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Abstract
Background To evaluate the association between retinal artery/arteriole occlusion (RAO) and unruptured intracranial aneurysm (UIA).
Methods Incident UIA patients from a nationwide cohort (n=253 240) were categorised into three groups based on subsequent treatment: observation (n=208 993), microsurgical clipping (n=14 168) and endovascular treatment (EVT) groups (n=30 079). The incidence and the incident time of RAO were analysed. HRs of RAO and associated risk factors were evaluated. Additionally, a hospital cohort comprising 2569 consecutive UIA patients treated at a tertiary hospital was analysed with detailed clinical information of UIAs.
Results In the nationwide cohort analysis, the incidence of RAO was significantly higher in EVT group than in observation and clipping groups, especially within 60 days (early RAO (within 60 days): HR=4.00, 95% CI: 2.44 to 6.56); delayed RAO (after 60 days): HR=1.74, 95% CI: 1.13 to 2.68). Multivariable analysis showed that the presence of chronic kidney disease (p=0.009) and use of a balloon microcatheter during the procedure (p=0.013) were associated with a higher risk of RAO. In hospital cohort analysis, 11 (0.8%) cases of RAO occurred after EVT, whereas none occurred after microsurgical clipping (p<0.001). Patients with RAO were younger and received balloon microcatheters more frequently than their counterparts. Ten cases of RAO (90.9%) occurred in paraclinoid aneurysms, where EVT was preferred over microsurgical clipping.
Conclusions Performing EVT for UIA may increase the risk of subsequent RAO. Care should be taken when treating paraclinoid aneurysms with balloon microcatheters.
- Aneurysm
- Coil
- Balloon
Data availability statement
Data are available on reasonable request. All raw data in nationwide cohort can be accessed via the Health Insurance Review and Assessment (HIRA) Healthcare Bigdata Hub server. The application of the claims data submitted through the HIRA Healthcare Bigdata Hub homepage (https://opendata.hira.or.kr/home.do) is reviewed by the deliberative committee of research support, and once approved, raw data are provided to the authoriszed researcher at a fee. After obtaining permission, data were analysed using remote access to the HIRA server. The entire dataset can be handled only through a connection to the HIRA server, and the analysed data can be exported with HIRA approval.The anonymised dataset and analytical codes of hospital cohort were available to researchers whose proposed use of the data has been approved by an independent review committee on request to the corresponding author (kyjcolor@yuhs.ac). To gain access, data requestors will need to sign a data access agreement.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Case reports on retinal artery/arteriole occlusion occurring after endovascular treatment (EVT) for unruptured intracranial aneurysm.
WHAT THIS STUDY ADDS
After EVT, retinal artery/arteriole occlusion occurs in 0.8% of cases, with paraclinoid aneurysms and the use of balloon microcatheters being risk factors.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Care should be taken when treating paraclinoid aneurysms with balloon microcatheters.
Introduction
Retinal artery/arteriole occlusion (RAO) is a major cause of sudden painless vision loss that often results in devastating impairment.1 The disease entity encompasses central RAO (CRAO), branch RAO (BRAO) and RAO. Typical RAO is most commonly caused by an impacted embolus in the narrowest part of the central retinal artery, where it enters the sheath of the optic nerve,2 or branch retinal arterioles. The main sources of emboli are the carotid artery and heart.2 Various cardiac conditions or invasive cardiovascular procedures cause RAO.3 Because the central retinal artery arises from the ophthalmic artery (OphA), the first major branch of the internal carotid artery,4 significant stenosis of either the OphA or internal carotid artery can result in the development of CRAO. Although much rarer, emboli from other intracranial vascular branches can also result in CRAO due to variations in the origin and course of the OphA.3 Thus, the presence of intracranial vascular abnormalities, such as unruptured intracranial aneurysm (UIA) and invasive vascular treatment procedures can cause thromboembolic complications in retinal vessels.
A UIA>7 mm has a higher risk of rupture and is warranted for treatment by endovascular treatment (EVT) and surgical clipping.5 Endovascular coil embolisation is widely practised in cases of UIA given its better safety, anatomical accessibility and higher success rate,5 whereas the surgical approach outweighs embolisation in complete occlusion and a lower recurrence rate. In cases of paraclinoid aneurysms, which arise from the segment of the internal carotid artery between the distal dural ring and origin of the posterior communicating artery, endovascular access is preferred over direct surgery because of technical difficulties caused by the anatomical complexity.6 7 Because paraclinoid aneurysms are located near or contain branches of the OphA, RAO might occur more frequently in paraclinoid aneurysms with or without treatment. In previous studies, most RAO cases were found post-treatment for paraclinoid aneurysms,8–15 although some have been reported in other types of UIAs.16–18 Currently, the frequency or risk factors of RAO occurring after EVT remain elusive.19 In this study, we first analysed a nationwide cohort to investigate the incidence rate of RAO in UIA according to the treatment protocol and to evaluate the risk factors associated with the incidence of RAO in patients with UIA. We further analysed the hospital cohort using detailed clinical information, including the location and size of UIAs.
Methods
Data source and study population
We used data recorded from January 2016 to July 2022 from the National Health Claims Database of the HIRA service in Korea. The data source has been described in detail elsewhere.20 Briefly, the HIRA database provides extensive information regarding all health claims in Korea, either submitted through the Korean National Health Insurance scheme or Medical Assistance Programme.21 This claims database includes direct medical costs, personal information, demographics, diagnoses, procedures and medical prescriptions of all Korean residents. As the database is based on unique identification numbers (Korean Resident Registration Number), that are given to all Korean residents at birth, it can be used to obtain the healthcare records and demographics of patients without duplication or omission.20
We identified 423 559 eligible patients diagnosed with UIA between January 2016 and July 2022 (figure 1). All diagnoses were based on the International Classification of Diseases, 10th edition (ICD-10). To clarify the primary risk of UIA on the incidence of RAO, we set a ‘washout period’ and excluded patients with any previous hospital claims for UIA, CRAO or BRAO between 2016 and 2017 (n=168 692). Patients diagnosed with RAO before the diagnosis of UIA (n=332) or before treatment for UIA (n=65) were excluded. Lastly, patients who underwent both microsurgical clipping and EVT for UIA were excluded (n=1230). Finally, 253 240 participants were included in this analysis.
Flow chart of patients excluded and included in the analysis in the current study. HIRA, Health Insurance Review and Assessment.
Exposure
We categorised patients with UIA into three groups based on subsequent treatment: observation (n=208 993), microsurgical clipping (n=14 168) and EVT groups (n=30 079). Patients were considered to have received specific treatment if relevant ICD-10 codes for microsurgical clipping (S4641 or S4642) and EVT (M1661 or M1662) were given after the diagnosis of UIA in the claims data.
Outcome and covariates
The primary outcome was the incidence rate of early (within 60 days) or delayed (after 60 days) RAO and the period from the index date of diagnosis or treatment of UIA to the incidence of RAO. The earliest date of the claim for RAO was considered the incident time of the disease. The secondary outcomes included factors associated with RAO development after EVT.
Baseline patient characteristics, including age, sex, type of medical insurance, residence and medical conditions, such as hypertension, diabetes, dyslipidaemia, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, myocardial infarction, chronic kidney disease (CKD), malignancy, hyperthyroidism, hypothyroidism, chronic liver disease, chronic obstructive pulmonary disease and Charlson Comorbidity Index (CCI), were collected. To ensure accuracy, comorbidities were established based on one inpatient or two outpatient records with ICD-10 codes in the database. Prescription histories of antithrombotic agents or anticoagulants within 6 months before baseline were obtained from the claims data. Details of the ICD-10 codes used to define the medical conditions, comorbidities, drug treatments and procedures are presented in online supplemental table 1.
Supplemental material
Hospital cohort study with detailed clinical information
As the claims data did not include detailed information on UIAs, such as location or size, we conducted additional analyses using a hospital cohort comprising consecutive patients who were treated with microsurgical clipping or EVT for UIAs at a tertiary high-volume hospital between January 2018 and June 2022. In total, 2569 consecutive patients with UIAs (2896 UIAs) treated with microsurgical clipping or EVT were eligible for the study. Patients were categorised based on treatment: 1176 patients with 1369 aneurysms treated with microsurgical clipping, and 1393 patients with 1527 aneurysms treated with EVT. Therapeutic decisions were discussed by a multidisciplinary team of neurosurgeons and neurointerventionists, and a final decision was made by consensus.
The analysed aneurysmal factors included the number of aneurysms, maximum aneurysm diameter, aneurysmal location, accompanying vascular problems and whether re-embolisation was performed. The locations of the aneurysms were classified as the internal carotid artery, which encompasses the distal paraclinoid artery, paraclinoid artery and proximal paraclinoid artery; anterior cerebral artery, including the anterior communicating artery; middle cerebral artery; or posterior circulation, including the vertebral artery, basilar artery, posterior cerebral artery and cerebellar arteries. Considering the proximity of the OphA branch and paraclinoid artery, the risk factors associated with development of RAO in paraclinoid aneurysms were assessed separately. Procedure-related factors included the emboliszation method (single or multiple microcatheter technique) and use of devices (balloon, stent, flow diverter or flow disruptor). For details of the collected data from the retrospective chart review and routine treatment protocols for EVT, seee online supplemental methods.
All patients who had acute-onset vision loss after treatment for UIA underwent complete ophthalmic evaluations, including best-corrected visual acuity, intraocular pressure, slit lamp biomicroscopy, dilated fundoscopic examination, fundus photography and spectral-domain optical coherence tomography. A visual field test and fluorescein angiography were additionally performed, if necessary. The diagnosis of RAO was made clinically by ophthalmologists at the initial assessment and additionally confirmed by two retinal specialists (HRK and YJK) during a retrospective chart review.3
Statistical analyses
Baseline characteristics are reported as mean±SD or frequency (per cent). Using the HIRA database, the cumulative incidence of RAO according to the subgroups was calculated using the Kaplan-Meier method. Age-adjusted and sex-adjusted standardised incidence ratios (SIR) of RAO were calculated using the RAO incidence rate in the entire Korean population between 2018 and 2019 as a reference. HRs and 95% CIs based on the Poisson distribution for RAO associated with the subgroups were calculated using Cox proportional hazards models, with untreated UIA as the reference. HRs were adjusted for age, sex and the presence of hypertension, diabetes mellitus or dyslipidaemia. The adequacy of the proportional hazard assumption was confirmed using log-minus-log survival plots and Schoenfeld residuals. Univariable and multivariable analyses of risk factors for RAO in UIA were performed.
For hospital cohort data analysis, Pearson’s χ2 test or Fisher’s exact test was used to determine the differences between categorical variables. The means for differences between continuous variables were analysed using the Student’s t-test. A logistic regression model was used to evaluate factors associated with RAO. The results are reported as ORs and 95% CIs.
Statistical analyses were performed using SAS (V.9.4, SAS Institute), SPSS (V.25.0; IBM) and R (V.3.5.3, R Foundation for Statistical Computing, Vienna, Austria). P values <0.050 were considered statistically significant.
Results
Baseline characteristics of the nationwide cohort
Of the 2 53 240 patients with UIA, 208 993 (82.5%) were observed without further treatment, 14 168 (5.6%) underwent microsurgical clipping and 30 079 (11.9%) underwent EVT. The mean ages were 62.46±13.82, 60.14±9.92 and 60.32±11.76 in the observation, microsurgical clipping and EVT groups, respectively. The three groups differed in age, sex, residence, comorbidities of systemic diseases, CCI and prescription history of antithrombotic agents or anticoagulants. Patients with UIA who required treatment with either microsurgical clipping or EVT were significantly younger, predominantly female and had urban residency than those who were observed without further treatment. The EVT group was more likely to have received aspirin or antiplatelet therapy than the other groups. The general characteristics of the nationwide cohort are presented in table 1.
Baseline characteristics of the nationwide cohort by subsequent treatment
Risks of RAO
The cumulative incidence of RAO was significantly higher in the EVT group (62.41 per 100 000 person-years) than in the other groups (30.49 and 18.39 per 100 000 person-years in the observation and microsurgical clipping groups, respectively). In the EVT group, early RAO (25 patients (0.08%)) was markedly observed compared with the other groups (observation group: 45 patients (0.02%), microsurgical clipping group: 4 patients (0.03%)) (figure 2 and online supplemental figure 1).
Cumulative incidence of retinal artery occlusion in patients with unruptured intracranial aneurysm according to the Kaplan-Meier method. EVT, endovascular treatment.
When age, sex and the presence of hypertension, diabetes or dyslipidaemia were adjusted, microsurgical clipping was not associated with higher RAO risks in comparison to conservative treatment (early RAO: HR=1.33, 95% CI: 0.48 to 3.72; delayed RAO: HR=0.45, 95% CI: 0.14 to 1.40). In the EVT group, early RAO developed in 25 (0.1%) patients and delayed RAO developed in another 25 (0.1%), with HRs of 4.00 (95% CI: 2.44 to 6.56) and 1.74 (95% CI: 1.13 to 2.68), respectively (figure 3). The characteristics of the patients who developed early and delayed RAO are presented in online supplemental table 2.
Cox regression analysis of retinal artery occlusion (RAO) risks by onset date. (A) Early RAO, which occurred within 60 days after the diagnosis or treatment of unruptured intracranial aneurysm (UIA), (B) delayed RAO, which occurred after 60 days or longer from the diagnosis or treatment of UIA. Group 1, patients with untreated UIA; Group 2, UIA patients treated with microsurgical clipping and Group 3, UIA patients treated with endovascular treatment. The Cox model was adjusted for age, sex and the presence of hypertension, diabetes mellitus or dyslipidaemia. The incidence rate is per 100 000 person-years.
Next, we investigated whether the RAO risk increased when each group was compared with the general population. The incidences of RAO in the general population were 13.96 and 9.40 per 100 000 person-years among men and women, respectively (online supplemental table 3). Age-adjusted and sex-adjusted SIR of RAO was also significantly higher in the EVT group (SIR=2.87, 95% CI: 1.24 to 4.02, p<0.001) than in the entire Korean population, whereas the values in observation (SIR=1.13, 95% CI: 0.93 to 1.19, p=0.120) and microsurgical clipping groups (SIR=0.87, 95% CI: 0.51 to 1.75, p=0.713) were similar to that of the general population (online supplemental table 4).
Risk factors of RAO after EVT for UIA
We assessed the risk factors for RAO after EVT for UIAs. In univariable analysis, female sex (HR=0.58, 95% CI: 0.33 to 1.02, p=0.058), CKD (HR=4.02, 95% CI: 1.45 to 11.17, p=0.022) and the use of a balloon microcatheter (HR=2.93, 95% CI: 1.16 to 7.39, p=0.008) were associated with RAO after EVT. Age, socioeconomic status, residence, hypertension, diabetes, dyslipidaemia, stroke, CCI and the use of anticoagulant/antithrombotic agents were not significantly associated with RAO after EVT. Multivariable analysis revealed that CKD (HR=3.98, 95% CI: 1.42 to 11.19, p=0.009) and the use of a balloon microcatheter (HR=3.33, 95% CI: 1.29 to 8.65, p=0.013) were significantly associated with RAO after EVT (table 2).
Results of univariable and multivariable analyses for the risk factors of retinal artery occlusion after endovascular treatment for unruptured intracranial aneurysm in the nationwide cohort
Hospital cohort analysis with detailed clinical information
In total, 1393 patients (female=1,075 (77.2%); mean age, 59.5 years) underwent EVT and 1176 patients (female=859 (73.0%); mean age, 60.6 years) underwent microsurgical clipping. Although RAO did not occur after microsurgical clipping, 11 cases (0.8%) occurred after EVT (p<0.001). All RAO cases occurred in the same direction as the right/left positions of the UIAs. Anatomically, RAO appeared to be prevalent after treatment of aneurysms located in the internal carotid artery (paraclinoid aneurysms, 10 (90.9%); and distal paraclinoid aneurysm located at posterior communicating artery, 1 (9.1%)), with borderline statistical significance (p=0.063). Previous studies reported that RAO cases after UIA treatment also occurred after EVT, and most UIAs were paraclinoid aneurysms. The detailed characteristics of the patients who developed RAO after treatment with UIAs are presented in online supplemental table 5. Subjective vision decreases or visual field defects of varying degrees occurred within 1–2 days of treatment. At the last follow-up, three patients (patients 3, 9, 11) had partial vision loss and one patient with CRAO (patient 2) had permanent vision loss. Representative images of RAO after EVT are shown in online supplemental figure 2. Notably, patients with RAO were younger and used balloon microcatheters more frequently than patients without RAO in the EVT group (table 3).
Characteristics of patients with hospital-based unruptured intracranial aneurysm (UIA) who underwent microsurgical clipping or endovascular treatment
We conducted a subgroup analysis of paraclinoid aneurysms which is close to the OphA. Among the 612 patients with 638 aneurysms, 10 (1.6%) patients developed RAO after EVT. Multivariable logistic regression analysis showed that the independent risk factors for RAO were the use of a balloon microcatheter (OR=7.56, 95% CI: 1.35 to 42.44, p=0.022). The details of the risk factor analysis are presented in table 4.
Risk factors of retinal artery occlusion (RAO) in paraclinoid aneurysm treated with endovascular treatment
Discussion
In this nationwide, population-based study, we elucidated the risk of RAO in patients with UIA according to subsequent treatment and the associated risk factors for RAO. Few case reports have been published regarding the development of RAO after endovascular coil embolisation for UIA, and there is no evidence regarding the association between RAO and UIA. Our results provide detailed information regarding the increased risk of RAO and the time of incident RAO, especially in patients treated with EVT for UIA. The rapid increase in the incidence of RAO during the first 60 days after treatment of UIA implicates a direct relationship between EVT and RAO. As patent artery occlusion (2%) and thromboembolism (2.4%) are the most common complications of this procedure,5 16 it is possible that coil embolisation itself may cause RAO. Moreover, the use of certain devices, direct contact with the wall of the intracranial artery or plaque break-off during catheter passage may play a role in the development of thrombus-related RAO.16 17 In our study, the use of a balloon microcatheter was significantly associated with higher risk of RAO in the HIRA dataset and hospital cohort. In cases of balloon-assisted coil embolisation, intermittent OphA occlusion caused by balloon inflation precedes coil insertion. Previous studies revealed that collateral OphA flow from the external carotid artery was present in 60%–84.6% of cases.22 23 Usually, distal flow is maintained because of collateral flow, and the possibility of RAO is low. It is assumed that, however, because of this collateral, a thrombus may develop at the proximal segment of the OphA during balloon inflation. Specifically, the usual blood flow from the internal carotid artery to the OphA changes to a flow directed from the external carotid artery to the OphA during balloon inflation, increasing the risk of thrombus formation at the site of flow retention. After balloon deflation, the thrombus may wash out into the OphA, causing RAO.
The microsurgical treatment of paraclinoid aneurysms remains challenging because of their anatomical features. Meticulous surgical techniques, including anterior clinoidectomy, optic strut removal and dissection of the distal dural ring, are required to fully expose the aneurysm. Simultaneously, surrounding anatomical structures (eg, optic nerves, oculomotor nerves, perforating arteries and cavernous sinuses) should be preserved. In previous studies, the rate of visual complications after microsurgical clipping was 4.3%–30%.24–26 Visual dysfunctions included optic neuropathy,24 visual field defects,25 26 vision loss of unmentioned cause and oculomotor nerve palsy25 other than retinal vessel occlusion. The recent introduction of new devices (eg, balloon microcatheter, stent, flow diverter and flow disruptor) to treat wide-neck aneurysms that are unsuitable for simple coil embolisation has broadened the range of endovascular approaches. Therefore, EVT is widely used for the treatment of paraclinoid aneurysms. In our hospital cohort, RAO did not occur after microsurgical clipping, whereas a few cases occurred after EVT (total EVT group, 0.8%; paraclinoid aneurysms treated with EVT, 1.6%). This implies a higher risk of RAO in cases of paraclinoid aneurysms than in other UIAs. Although the location of the UIA showed borderline significance owing to the small number of RAO cases in the hospital cohort, all RAO cases were reported as internal carotid artery aneurysms, mostly paraclinoid aneurysms. Perhaps the position of the balloon during balloon-assisted coil embolisation might be similar, resulting in a similar risk of consecutive RAO. Interpretations of the results were limited because the number of RAO after EVT was very small and none occurred after microsurgical clipping. Further studies are warranted to recruit a larger cohort encompassing untreated UIAs and the location of the UIAs.
We speculate that the presence of UIA itself might cause thromboembolic complications in the OphA and retinal artery. A comparison of patients with UIA with the general population showed that untreated UIA and microsurgical clipping for UIA did not increase the risk of consecutive RAO. Blood flow from the heart and carotid artery is directed towards the OphA, and emboli from those vessels mainly cause RAO.2 However, intracranial vessels are located more distal to the OphA branch and have different courses of circulation. Therefore, UIAs other than paraclinoid aneurysms are less likely to cause RAO. Different aetiologies may play a role in the occurrence of RAO in the UIAs located elsewhere. Bae et al reported a case of cilioretinal artery occlusion after EVT of the anterior communication artery.16 Considering the distal location of the aneurysm from the OphA and the direction of blood flow, it is unlikely that the thrombus caused RAO. Air embolism during heparin injection into the catheter may cause microembolism-related retinal infarction.27 Structural changes in the arterial wall, breakdown of blood products or inflammation due to catheter-induced stimulation of the endothelium may result in vasospasm and then hypoxia.16 28
Interestingly, the presence of CKD was significantly associated with an increased risk of RAO in EVT group. The correlation between end-stage renal disease and RAO risk has been well described.29 30 As RAO and CKD share common risk factors (eg, hypertension, diabetes mellitus, hyperlipidaemia and atherosclerosis), the incidence of RAO can be higher in patients with CKD.30 Moreover, chronic inflammation, which is prevalent in CKD, may contribute to the development of RAO. However, these studies were limited to patients on dialysis. The relationship between the presence of CKD and RAO needs to be evaluated further.
The strength of this study is that it was based on a nationwide population-based dataset, representative of the entire Korean population. Furthermore, we introduced an inpatient dataset to supplement clinical data that were not provided in the nationwide cohort. However, this study has the following limitations. First, the data were based on diagnostic codes and insurance claims; therefore, it is possible that misclassification or miscategorisation could have occurred. Second, information related to the clinical characteristics of UIA could not be assessed in the nationwide cohort, given that factors other than treatment method might interfere with the risk of RAO. To compensate for this, a comparison with the general population using age-adjusted and sex-adjusted SIR and additional analysis using the hospital cohort were conducted. Third, because not all patients with UIA underwent ophthalmic examinations, asymptomatic patients with RAO were not evaluated. Lastly, confounding factors, such as smoking history and alcohol consumption, which were not available in the HIRA dataset, could not be adjusted.
Because the most dreaded risk of intracranial aneurysms is rupture, which leads to a mortality rate as high as 80%, timely treatment is essential for UIA. However, caution should be exercised when deciding on UIA treatment, as indiscriminate endovascular or surgical treatment may increase the risk of RAO and irreversible vision loss. With the development of EVT, the treatment of UIA, especially paraclinoid aneurysms, has become easier. However, clinicians should be aware of the increased risk of RAO after EVT for paraclinoid aneurysms and the use of balloon-assisted coil embolisation. Also, further studies are warranted to recruit a larger cohort to elucidate associated factors of RAO in patients with UIAs.
Data availability statement
Data are available on reasonable request. All raw data in nationwide cohort can be accessed via the Health Insurance Review and Assessment (HIRA) Healthcare Bigdata Hub server. The application of the claims data submitted through the HIRA Healthcare Bigdata Hub homepage (https://opendata.hira.or.kr/home.do) is reviewed by the deliberative committee of research support, and once approved, raw data are provided to the authoriszed researcher at a fee. After obtaining permission, data were analysed using remote access to the HIRA server. The entire dataset can be handled only through a connection to the HIRA server, and the analysed data can be exported with HIRA approval.The anonymised dataset and analytical codes of hospital cohort were available to researchers whose proposed use of the data has been approved by an independent review committee on request to the corresponding author (kyjcolor@yuhs.ac). To gain access, data requestors will need to sign a data access agreement.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Health Insurance Review and Assessment (HIRA) Deliberative Committee (approval number: M20220222838). Use of the national health claims data was approved by the Institutional Review Board (IRB)/Ethics Committee (approval number: 4-2022-1028), which waived the requirement for informed consent owing to the retrospective study design and use of deidentified data. Additional analyses with the hospital cohort were approved by the same IRB (approval number: 4-2022-1025), which also waived the requirement for informed consent because of the retrospective design. This study adhered to the tenets of the Declaration of Helsinki.
References
Supplementary material
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
HRK and MJK are joint first authors.
HRK and MJK contributed equally.
Contributors HRK and MJK contributed equally to this work as co-first authors. YJK and SWL contributed equally to this work as co-corresponding authors. YJK and SWL are responsible for the overall content as guarantors. YJK and SWL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: SWL and YJK. Acquisition, analysis or interpretation of data: HRK, MJK, SK, MSC, DJK, BMK, KYP, YBK, CSL, SHB, SSK, SWL and YJK. Drafting of the manuscript: HRK, MJK, SWL and YJK. Critical revision of the manuscript for important intellectual content: DJK, BMK, KYP, YBK, CSL, SHB, SSK, SWL and YJK. Statistical analysis: HRK, MJK, SK, SWL and YJK. Obtained funding: YJK. Supervision: SWL and YJK.
Funding This research was supported by Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2022R1I1A1A01059209). This research was also supported by grants of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI21C1705, HI22C0782).
Disclaimer The funding organisations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. No financial disclosures exists for any author.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.