Secular trends of health care resource utilization and costs between Brugada syndrome and congenital long QT syndrome: A territory‐wide study

Abstract Background Health care resource utilization (HCRU) and costs are important metrics of health care burden, but they have rarely been explored in the setting of cardiac ion channelopathies. Hypothesis This study tested the hypothesis that attendance‐related HCRUs and costs differed between patients with Brugada syndrome (BrS) and congenital long QT syndrome (LQTS). Methods This was a retrospective cohort study of consecutive BrS and LQTS patients at public hospitals or clinics in Hong Kong, China. HCRUs and costs (in USD) for Accident and Emergency (A&E), inpatient, general outpatient and specialist outpatient attendances were analyzed between 2001 and 2019 at the cohort level. Comparisons were made using incidence rate ratios (IRRs [95% confidence intervals]). Results Over the 19‐year period, 516 BrS (median age of initial presentation: 51 [interquartile range: 38−61] years, 92% male) and 134 LQTS (median age of initial presentation: 21 [9−44] years, 32% male) patients were included. Compared to LQTS patients, BrS patients had lower total costs (2 008 126 [2 007 622−2 008 629] vs. 2 343 864 [2 342 828−2 344 900]; IRR: 0.857 [0.855−0.858]), higher costs for A&E attendances (83 113 [83 048−83 177] vs. 70 604 [70 487−70 721]; IRR: 1.177 [1.165−1.189]) and general outpatient services (2,176 [2,166−2,187] vs. 921 [908−935]; IRR: 2.363 [2.187−2.552]), but lower costs for inpatient stay (1 391 624 [1 391 359−1 391 889] vs. 1 713 742 [1 713 166−1 714 319]; IRR: 0.812 [0.810−0.814]) and lower costs for specialist outpatient services (531 213 [531 049−531 376] vs. 558 597 [558268−558926]; IRR: 0.951 [0.947−0.9550]). Conclusions Overall, BrS patients consume 14% less health care resources compared to LQTS patients in terms of attendance costs. BrS patients require more A&E and general outpatient services, but less inpatient and specialist outpatient services than LQTS patients.

Accident and Emergency (A&E), inpatient, general outpatient and specialist outpatient attendances were analyzed between 2001 and 2019 at the cohort level.Comparisons were made using incidence rate ratios (IRRs [95% confidence intervals]).
Results: Over the 19-year period, 516 BrS (median age of initial presentation: 51 [interquartile range: 38−61] years, 92% male) and 134 LQTS (median age of initial presentation: 21 [9−44]  Conclusions: Overall, BrS patients consume 14% less health care resources compared to LQTS patients in terms of attendance costs.BrS patients require more A&E and general outpatient services, but less inpatient and specialist outpatient services than LQTS patients.

K E Y W O R D
Health care resource utilization

| INTRODUCTION
Cardiac channelopathies can be categorized by the development of arrhythmias due to abnormalities in the function and/or structure of ion channels, resulting in syncope and sudden cardiac death (SCD). 1 In recent years, there has been rising interest regarding the management of Long QT Syndrome (LQTS) and Brugada Syndrome (BrS).Both conditions can involve mutations in the SCN5A gene which encodes for the pore-forming subunit of the cardiac sodium ion channel. 2 LQTS is a relatively well-documented cardiac condition, with more than 15 disease-causing genes identified and may be seen in approximately 0.1% of the general population. 3In contrast, the interpretation of genetic variants in BrS is difficult, with approximately 25% of cases attributed to SCN5A mutations. 4[7] However, there is little understanding of the healthcare burden of LQTS and BrS patients.The provision of genetic testing options, implantable cardioverter-defibrillators (ICD), hospital admissions from arrhythmia-related symptoms, and the need for specialist outpatient services follow-up for device and arrhythmia management and monitoring are major drivers for health care expenditure. 8,9As of now, little research has been dedicated to investigating the attendance-related health care resource utilization (HCRU) and related costs in the setting of cardiac ion channelopathies.With increasing awareness and diagnosis of both conditions, there may be a subsequent increase in service demand, thus raising the concern for prioritization in health care interventions and specific costeffectiveness estimations.Without a comprehensive analysis of the cost-effectiveness of medical technologies, this may undermine the benefit of health care policies.Locally in Hong Kong, administrative data are available on the types of attendances (such as those to Accident and Emergency (A&E) departments, inpatient admissions and their length-of-stay, as well as specialist and general outpatient clinics).
Their official costs are published by the local government.Hence, the aim of this study is to compare the attendance-related HCRUs and related costs between BrS and LQTS patients in Hong Kong, China.

| Study population
The study received ethical approval from The Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee.This territory-wide retrospective cohort study includes patients diagnosed with BrS or LQTS between the January 1, 1997 to the December 31, 2020 in public hospitals or clinics in Hong Kong.
Centralized electronic health records from the Clinical Data Analysis and Reporting System (CDARS) were used for patient identification and data extraction.This system has been used previously by our team and other teams for health care resource utilization (HCRU) and cost analysis for catecholaminergic polymorphic ventricular tachycardia, 10 LEE ET AL. cancer patients receiving immunotherapy, 11 and COVID-19. 12,13The diagnosis of LQTS and BrS was made initially by case physicians and was further verified by G.T. through documented electrocardiograms (ECGs), case notes, genetic reports and diagnostic test results in accordance with the 2017 Expert Consensus Statement for BrS. 14

| Clinical and electrocardiographic data collection
Our team has published previously using these LQTS and BrS cohorts for risk prediction. 15Baseline clinical data was extracted from the electronic health records.This included: (1) sex; ( 2

| Baseline characteristics
In this study, 516 BrS patients and 134 LQTS patients were included.
The average age at first presentation was much younger for the LQTS cohort compared to the BrS cohort (27.6 ± 23.8 vs. 49.9 ± 16.2).In addition, the LQTS cohort had a greater percentage of females (67.9% vs. 7.6%), as well as more patients with a family history of the disease (43.3% vs. 3.1%) and VF/SCD (14.9% vs. 7.9%) compared to the BrS cohort.The number of genetic tests performed was also higher in the LQTS cohort compared to the BrS cohort (84 vs. 51).
Interestingly, the BrS cohort performed significantly more EPS (112 vs. 6) and had a greater proportion of induced VT/VF (14.7% vs.
3.0%).In regard to the baseline ECG characteristics, BrS patients had overall longer PR interval (169.5   This is the first territory-wide cohort study in Hong Kong to compare the attendance-related health care costs of LQTS and BrS patients. The major findings of this study is as follows: (1) BrS patients consume 14% less health care resources compared to LQTS patients; (2) BrS patients require more services from A&E and general outpatient setting; (3) LQTS patients require more services from inpatient and special outpatient setting.
The present study suggests that there are drastic differences in the health care burden of the two cardiac channelopathies.Due to the lower caseload of LQTS compared to BrS in Hong Kong, [16][17][18] a greater percentage of patients had to undergo more cardiological examinations and consultations at a clinical genetics department.It may be argued that genetic testing plays a greater role in the diagnosis of LQTS relative to BrS because current genetic knowledge of LQTS is more advanced and the disease is more likely to have a genetic origin. 19Even for patients with inconclusive clinical scores, the current referral practice for LQTS often entails for aggressive treatment including rigorous restrictions on the patient's lifestyle and primary ICD implantation. 20Resultantly, this may warrant unnecessary expenditure on patients who are at low-risk or have no risk of LQTS.
This notwithstanding, the family members of the LQTS patient are often included in the confirmatory testing process to screen for concealed or preclinical LQTS. 21Through early identification of familial LQTS, this will allow patients to receive timely secondary and tertiary prevention.Subsequently, this may lead to the increase in financial costs and anxiety for the patient.The 5-gene version of the FAMILION LQTS test costs approximately $5400 per index case and $900 per family member as a confirmatory test. 22Although newer technologies demonstrate great potential in reducing costs of intervention and detection of new mutations, 23 the lack of competition minimizes the commercial incentive in finding new alternatives.
However, current prices for diagnostic assessments were still significantly less expensive compared to previous genetic tests without genetic testing strategies. 24Despite advancements made in the understanding of LQTS genetics, the distinction between pathogenic and benign variants in LQTS-susceptibility genes remains challenging for physicians. 25Hence, this also warrants the need for further refinement of the clinical interpretation of LQTS to reduce the number of false positive and familial LQTS patients, and ultimately health care costs. 26Furthermore, it is also crucial to consider the relevant health care policies and insurance regulations of individual hospitals.Therefore, this may explain the health care cost discrepancies between the LQTS and BrS cohort.

| Strengths and limitations
Several major strengths were demonstrated in this study: (1) costs were estimated using standardized unit costs across extended followup periods; (2) the sampling of one of the largest cardiac T A B L E 3 Cohort-level health care utilization and costs for BrS and LQTS patients.| 1199 channelopathies cohorts available enhances the reliability of study findings; (3) the use of a public, comprehensive electronic health record system from the city, incorporating attendances from 43 hospitals and their associated outpatient and ambulatory care facilities.
Several limitations should also be noted.The retrospective observational nature of this study suggests that results may be prone to coding errors, under-coding or missing data, resulting in information and selection bias.However, as the majority of patients were closely followed-up through annual consultations, the bias was amended with detailed follow-up and patient documentation.Although the database used already documents one of the largest cohorts of cardiac channelopathies in Asia, the sample size is still small compared to other cardiac diseases, especially the LQTS cohort.Consequently, this limits the validity of study findings.This is due to the fact that the prevalence of BrS and LQTS is low relative to other cardiac diseases in Hong Kong.It is prudent to recognize that our cost analyses require additional external validation in future studies.

| CONCLUSIONS
In conclusion, major differences in economic burden between BrS and LQTS patients were identified in this study.These findings can offer novel insight into the financial management of clinical interventions and optimization of health care policies surrounding BrS and LQTS.However, it is imperative that further research is conducted to extend the costs analysis amongst subgroups in both cohorts.
) age of first characteristic ECG presentation and last follow-up; (3) follow-up duration; (4) syncope manifestation and its frequency; (5) family history of SCD and the specific ion channelopathy; (6) performance of electrophysiological study (EPS), 24-hours Holter study, ion channelopathy-specific genetic testing of the RYR2 gene, and the respective results; (7) presentation of sustained VT/VF and its frequency; (8) presence of other arrhythmias; (9) implantation of ICD; (10) ECG performance; (11) period between the initial presentation of characteristic ECG and the first postdiagnosis VT/ VF episode; (12) initial disease manifestation (asymptomatic, syncope, VT/VF); (13) occurrence, cause and age of death.The baseline ECG was extracted at the earliest time possible after the presentation of an initial characteristic ECG pattern.

2. 3 |
Statistical, HCRU and cost analyses Categorical variables were represented as a total sum and percentage.Continuous and discrete variables were expressed as a mean and standard deviation (SD) value.Locally in Hong Kong, the various attendances to A&E, inpatient admissions, specialist or general outpatient clinic consultations are all captured by CDARS.The dates of admissions, discharges or attendances are also recorded.The official costs are published in the public domain (https://www.ha.org.hk/haho/ho/cs/238766_en.pdf).This information enabled us to calculate the HCRU and costs for A&E, inpatient, general outpatient and specialist outpatient attendances over a 19-year period (2001−2019).Incidence rate ratios (IRRs [95% confidence intervals]) were used to conduct comparisons between the BrS and LQTS cohort.The attendance costs were calculated using unit costs in reference to the standard of the local government.Final cost values were presented in USD.Statistical significance was defined as p < .05.All statistical analysis was performed using R Studio (Version: 1.3.1073).

Table 1 .
T A B L E 1 Baseline characteristics of the study cohort.The total number of attendances for A&E, inpatient, general and specialist outpatient setting in the cohort is as follows: 5154, 4140, 373 and 34 049 for the BrS cohort and 1137, 1285, 41, 9298 for the LQTS cohort.Both cohorts demonstrated the highest number of attendance in the specialist outpatient settings, however the BrS cohort had a greater overall number of attendance compared to the LQTS cohort (43 716 vs. 11 761).In addition, the attendance number of inpatient length of stays of the BrS cohort were also significantly higher than the LQTS cohort (20 813 vs. 6656).The attendance and costs of the BrS and LQTS cohort are shown in Table2.Cohort-level attendance, length of stay and costs for BrS and LQTS patients.Additionally, the number of attendances in specialist A&E, general outpatient and general inpatient settings were consistently higher in the BrS cohort throughout the time period, with the exception of 2009 and 2010, where the number of attendances in general outpatient setting was slightly higher in the LQTS cohort.The results of the total number of attendances in A&E, general outpatient, general inpatient, and specialist outpatient settings for the BrS and LQTS cohorts from 2001 to 2019 are shown in Note: Categorical and continuous variables were compared between LQTS and BrS patients.Abbreviations: BrS, Brugada syndrome; LQTS, long QT syndrome.3.2 | HCRU and cost analysisNote: Median (lower and upper 95% confidence intervals) values are presented.Costs shown are in US dollars.Abbreviations: BrS, Brugada syndrome; LQTS, long QT syndrome.