence or history of significant valvular heart disease or coronary artery disease in at least one major coronary artery, patients with a diagnosis of the origin of hypertrophic cardiomyopathy or restrictive cardiomyopathy (cardiomyopathy with sarcomeric mutation, myeloma, Fabry disease, sarcoidosis, any type of amyloidosis), and withdrawal of informed consent.
Healthcare and non-healthcare resource utilization
As this economic analysis was a secondary objective of the cross-sectional and retrospective PRACTICA study [17], only resources consumption available in patient´s records were abstracted. The number and type of unitary healthcare resources used by study participants (Tables 1 and 2), including outpatient medical visits, hospitalization days, medical tests, etc., during the 12 months prior to enrolment in the study were recorded in the case report form (study time horizon) abstracting the data from medical records. Medical visits included Primary Care physicians, nurses, medical specialties, and emergency department visits. Medical tests included any kind of laboratory or diagnostic test requested by physicians. Hospitalizations and general length of hospital stay in days were also assessed. Healthcare resources used by patients and funded by the patient themselves or their family, such as medical transport, and other health materials, including crutches, wheelchair, home adaptations, walking sticks, and others, were also recorded. Recording was carried out during the enrollment visit by means of a face-to-face interview. Non-healthcare resource use included sick leave days due to the disease, hours of work lost by the patient/career and the companion were also collected. Collection of these data was also carried out using the same face-to-face visit at enrollment of the participant in the study.
Table 1.
Healthcare resource utilization per-patient-per-year by ATTR-CA status
| Resource | ATTR-CA | Non ATTR-CA | ATTR-CA inconclusive | p value* |
|---|---|---|---|---|
| Medical visits | n = 65 | n = 306 | n = 16 | |
| Specialist | 2.3 (3.0) | 3.0 (3.5) | 2.2 (1.8) | 0.254 |
| Emergency department | 1.5 (1.6) | 1.6 (1.7) | 1.1 (1.5) | 0.307 |
| Primary care | 4.0 (5.5) | 4.5 (5.7) | 4.9 (5.5) | 0.882 |
| Outpatient hospital | 0.3 (1.0) | 0.4 (1.6) | 0.0 (0.0) | 0.275 |
| Surgery | 0.4 (1.3) | 0.2 (0.8) | 0.0 (0.0) | 0.342 |
| Nursing | 1.8 (4.1) | 3.0 (7.1) | 2.8 (5.8) | 0.332 |
| Hospitalizations | n = 65 | n = 306 | n = 16 | |
| Intensive care unit | 0.0 (0.0) | 0.0 (0.2) | 0.0 (0.0) | 0.468 |
| General ward | 1.3 (0.8) | 1.7 (1.6) | 1.4 (0.7) | 0.076 |
| Complementary and diagnostic tests | n = 60 | n = 281 | n = 15 | |
| Any complementary and diagnostic test | 76.7% | 77.6% | 73.3% | 0.847 |
| Cardiac catheterization | 0.0% | 4.6% | 0.0% | 0.195 |
| Cystoscopy | 0.0% | 0.3% | 0.0% | 0.876 |
| Colonoscopy | 1.5% | 2.3% | 0.0% | 0.779 |
| Coronarography | 0.0% | 2.3% | 0.0% | 0.390 |
| Electrocardiogram | 26.2% | 63.7% | 50.0% | 0.128 |
| Thyroid or abdominal ultrasound | 1.5% | 2.9% | 6.3% | 0.582 |
| Electromyogram | 1.5% | 1.0% | 0.0% | 0.845 |
| Upper endoscopy | 0.0% | 0.3% | 0.0% | 0.876 |
| Fibro gastroscopy | 0.0% | 1.0% | 0.0% | 0.671 |
| Scintigraphy | 40.0% | 23.2% | 12.5% | 0.007 |
| Holter | 3.1% | 3.3% | 12.5% | 0.152 |
| Pacemaker (implant/revision/replacement) | 1.5% | 0.3% | 0.0% | 0.446 |
| Removal of fluid from the abdomen | 0.0% | 6.5% | 0.0% | 0.876 |
| Outpatient respiratory polygraphy | 0.0% | 0.3% | 0.0% | 0.876 |
| Respiratory functional tests | 4.6% | 2.9% | 6.3% | 0.117 |
| Fine needle puncture-aspiration | 0.0% | 0.3% | 0.0% | 0.068 |
| Chest x-ray | 20.0% | 42.8% | 43.8% | 0.750 |
| Heart or prostate magnetic resonance | 7.7% | 2.6% | 0.0% | 0.058 |
| Cardiac SPECT | 0.0% | 0.3% | 0.0% | 0.876 |
| Coronary/cardiac computed axial tomography | 1.5% | 2.6% | 12.5% | 0.037 |
| Brain computed tomography | 4.6% | 6.2% | 6.3% | 0.884 |
| Retrograde urethral cystoscopy | 0.0% | 0.3% | 0.0% | 0.876 |
| Other medical exams | n = 65 | n = 306 | n = 16 | |
| Light chains test | 98.5% | 10.5% | 100.0% | < 0.001 |
| Genetic test | 86.2% | 1.0% | 68.8% | 0.001 |
| Implantable cardiac defibrillator | 1.5% | 0.3% | 0.0% | 0.446 |
| Bone marrow biopsy | 0.0% | 0.3% | 0.0% | 0.876 |
| Unspecified biopsy | 18.5% | 0.7% | 12.5% | < 0.001 |
| Other healthcare resource # | n = 48 | n = 232 | n = 12 | |
| Physiotherapy | 0.1 (0.4) | 0.0 (0.4) | 1.0 (2.4) | < 0.001 |
| Rehabilitation | 0.4 (2.2) | 0.0 (0.5) | 0.0 (0.0) | 0.031 |
| Optometry (%) | 0.0% | 1.0% | 0.0% | 0.671 |
| Home health care (%) | 23.7% | 13.9% | 14.3% | 0.153 |
| Physiotherapy | 3.0% | 1.6% | 0.0% | 0.521 |
| Rehabilitation | 0.0% | 0.3% | 0.0% | 0.999 |
| Nursing | 12.0% | 6.2% | 6.0% | 0.201 |
ATTR-CA transthyretin amyloidosis with cardiomyopathy, SPECT single photon emission computed tomography. Data are expressed as mean (standard deviation) or percentage. Non parametric estimates (median, P25 and P75) are included in supplementary information.
* Kruskal-Wallis or Fisher exact test. Numbers in bold are statistically significant. # in the last month
Measurement of costs
The costs included in the analysis were those corresponding to healthcare and non-healthcare resource utilization. Healthcare resources included medical visits, hospitalizations, specialist visits, complementary tests, etc. Unitary costs were obtained from the Spanish healthcare cost database, the eSalud Healthcare Cost Database [23], or published prices for non-healthcare resources. Non-healthcare resources were those related to lost work hours for employed patients and their caregivers, as well as other resources paid by the patient themselves and not reimbursed by the Spanish NHS [18–20]. Cost per work hour and cost per working day were obtained from the Spanish National Statistics Institute, corresponding to the average salary for the year 2021 [24], and the human capital method was applied to compute indirect cost due to lost work hours [19, 20]. Supplementary table S1 includes the list of resources analyzed and their unitary prices. All costs were computed in Euros for the year 2021 from the societal perspective. Due to the 12-month study (time horizon), no discount rate was applicable to update the cost at present. Resource costs were calculated for each concept analyzed by multiplying the total amount of resource used by the unitary cost of each resource, as follows: Resource cost = (amount of resource) x (unit cost of the resource). The cost-per-patient (minimum, average, and maximum) was obtained by dividing the total resources used by the total number of patients in the study in each group, giving the average number of resources used per patient. This average number was multiplied by its cost to give the minimum, average, and maximum cost, as follows: Cost-per-patient = (average amount of resource/total N of patients) x (unit cost of the resource). The cost analysis did not compute the cost corresponding to medication or therapies used in the evaluated patients.
Statistical analysis
The normality of data assessed was checked by means of the Shapiro-Wilk test. For qualitative data, descriptive univariate analysis was conducted including absolute and relative frequencies. For quantitative data, the analysis used central and dispersion measures: mean, standard deviation, minimum and maximum observed values. These measures might facilitate readers and/or health decision maker to make projections and/or forecasting costs using other samples or moment different than the one collected in this study. Also, median and percentiles 25 (P25) and 75 (P75) are included in supplementary tables (see supplemental information tables S3 to S6). Comparative analysis included the analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis test for non-normal variables. Analysis of contingency tables was used for qualitative variables, as well as for the comparison of proportions and/or frequency distributions, using the chi-square test (or Fisher’s exact test when appropriate). In all cases the significance level was set to be 0.05 and two-sided. The data was analyzed using the statistical programming language R (v. 4.0.3). As a sensitivity analysis, the economic evaluation computed not only the average cost for each group of patients evaluated, but also the high and low mean cost, applying the minimum and maximum prices for each resource used by patients [19, 20].
The manuscript was prepared according to the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement (see supplementary information, table S7) [25].
RESULTS
At the time of database closure, a total of 422 individuals fulfilling inclusion criteria had been included in the study, 35 (8.3%) of whom lacked scintigraphy and protein studies to establish an ATTR-CA status. Briefly, the analyzed sample was constituted by 306 (79.1%) non-ATTR-CA, 65 (16.8%) ATTR-CA, and 16 (4.1%) inconclusive ATTR-CA. Four of the ATTR-CA patients had hereditary form. The demographic and clinical characteristics of these patients have already been published [17] and are also summarized in supplementary table S2. By gender, 52.5% of patients were male, with a mean age of 79.6 years (SD = 8.2). A total of 60.7% of patients were evaluated during a HF hospitalization (67.7% ATTR-CA and 59.2% non-ATTR-CA, p = 0.448, Kruskal-Wallis), while the rest of the participants were enrolled in an outpatient medical facility. The most common comorbidities were hypertension (79%), diabetes mellitus (37%), renal failure (34%), and ischemic cardiomyopathy (11%). Only 5 out of 385 patients (all non-ATTR-CA) were employed, who worked a mean of 16 ± 21.9 h and lost a mean of 15 ± 20.6 h in the previous 7 days due to health issues. There were no significant differences in annual lost work hours of caregivers, with ~ 15% of the caregivers being impacted a median of 16 h (IQR 14–42) for ATTR-CA (n = 7), 30 h (IQR 14–50) for non-ATTR-CA (n = 41).A significantly high percentage of ATTR-CA patients had traveled for medical assistance in the last month (94.9% for ATTR-CA vs. 82.9% non-ATTR-CA vs. 73.3%, inconclusive patients, p = 0.016, Kruskal-Wallis). Regarding the impact of health issues on the ability to perform daily activities, there was a significant difference between ATTR-CA and non-ATTR-CA patients in a 0–10 points scale (from no interference to completely impaired, respectively) (mean 7 ± 2.5 vs. 6 ± 2.7, respectively, p = 0.003, Kruskal-Wallis).
Healthcare and non-healthcare resource utilization
Healthcare and non-healthcare resource utilization are shown in Tables 1 and 2, respectively. No significant differences were found among populations in terms of medical visits and hospitalizations. All analyzable patients had scintigraphy performed at diagnosis, and additional scintigraphy was also used by 40% of ATTR-CA patients, compared with 23.2% and 12.5% used by non-ATTR-CA and inconclusive patients, respectively (Table 1, p = 0.007, Kruskal-Wallis). Hematological tests were performed as per diagnostic flow in clinical practice in each center, with a higher number of ATTR-CA or inconclusive patients tested in comparison with non-ATTR-CA patients (p < 0.001, Kruskal-Wallis). As expected, use of genetic testing was significantly higher in ATTR-CA than in non-ATTR-CA patients (see Table 1, p < 0.01, Kruskal-Wallis). As per clinical indication, biopsies were performed in a significantly higher number of ATTR-CA patients: 18.5% versus 0.7% and 12.5% in non-ATTR-CA and inconclusive patients, respectively (p < 0.001, Kruskal-Wallis). Furthermore, coronary/cardiac computed axial tomography was used significantly less by ATTR-CA patients (p = 0.037, Kruskal-Wallis).
Table 2.
Non-healthcare resource utilization per individual per year by ATTR-CA status
| Resource | ATTR-CA | Non ATTR-CA | ATTR-CA inconclusive | p value* |
|---|---|---|---|---|
| Labor | ||||
| Active worker | 0.0% | 1.6% | 0.0% | 0.670 |
| Annual working hour lost | ||||
|
Patient Caregiver |
n = 0 - n = 7 23.1 (16.6) |
n = 5 15.0 (20.6) n = 41 33.6 (25.9) |
n = 0 - n = 1 240.0 (-) |
- 0.160 |
| Home adaptations #,** | n = 61 | n = 273 | n = 15 | |
| 6.6% | 2.6% | 13.3% | 0.031 | |
| Handle | 1.5% | 0.0% | 0.0% | 0.084 |
| Shower | 0.0% | 0.3% | 6.3% | 0.005 |
| Bath | 1.5% | 0.3% | 0.0% | 0.446 |
| Corridor railing | 0.0% | 0.3% | 0.0% | 0.876 |
| Bed railing | 0.0% | 0.0% | 6.3% | < 0.001 |
| Emergency caller bottom | 0.0% | 0.3% | 0.0% | 0.876 |
| Orthopedic bed | 3.1% | 0.0% | 0.0% | 0.076 |
| Shower plate | 1.5% | 0.0% | 0.0% | 0.084 |
| Recliner chair | 1.5% | 0.3% | 0.0% | 0.446 |
| n = 61 | n = 273 | n = 15 | ||
| Other resources# | 34.9% | 27.6% | 46.7% | 0.179 |
| Walker | 4.6% | 4.9% | 12.5% | 0.400 |
| Walking stick | 16.9% | 13.7% | 18.8% | 0.709 |
| Caregiver | 0.0% | 0.3% | 0.0% | 0.876 |
| Crutch | 7.7% | 1.3% | 12.5% | 0.001 |
| Domestic cleaning | 0.0% | 0.3% | 0.0% | 0.876 |
| Wheelchair | 12.3% | 8.8% | 0.0% | 0.295 |
| Electric wheelchair | 1.5% | 0.0% | 0.0% | 0.084 |
ATTR-CA transthyretin amyloidosis with cardiomyopathy. Data are expressed as mean (standard deviation) or percentage. Non parametric estimates (median, P25 and P75) are included in supplementary information
* Kruskal-Wallis or Fisher exact test.
** Home adaptations were observed in 13 patients only. Numbers in bold are statistically significant. # in the last month.
Regarding out-of-pocket healthcare resources, physiotherapy was used significantly more by patients without a final diagnosis (inconclusive patients) than in the other groups (p < 0.001, Kruskal-Wallis), in contrast with rehabilitation, which was most used by ATTR-CA patients (p = 0.031) (Table 1). The analysis did not find any other statistical differences in healthcare resource utilization or home healthcare between groups. Among non-healthcare resource utilization, home adaptations were recorded in 13 participants only (Table 2). Non-healthcare resource utilization was similar in ATTR-CA and non-ATTR-CA patients, while inconclusive ATTR-CA subjects showed statistically higher utilization of shower adaptations, bed rails, and crutches (Table 2, p < 0.01, Kruskal-Wallis).
Resource utilization costs
Tables 3 and 4; Fig. 1 show the cost analysis of the study. Mean total cost per-patient-per-year was significantly higher in ATTR-CA patients: €3,407 (Min-Max; €1,067-€6,473) vs. €3,203 (€1,168-€5,646) and €2,920 (€1,165-€5,080) in non-ATTR-CA and inconclusive ATTR-CA patients, respectively (p < 0.001, Kruskal-Wallis, Fig. 1). These differences were mainly due to diagnostic tests, such as light chain tests, genetic testing, unspecified biopsy, or scintigraphy (Table 3). No significant differences were observed in mean non-healthcare resources paid by the patient themselves, although inconclusive patients showed significantly higher home adaptation (shower, bed rail) and crutch utilization (p = 0.001, Kruskal-Wallis, Table 4.). This component represented less than 10% of total cost: 7.9% in ATTR-CA, 6.7% in non-ATTR-CA, and 12.8% in inconclusive ATTR-CA patients (Fig. 1).
Table 3.
Mean healthcare resource cost (€, 2021) per-patient-per-year by ATTR-CA status
| Resource | ATTR-CA | Non ATTR-CA | ATTR-CA inconclusive | p value* | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Medical visits | n = 65 | n = 306 | n = 16 | ||||||||||||||
| Mean | Min | Max | Mean | Min | Max | Mean | Min | Max | |||||||||
| Specialist | 345.7 (448.3) | 135.3 | 569.9 | 441.1 (510.5) | 172.6 | 727.1 | 332.6 (261.7) | 130.2 | 548.3 | 0.254 | |||||||
| Emergency department | 309.9 (351.3) | 24.1 | 535.1 | 350.8 (365.3) | 27.3 | 605.8 | 241.1 (280.7) | 18.8 | 416.3 | 0.307 | |||||||
| Primary care | 225.6 (306.9) | 112.3 | 380.4 | 252.4 (322.9) | 125.7 | 425.7 | 277.3 (310.7) | 138.1 | 467.8 | 0.882 | |||||||
| Outpatient hospital | 69.2 (239.5) | 32.0 | 131.3 | 99.9 (387.1) | 51.6 | 211.6 | 0.0 (0.0) | 0.0 | 0.0 | 0.275 | |||||||
| Surgery | 96.8 (319.5) | 50.2 | 163.3 | 56.9 (193.5) | 29.6 | 96.1 | 0.0 (0.0) | 0.0 | 0.0 | 0.342 | |||||||
| Nursing | 56.3 (128.5) | 21.0 | 92.5 | 94.1 (231.2) | 35.0 | 154.4 | 88.7 (184.4) | 33.1 | 145.7 | 0.332 | |||||||
| Hospitalizations | n = 65 | n = 306 | n = 16 | ||||||||||||||
| Intensive care unit | 0.0 (0.0) | 0.0 | 0.0 | 113.5 (804.2) | 33.3 | 188.1 | 0.0 (0.0) | 0.0 | 0.0 | 0.468 | |||||||
| General ward | 856.8 (857.4) | 367.8 | 1345.7 | 1201.2 (1445.3) | 515.7 | 1886.7 | 870.2 (792.6) | 373.6 | 1366.8 | 0.076 | |||||||
| Complementary and diagnostic tests | n = 60 | n = 281 | n = 15 | ||||||||||||||
| Biochemistry and blood counts | 50.0 (140.0) | NA | NA | 37.7 (105.9) | NA | NA | 20.3 (57.2) | NA | NA | 0.583 | |||||||
| Cardiac catheterization | 0.0 (0.0) | 0.0 | 0.0 | 52.6 (274.5) | 6.8 | 133.6 | 0.0 (0.0) | 0.0 | 0.0 | 0.195 | |||||||
| Cystoscopy | 0.0 (0.0) | 0.0 | 0.0 | 0.8 (13.6) | 0.2 | 2.2 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Colonoscopy | 4.6 (36.8) | 1.2 | 9.3 | 6.8 (44.4) | 1.8 | 13.8 | 0.0 (0.0) | 0.0 | 0.0 | 0.779 | |||||||
| Coronarography | 0.0 (0.0) | 0.0 | 0.0 | 21.8 (142.4) | 10.2 | 29.3 | 0.0 (0.0) | 0.0 | 0.0 | 0.390 | |||||||
| Electrocardiogram | 14.1 (60.5) | 2.2 | 47.3 | 34.5 (106.2) | 5.2 | 115.3 | 26.9 (55.7) | 4.1 | 90.5 | 0.128 | |||||||
| Thyroid or abdominal ultrasound | 1.3 (10.6) | 0.6 | 2.2 | 2.5 (14.4) | 1.1 | 4.2 | 5.3 (21.3) | 2.2 | 8.9 | 0.582 | |||||||
| Electromyogram | 2.4 (19.0) | 1.4 | 4.0 | 1.5 (15.1) | 0.9 | 2.5 | 0.0 (0.0) | 0.0 | 0.0 | 0.845 | |||||||
| Upper endoscopy | 0.0 (0.0) | 0.0 | 0.0 | 1.6 (28.1) | 1.1 | 2.1 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Fibro gastroscopy | 0.0 (0.0) | 0.0 | 0.0 | 1.8 (18.5) | 0.6 | 4.3 | 0.0 (0.0) | 0.0 | 0.0 | 0.671 | |||||||
| Scintigraphy | 121.5 (149.9) | 29.29 | 208.1 | 70.5 (135.3) | 16.9 | 120.7 | 38.0 (103.7) | 9.1 | 65.0 | 0.007 | |||||||
| Holter | 4.0 (22.8) | 1.5 | 7.5 | 4.3 (23.3) | 1.6 | 7.9 | 16.4 (44.7) | 6.2 | 30.4 | 0.152 | |||||||
| Pacemaker (implant/revision/replacement) | 72.0 (580.6) | 3.7 | 191.8 | 15.3 (267.6) | 0.8 | 40.8 | 0.0 (0.0) | 0.0 | 0.0 | 0.446 | |||||||
| Removal of fluid from the abdomen | 0.0 (0.0) | 0.0 | 0.0 | 6.0 (105.3) | 4.3 | 8.3 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Outpatient respiratory polygraphy | 0.0 (0.0) | 0.0 | 0.0 | 1.3 (22.5) | 0.3 | 1.7 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Respiratory functional tests | 2.7 (12.6) | 0.8 | 6.1 | 1.7 (21.2) | 0.5 | 3.9 | 3.7 (14.9) | 1.1 | 8.3 | 0.117 | |||||||
| Fine needle puncture-aspiration | 7.5 (42.4) | 0.0 | 0.0 | 0.8 (13.9) | 0.2 | 1.9 | 0.0 (0.0) | 0.0 | 0.0 | 0.068 | |||||||
| Chest x-ray | 4.5 (12.7) | 1.9 | 6.9 | 9.7 (27.7) | 4.1 | 14.7 | 9.9 (28.5) | 4.1 | 15.1 | 0.750 | |||||||
| Heart or prostate magnetic resonance | 28.6 (100.0) | 22.7 | 36.9 | 9.7 (66.7) | 7.7 | 12.6 | 0.0 (0.0) | 0.0 | 0.0 | 0.058 | |||||||
| Cardiac SPECT | 0.0 (0.0) | 0.0 | 0.0 | 1.0 (18.1) | 0.5 | 1.9 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Coronary/cardiac computed axial tomography | 3.9 (31.8) | 0.8 | 5.9 | 6.7 (40.9) | 1.4 | 10.0 | 32.0 (87.5) | 6.8 | 47.9 | 0.037 | |||||||
| Brain computed tomography | 11.2 (51.1) | 4.3 | 18.6 | 15.0 (61.6) | 5.7 | 25.0 | 15.1 (60.4) | 5.8 | 25.2 | 0.884 | |||||||
| Retrograde urethral cystoscopy | 0.0 (0.0) | 0.0 | 0.0 | 0.5 (9.5) | 0.5 | 0.7 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Other medical exams | n = 65 | n = 306 | n = 16 | ||||||||||||||
| Light chains test | 20.7 (2.6) | 9.2 | 27.1 | 2.2 (6.4) | 1.0 | 2.9 | 21.0 (0.0) | 9.4 | 27.5 | < 0.001 | |||||||
| Genetic test | 509.8 (206.0) | 114.0 | 1027.9 | 5.8 (58.4) | 1.3 | 11.7 | 406.8 (283.3) | 91.0 | 820.3 | 0.001 | |||||||
| Implantable cardiac defibrillator | 299.8 (2417.3) | 22.7 | 697.3 | 63.7 (1114.1) | 4.8 | 148.1 | 0.0 (0.0) | 0.0 | 0.0 | 0.446 | |||||||
| Bone marrow biopsy | 0.0 (0.0) | 0.0 | 0.0 | 0.4 (6.5) | 0.2 | 0.6 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Unspecified biopsy | 34.8 (73.8) | 15.6 | 47.0 | 1.2 (15.2) | 0.6 | 1.7 | 23.6 (64.4) | 10.5 | 31.8 | < 0.001 | |||||||
| Other healthcare resources | n = 48 | n = 232 | n = 12 | ||||||||||||||
| Physiotherapy | 1.2 (9.4) | 0.2 | 4.1 | 0.7 (9.2) | 0.1 | 2.6 | 18.9 (52.6) | 3.2 | 67.3 | < 0.001 | |||||||
| Rehabilitation | 9.0 (58.3) | 1.1 | 26.2 | 1.0 (12.4) | 0.1 | 2.9 | 0.0 (0.0) | 0.0 | 0.0 | 0.031 | |||||||
| Optometry | 0.0 (0.0) | 0.0 | 0.0 | 0.3 (4.7) | 0.2 | 0.3 | 0.0 (0.0) | 0.0 | 0.0 | 0.671 | |||||||
ATTR-CA transthyretin amyloidosis with cardiomyopathy, SPECT single photon emission computed tomography, Data are expressed as mean (standard deviation). Minimum and maximum costs. Non parametric estimates (median, P25 and P75) are included in supplementary information. * Kruskal-Wallis test. NA not available. Numbers in bold are statistically significant
Fig. 1.
Total cost (€, year 2021) per-patient-per-year and relative cost (%) by healthcare and non-healthcare components in ATTR-CA, non-ATTR-CA and inconclusive patients
Table 4.
Mean non-healthcare resource cost (€, 2021) per individual per year by ATTR-CA status
| Resource | ATTR-CA | Non ATTR-CA | ATTR-CA inconclusive | p value* | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Min | Max | Mean | Min | Max | Mean | Min | Max | |||||||||
| Labor | n = 7 caregivers | n = 41 caregivers + 5 patients | n = 1 | ||||||||||||||
| Working hour lost (patient and/or caregiver) | 50.3 (178.4) | 43.8 | 54.5 | 91.0 (299.1) | 79.3 | 98.6 | 302.8 (1211.4) | 263.9 | 328.2 | 0.677 | |||||||
| Home adaptations | n = 61 | n = 273 | n = 15 | ||||||||||||||
| Handle | 0.5 (3.9) | 0.1 | 1.8 | 0.0 (0.0) | 0.0 | 0.0 | 0.0 (0.0) | 0.0 | 0.0 | 0.084 | |||||||
| Shower | 0.0 (0.0) | NA | NA | 1.4 (23.7) | NA | NA | 25.9 (103.7) | NA | NA | 0.005 | |||||||
| Bath | 7.4 (59.5) | NA | NA | 1.6 (27.4) | NA | NA | 0.0 (0.0) | NA | NA | 0.446 | |||||||
| Corridor railing | 0.0 (0.0) | 0.0 | 0.0 | 0.3 (4.6) | 0.1 | 0.8 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Bed railing | 0.0 (0.0) | 0.0 | 0.0 | 0.0 (0.0) | 0.0 | 0.0 | 4.1 (16.5) | 1.6 | 8.6 | 0.001 | |||||||
| Emergency caller bottom | 0.0 (0.0) | 0.0 | 0.0 | 0.1 (2.4) | 0.1 | 0.3 | 0.0 (0.0) | 0.0 | 0.0 | 0.876 | |||||||
| Orthopedic bed | 18.2 | 7.7 | 36.6 | 0.0 (0.0) | 0.0 | 0.0 | 0.0 (0.0) | 0.0 | 0.0 | 0.084 | |||||||
| Shower plate | 4.5 (36.6) | 1.7 | 8.2 | 0.0 (0.0) | 0.0 | 0.0 | 0.0 (0.0) | 0.0 | 0.0 | 0.084 | |||||||
| Recliner chair | 0.0 (0.0) | 2.6 | 6.1 | 0.0 (0.0) | 0.6 | 1.3 | 18.4 (73.7) | 0.0 | 0.0 | < 0001 | |||||||
| Other resources | n = 61 | n = 273 | n = 15 | ||||||||||||||
| Walker | 4.4 (20.2) | 1.6 | 11.5 | 4.7 (20.7) | 1.7 | 12.2 | 11.9 (32.6) | 4.3 | 31.1 | 0.400 | |||||||
| Walking stick | 4.3 (9,6) | 2.5 | 10.7 | 3.5 (9.0)) | 2.0 | 8.7 | 4.8 (10.3) | 2.8 | 11.8 | 0.709 | |||||||
| Caregiver (€/h) | 0.0 (0.0) | NA | NA | 0.0 (0.0) | NA | NA | 1.6 (6.4) | NA | NA | < 0.001 | |||||||
| Crutch | 4.3 (9.6) | 1.5 | 9.9 | 3.5 (9.0) | 0.3 | 1.7 | 4.8 (10.3) | 2.5 | 16.1 | 0.669 | |||||||
| Domestic cleaning (€/h) | 0.0 (0.0) | NA | NA | 0.1 (0.9) | NA | NA | 0.0 (0.0) | NA | NA | 0.876 | |||||||
| Wheelchair | 118.6 (343.9) | 17.9 | 691.2 | 100.7 (317.9) | 12.8 | 495.5 | 0.0 (0.0) | 0.0 | 0.0 | 0.401 | |||||||
| Electric wheelchair | 24.8 (200.0) | 11.6 | 49.5 | 0.0 (0.0) | 0.0 | 0.0 | 0.0 (0.0) | 0.0 | 0.0 | 0.084 | |||||||
ATTR-CA transthyretin amyloidosis with cardiomyopathy. Data are expressed as mean (standard deviation). Minimum and maximum costs. Non parametric estimates (median, P25 and P75) are included in supplementary information. NA Not available * Kruskal-Wallis test
Sensitivity analysis
In the sensitivity analysis, using the high and low mean prices for healthcare and non-healthcare resources, mean total cost per-patient-per-year ranged between €1,067 and €6,473 in ATTR-CA patients versus €1,168 to €5,646, and €1,165 to €5,080 in non-ATTR-CA and inconclusive ATTR-CA patients (p < 0.001, Kruskal-Wallis, Fig. 1). While low prices utilization showed similar annual total cost per patient, applying higher prices, there were significant differences between the three groups analyzed: between €800 and 1,600 per year. Scintigraphy and genetic tests (see Table 3) were the major determinants for such differences (p < 0.001, Kruskal-Wallis in both cases). Coronary/cardiac computed axial tomography, although to a lower extent, was also a contributed determinant for the statistical differences in total cost per patient per year (p < 0.05, Kruskal-Wallis, Table 3), while other resources, even of statistical significance, were of a lower contribution to the observed differences between groups.
Discussion and conclusion
PRACTICA is the first study to provide data on the utilization and costs of healthcare and non-healthcare resources in ATTR-CA and non-ATTR-CA patients in a real-world setting. The cost per-patient per-year of ATTR-CA patients with HFpEF in 2021 was found to be significantly higher compared with non-ATTR-CA or inconclusive ATTR-CA patients, although the difference, approximately €200 per year, with a range variation from a minimum of €100 to a maximum of ~€800, could be considered of a magnitude of small effect size [26]. This differential economic impact is of a similar magnitude to the cost of delaying the diagnosis of ATTR-CA one year, which corresponds to €212, as reported by Formiga et al., also in Spain [12]. As expected, the main driver of the incremental cost of ATTR-CA patients versus non-ATTR-CA was the performance of genetic testing in 86% of ATTR-CA patients, versus barely 1% in non-ATTR-CA. Furthermore, requests for light chain tests were significantly higher in ATTR-CA, which was accompanied by a significantly higher cost. Although current guidelines recommend performing scintigraphy and light chain testing simultaneously [27], it is possible that, following clinical practice at the time of the study, some centers did not request the hematological study until the result of the scintigraphy was confirmed. Thus, with the current recommendations, this difference could be smaller. Another important determinant of higher cost in ATTR-CA was the request of scintigraphy in many more patients: 40% versus 23% approximately. Since all analyzable patients had a scintigraphy, we cannot confirm whether this difference is due to additional requests or other, un-recorded reasons such as differences in local patient management guidelines, etc. Hospitalization costs, representing between 25 and 35% of total cost, depending on the group, could be considered low in this type of patients, even compared with the study conducted in Spain by Escobar et al. [28]. This low cost was due to fewer days on the general ward and in the intensive care unit, which may be surprising in patients with HFpEF. Perhaps the fact that ~ 50% of included patients had NYHA class I or II could be the reason for such low number of hospitalization days.
From the patient perspective, more than 13% of included patients required some type of home health care, reaching up to 23.7% for ATTR-CA patients. The differences did not reach statistical significance among groups, probably due to the limited sample size in the ATTR-CA group. In all groups, nursing was the main resource, with 12% of the ATTR-CA patients vs. ~ 6% for non-ATTR-CA and inconclusive patients, without statistical significance. Out-of-pocket cost was nearly similar in both groups of patients, except rehabilitation cost, which was also significantly higher in ATTR-CA patients, even though the magnitude of difference was small. Other resource consumption and the corresponding cost showed null or insignificant differences. As observed in transthyretin amyloidosis with polyneuropathy (ATTR-PN), in Spain the majority (90%) of the cost of illness in ATTR-CA patients is covered by the NHS, with the remaining percentage covered by the patient [13, 14, 28].
The cost per-patient-per-year to society in ATTR-CA computed in the PRACTICA study, €3,407 (€1,067-€6,473), is of a magnitude similar to that observed in patients with ATTR-PN, which in a cost-of-illness study showed a cost of €3,105 per patient-per-year in Spain [29]. As this is the first study of its kind, considering healthcare and non-healthcare resource utilization and corresponding costs in HFpEF patients due to ATTR-CA, and also the first time a cost comparison on cost between ATTR-CA and non-ATTR-CA patients, it is difficult to put it into context the magnitude of cost observed in our study. Regarding the cost in patients with HFpEF, a previous study in Spain found a cost per-patient per-year of €1,492, which is rather lower than the value observed in our study, €3,203-(€1,168 -€5,646) [28]. There are several reasons that may explain such discrepancy: the age of the patients enrolled on the PRACTICA study (≥ 50 years), differences in understanding of preserved ejection fraction, NYHA class of included patients, sample size of the study, or the year of costing resources consumed. Toth et al. also reported increased resource utilization and caregiver impact in patients with HFpEF in the United States [30], although a cost quantification was not provided in their work. In our study, we also noted the impact on caregivers, although the PRACTICA study failed to properly capture the impact of both ATTR-CA and non-ATTR-CA on lost caregiver work hours due to the limited sample size. In a recent publication, Reddy et al. found an annual cost of $64,066 [15], with most expenses corresponding to inpatient services ($34,461), followed by outpatient ($23,853), and then pharmacy ($5,752), in patients aged 18 years or older with newly diagnosed ATTR amyloidosis. In Denmark, Pilgaard et al. calculated the total hospital costs covering the median lifespan of patients from onset of symptoms [31], which is 13 months prior to diagnosis, to 52 months after diagnosis, which is the median survival time after diagnosis in wild-type ATTR-CA, resulting in total costs associated with the condition of $68,069. The costs they found were approximately four times higher than those observed in our study, probably due to the length of the included costs. However, our cost findings are higher than those found in South Korea by Jang et al. in newly diagnosed ATTR-CA patients at $1,864 per patient, although the study did not specify the ejection fraction status of patients [32]. Apart from the cost, it seems crucial to look for the etiology of HF, since the diagnosis of ATTR-CA modifies the management of these patients [5, 6].
Cost analysis refers to a particular type of economic evaluation that researchers have used to measure and describe the costs associated with different forms of a specific disease [18–20]. The main strength of our study in ATTR-CA patients with HFpEF is its innovative observational real-world bottom-up design, capable of capturing the overall cost to society, including not only costs for the Spanish NHS, but also resource consumption funded by the patients themselves. Also, as the study enrolled patients from all over the country, it mostly has national representability. The study not only estimated the cost per-patient-per-year of ATTR-CA with HFpEF to Spanish society but was also able to use a group of non-ATTR-CA patients with HFpEF, which provided comparative information on disease cost compared to other similar clinical situations. Also, as far as we know, this is the first time a cost analysis has been carried out considering health and non-health resource utilization and corresponding costs in HFpEF patients with ATTR-CA compared with patients with non-ATTR-CA, since previous research in such patients focused on estimating the health and economic impact of the reduction in mortality and cardiovascular hospitalizations associated with correct diagnosis of ATTR-CA [12, 21].
The study has some limitations. Firstly, the analysis did not include the cost of pharmacological therapies of HFpEF regardless of type of etiology, as the study did not collect such information. Since the economic analysis included here was a secondary objective of the PRACTICA study, the required sample size was not estimated for this secondary objective, then, sample size for certain resources such as transportation cost due to the disease or home medical assistance were not taken into account. Furthermore, few patients were able to provide data on absenteeism (5 patients) or costs due to home adaptations (13 patients). Nonetheless, despite this limitation, the research had enough statistical power to identify differences between the study groups in their main components. Our data showed that the main determinant of cost in ATTR-CA patients was the cost of diagnosis. However, the lack of a diagnosis (inconclusive patients) increased the non-healthcare resources, indicating the need to perform a full diagnostic workflow until ATTR-CA is ruled out.
In conclusion, this is the first multicenter nationwide study assessing the economic impact of ATTR-CA patients aged ≥ 50 years with HFpEF and LVH ≥ 12 mm on society in Spain. Differences observed between ATTR-CA and non-ATTR-CA were small. Nonetheless, the cost was substantial, with negative implications particularly for the Spanish National Healthcare System.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to thank all the PRACTICA investigators.
Author contribution
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article. All authors had full access to the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. 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. The economic analysis was carried out by CRO Dynamic, Madrid, Spain. Medical writing support was provided by Department of Social Psychology and Methodology, School of Psychology, Universidad Autónoma de Madrid, Spain.
Funding
Pfizer S.L.U., Spain sponsored this study. The economic analysis was carried out by CRO Dynamic, Madrid, Spain, and was funded by Pfizer, SLU. JRG is an independent member of the EACCOS Research group. Medical writing support was provided by Department of Social Psychology and Methodology, School of Psychology, Universidad Autónoma de Madrid, Spain and was funded by Pfizer, SLU.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Consent to participate
All patients provided written informed consent prior to study enrollment.
Consent for publication
All authors 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.
Competing interests
PGP reports speaking fees from Alnylam Pharmaceuticals, AstraZeneca, Bridgebio, Intellia, Ionis Pharmaceuticals, NovoNordisk, and Pfizer, consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Bayer, Bridgebio, Intellia, Ionis Pharmaceuticals, Pfizer, Neuroimmune, and NovoNordisk, and research/educational support to my institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, Intellia and Alnylam Pharmaceuticals. JMGP reports speaking fees from Pfizer, AstraZeneca, Alnylam Pharmaceuticals, Boehringer-Ingelheim, Abbott, Medtronic, Impulse Dynamics, Novartis, Rovi, and Orion Pharma; consulting fees from Pfizer, Alnylam Pharmaceuticals, and Bristol-Myers Squibb; and research support to his institution from Novartis. PGP and JMGP received honoraria from Pfizer, S.L.U. as coordinators of the PRACTICA study. LB, PT and CP have disclosed that they are full-time employees of Pfizer, S.L.U. and LB, PT and CP have stocks and stock options in Pfizer Inc.
Footnotes
Publisher’s note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.