Background The long-term outcomes of endovascular coiling and surgical clipping for the treatment of unruptured intracranial aneurysms are unclear.
Methods We performed a nationwide retrospective cohort study using claims data from the Korean Health Insurance Review and Assessment Service on patients undergoing surgical clipping or endovascular coiling from 2008 to 2014. Inverse probability treatment weighting for average treatment effect on the treated and the multiple imputation method were used to balance covariates and handle missing values. The primary outcome was all-cause mortality at 7 years.
Results We identified 26 411 patients of whom 11 777 underwent surgical clipping and 14 634 underwent endovascular coiling. After adjustment with the use of inverse probability treatment weighting for average treatment effect on the treated, all-cause mortality rates at 7 years were 3.8% in the endovascular coiling group and 3.6% in the surgical clipping group (HR 1.05; 95% CI 0.86 to 1.28; P=0.60, log-rank test). The adjusted probabilities of aneurysm rupture at 7 years were 0.9% after endovascular coiling and 0.7% after surgical clipping (HR 0.9; 95% CI 0.61 to 1.34; P=0.63, log-rank test). The probabilities of retreatment at 7 years after adjustment were 4.9% in the endovascular coiling group and 3.2% in the surgical clipping group (HR 1.52; 95% CI 1.28 to 1.81; P<0.001, log-rank test).
Conclusions All-cause mortality at 7 years was similar between the elective surgical clipping and endovascular coiling groups in patients with unruptured aneurysms who had no history of subarachnoid hemorrhage due to aneurysm rupture.
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Subarachnoid hemorrhage due to rupture of intracranial aneurysms leads to high mortality and morbidity.1 Surgical clipping and endovascular coiling are the most common treatment strategies for preventing rupture.
The International Subarachnoid Aneurysm Trial (ISAT) showed that endovascular coiling had favorable outcomes compared with surgical clipping.2 3 However, results from ISAT cannot be applied directly to patients with unruptured intracranial aneurysms.
Guidelines for the management of patients with unruptured intracranial aneurysms have been published by the American Heart Association, but they did not contain information comparing long-term outcomes of surgical clipping and endovascular coiling.4 Additionally, several published database studies were limited by the fact that they did not consider the characteristics of the aneurysms, were restricted to an elderly population, or only considered periprocedural outcomes.5–12
The purpose of our study was to compare the long-term outcomes (up to 7 years) of surgical clipping and endovascular coiling for unruptured intracranial aneurysms in the Korean population. We conducted a large retrospective cohort study using a claims database that includes the entire population of South Korea.
In this retrospective claims data-based cohort study, we identified all patients in South Korea who underwent elective surgical clipping or endovascular coiling of an unruptured intracranial aneurysm from 1 January 2008 to 31 December 2014, and we followed them up to 31 December 2015. The study was approved by the institutional review board of the Ministry of Health and Welfare. The requirement for informed consent was waived because all patients in the database were anonymized.
The patients’ data included in the study were collected from the claims database of the Korean Health Insurance Review and Assessment Service (HIRA). HIRA is a government agency that examines the accuracy and constructs databases of claims for the National Health Insurance and Medical Aid program. The former is a mandatory social insurance and healthcare provider, and the latter is a service providing public assistance with healthcare costs for low income households, which covers the entire population of South Korea and is based on a fee-for-service model. All clinics and hospitals in South Korea participate in these two programs.
Patients were eligible if they were older than 18 years, had no history of subarachnoid hemorrhage (I60.X) from 1 January 2007 to the date of index admission, were admitted electively between 1 January 2008 and 31 December 2014, had procedure codes for surgical clipping (S4641, S4642) or endovascular coiling (M1661, M1662), and had a primary diagnosis of unruptured intracranial aneurysm (I67.1).
We excluded all patients with procedure codes for surgical clipping or endovascular coiling between 1 January 2007 and 31 December 2007. Additionally, patients who were admitted to the emergency room or underwent staged treatment were excluded. Staged treatment was defined as endovascular coiling or surgical clipping performed separately during the index admission or elective readmission for endovascular coiling or surgical clipping within 180 days after the index admission. We also excluded those who had the following during admission: intracranial artery bypass operation, resection or endovascular embolization of an arteriovenous malformation, arteriovenous fistula, cavernous malformation, and any tumor located in the brain or dura mater. Detailed lists of procedure codes are provided in online supplementary table 1.
Supplementary file 1
Identification of aneurysm characteristics and coexisting conditions
The size, location, and multiplicity of treated aneurysms were identified based on the description of the procedure codes for surgical clipping, number of clips used for each aneurysm, frequency of general endotracheal anesthesia and procedures during the index admission, claim guidelines for treating multiple aneurysms, and claim guidelines for usage of coils. Procedure codes for diagnostic digital subtraction angiography were also used for identification.
When submitting a claim after surgical clipping, neurosurgeons should enter the proper procedural code for surgical clipping according to whether or not the size of the treated aneurysm was ≥7 mm. Therefore, we categorized the size of the treated aneurysm into <7 or ≥7 mm. Patients who had at least one treated aneurysm of ≥7 mm in size were allocated to the ≥7 mm size variable.
We categorized the location of the treated aneurysm into anterior circulation (internal carotid artery, anterior cerebral artery, or middle cerebral artery) or posterior circulation (vertebrobasilar system) with the use of procedural codes for diagnostic digital subtraction angiography and surgical clipping. If patients underwent surgical clipping or endovascular coiling of posterior circulation aneurysms or had concurrent anterior and posterior circulation aneurysms, they were allocated to the posterior circulation location group.
We determined patients’ coexisting conditions by analyzing the primary and secondary diagnosis of claims data between 1 January 2007 and the index admission. The International Classification of Diseases 10th version of the Elixhauser algorithm from the Healthcare Cost and Utilization Project was used to identify coexisting conditions, except for hemorrhagic stroke, ischemic stroke, and hyperlipidemia in the inpatient and outpatient settings.13 14 To enhance the accuracy of determination, any diagnosis code that was found only once in an outpatient claim was not considered as a coexisting condition.
Detailed descriptions of procedures, the algorithm for identifying the location of aneurysms, claim guidelines, and diagnostic codes for hyperlipidemia, cerebral hemorrhagic and ischemic stroke are provided in online supplementary material figure 1, table 2.
Management of missing values
Missing values were found in 47.6% and 41.9% of the size and location variables, respectively. We applied multiple imputations to manage them. Since the missing pattern was arbitrary and missing variables were binary, we used a fully conditional specification as an imputation algorithm and a logistic regression model as an imputation model.15 Explanatory variables of the logistic regression model for imputation included baseline covariates and outcome variables. One hundred datasets were created and statistically analyzed. Results from each dataset were combined using Rubin’s Rule with appropriate transformation.16
Multiple imputation was performed under the assumption that missing at random (MAR) was the missing mechanism, but it is possible that the missing mechanism is missing not at random (MNAR). To confirm whether our results of primary outcome after multiple imputation are perusable, sensitivity tests were performed under several scenarios with the assumption of MNAR. We used the MNAR multiple imputation procedure provided in the SAS Enterprise Guide Version 6.3 (SAS Institute, Cary, North Carolina, USA), which was based on a pattern-mixture model approach.17
Adjustment for unbalanced covariates
We calculated the propensity score and used it for inverse probability treatment weighting (IPTW) for average treatment effect on the treated (ATT) to control for unbalanced baseline covariates and to estimate ATT.18 The propensity score was the probability that patients would be selected for surgical clipping given baseline covariates. It was estimated with the use of a logistic regression model that included patients’ demographics and coexisting conditions as explanatory variables. After IPTW for ATT, the weight of patients who underwent surgical clipping was fixed to 1, and the weight of patients who underwent endovascular coiling was calculated using the propensity score. This made it possible to compare the outcomes of patients who underwent surgical clipping with the predicted outcomes of those who underwent endovascular coiling.
The standardized difference was estimated to evaluate the balance of baseline covariates before and after weighting. If the standardized difference was less than 10.0%, we considered them appropriately balanced.
The primary outcome was all-cause mortality at 7 years after index admission. Secondary outcomes included periprocedural outcomes, the incidence of aneurysm rupture after treatment, and retreatment for any cause (eg, recanalization of treated aneurysm, de novo formation, or growth of observed aneurysm). Periprocedural outcomes were defined as all-cause mortality and adverse events that were identified from the corresponding procedure or diagnosis code within 30 days after the index admission. We defined aneurysm rupture as emergent readmission with a primary or secondary diagnosis code of I60.x or emergent readmission with a surgical clipping or endovascular coiling code. Retreatment for any cause was defined as elective readmission with a surgical clipping or endovascular coiling code 180 days after index admission. A list of the procedure codes used in the analysis of periprocedural outcomes is provided in online supplementary table 3.
We presented categorical variables as percentages and continuous variables as means with SD or medians with interquartile ranges. The primary outcome was estimated using the Kaplan–Meier method, and the log-rank test was performed to compare the groups. In the analysis of the incidence of aneurysm rupture and retreatment, the Kaplan–Meier method and log-rank test were used after censoring death. The 30-day mortality of periprocedural complications was estimated using the Kaplan–Meier method, and comparisons between the treatment groups were performed using the log-rank test. Cox proportional hazard models were used to estimate the hazard ratios (HRs) of the primary outcome, incidence of aneurysm rupture and retreatment, and 30-day mortality. The assumption of proportional hazard was tested and confirmed by including a time-treatment covariate as an interaction term. Categorical variables in periprocedural complications, except 30-day mortality, were compared using the χ2 test, and the relative risk (RR) was estimated for treatment effects. For continuous variables related to periprocedural complications (for example, length of hospitalization), the Wilcoxon rank-sum test was performed to compare the median between the treatment groups. All P values were two-sided and if the P value was <0.05 the result was considered statistically significant. All analyses were performed using SAS Enterprise Guide Version 6.3.
We identified 26 411 patients of whom 11 777 underwent surgical clipping and 14 634 underwent endovascular coiling. Table 1 shows the baseline characteristics of patients before and after adjustment using IPTW for ATT. There were notable differences between the treatment groups in the proportion of female sex (surgical clipping group 67.3%; endovascular coiling group 72.4%; absolute standardized difference 11.1%), multiplicity (surgical clipping group 9.4%; endovascular coiling group 6.2%; absolute standardized difference 11.8%), and posterior location of aneurysm (surgical clipping group 0.7%; endovascular coiling group 10.0%; absolute standardized difference 42.3%) before adjustment. After adjustment with the use of IPTW for ATT, the standardized differences of all baseline covariates were less than 1%, which indicated that all observed baseline covariates were appropriately balanced.
The overall median durations of follow-up were 3.5 years (IQR 2.1–5.2), 3.6 years (IQR 2.1–5.3) in the surgical clipping group, and 3.3 years (IQR 2.0–5.1) in the endovascular coiling group.
Figure 1 shows the unadjusted mortality in the endovascular coiling and surgical clipping groups. The unadjusted all-cause mortality rates at 7 years were 3.6% in the surgical clipping group and 4.3% in the endovascular coiling group (HR 1.20; 95% CI 1.01 to 1.43; P=0.04, log-rank test). After adjustment with the use of IPTW for ATT, all-cause mortality rates at 7 years were 3.6% in the surgical clipping group and 3.8% in the endovascular coiling group (HR 1.05; 95% CI 0.76 to 1.28; P=0.60, log-rank test) (figure 2).
In the analysis to test the consistency of all-cause mortality at 7 years across various subgroups, there were no significant interactions between surgical clipping and endovascular coiling (see online supplementary figure 2). In the sensitivity analysis that was performed under several scenarios with assumption of MNAR, we modified the proportion of aneurysms ≥7 mm in the endovascular coiling group, the proportion of aneurysms ≥7 mm in the surgical clipping group, and the proportion of posterior circulation located aneurysms in the endovascular group up to approximately 55%, 48%, and 30%, respectively. The result of each scenario showed that the primary outcome was consistent within the given proportions of scenarios, although the mechanism of missing data in our study is MNAR (online supplementary table 4).
Adjusted periprocedural outcomes are shown in online supplementary table 5. The 30-day all-cause mortality rates were 0.2% in the surgical clipping group and 0.2% in the endovascular coiling group (HR 0.91; 95% CI 0.53 to 1.56; P=0.73, log-rank test). Periprocedural aneurysm rupture occurred in 1.6% of patients in the endovascular coiling group and 1.6% in the surgical clipping group (RR 1.06; 95% CI 0.87 to 1.30; P<0.55). Reoperation for any cause was needed in 1.0% of patients in the endovascular coiling group and 0.6% in the surgical clipping group (RR 1.68; 95% CI 1.24 to 2.28; P<0.001). Immediate conversion to surgical clipping from endovascular coiling occurred in 0.1%. Epidural or subdural hematomas requiring operation occurred in 0.5% of the surgical clipping group (unavailable in the endovascular coiling group). Intracerebral hematoma requiring operation occurred in 0.1% of patients in the endovascular coiling group and 0.4% in the surgical clipping group (RR 0.22; 95% CI 0.10 to 0.47; P<0.001). Thromboembolic events requiring endovascular thrombolysis or mechanical thrombectomy occurred in 0.4% of patients in the endovascular coiling group and <0.1% in the surgical clipping group (RR 9.46; 95% CI 3.74 to 23.93; P<0.001). Transfusion of red blood cells was needed in 2.6% of patients in the endovascular coiling group and 24.0% in the surgical clipping group (RR 0.11; 95% CI 0.10 to 0.12; P<0.001). Tracheostomy was needed in 0.2% of patients in the endovascular coiling group and 0.5% in the surgical clipping group (RR 0.40; 95% CI 0.23 to 0.71; P<0.001). Median lengths of hospitalization were 4 days (IQR 3–7) in the endovascular coiling group and 11 days (IQR 8–16) in the surgical clipping group (P<0.001). Transfer to other hospital and hospital stays of more than 30 days were needed in 0.4% of patients in the endovascular coiling group and 1.4% of the surgical clipping group (RR 0.28; 95% CI 0.19 to 0.40; P<0.001).
The unadjusted probabilities of aneurysm rupture were 0.9% in the endovascular coiling group and 0.7% in the surgical clipping group (HR 1.08; 95% CI 0.77 to 1.52; P=0.65, log-rank test) (online supplementary figure 3). After adjustment with the use of IPTW for ATT, the probabilities of aneurysm rupture were 0.9% in the endovascular coiling group and 0.7% in the surgical clipping group (HR 0.90; 95% CI 0.61 to 1.34; P=0.63, log-rank test) (figure 3A).
The unadjusted probabilities of retreatment were 5.4% in the endovascular coiling group and 3.2% in the surgical clipping group (HR 1.69; 95% CI 1.45 to 1.97; P<0.001, log-rank test) (online supplementary figure 4). After adjustment with the use of IPTW for ATT, the probabilities of retreatment were 4.9% in the endovascular coiling group and 3.2% in the surgical clipping group (HR 1.52; 95% CI 1.28 to 1.81; P<0.001, log-rank test) (figure 3B).
In this study we could not find a significant difference in all-cause mortality at 7 years. Considering the differences in risk, it could be interpreted that all-cause mortality at 7 years was similar between the groups.
The International Study of Unruptured Intracranial Aneurysms (ISUIA) showed that mortality rates at 1 year after treatment were 2.7% in the surgical treatment group and 3.4% in the endovascular treatment group in patients with no history of aneurysm rupture.19 However, the ISUIA study was not designed to compare mortality rates, and there was heterogeneity in the baseline characteristics between the treatment groups. A study using the California Office of Statewide Health Planning and Development database with a median follow-up period of 7 years demonstrated no significant difference in mortality between a surgical clipping group of 1565 patients and an endovascular group of 943 patients.8 This result was similar to ours, but the study was limited by the use of unadjusted covariates and lack of information on aneurysm characteristics in the database.
There was no significant difference in aneurysm rupture rates after treatment between the groups in our study. Additionally, the rate of periprocedural rupture was not significantly different. As the primary outcome, the rate of aneurysm rupture after treatment and periprocedural rupture could also be considered similar between the treatment groups. The Unruptured Cerebral Aneurysm Study of Japan (UCAS) showed that the overall annual rupture risk of untreated aneurysms was 0.95%.20 A direct comparison of rupture rates in the UCAS and our study is impossible because of the heterogeneity of the populations. Although we could not infer the efficacy of surgical clipping or endovascular coiling compared with conservative care in terms of rupture risk, our result could be interpreted to indicate that surgical clipping and endovascular coiling are both reasonably safe modalities for preventing aneurysm rupture.
We found a significantly higher risk of retreatment after endovascular coiling than after surgical clipping. A propensity score-matched study using the Thomson Reuters MarketScan database showed that the rate of retreatment at 5 years was higher in the endovascular coiling group.21 We confirmed this result, but one should interpret these results with caution because they included recanalization of treated aneurysms and de novo formation and growth of the observed aneurysm.
Several limitations of our study should be considered. Since our study was based on a claims database, it may have potential coding errors and did not contain detailed characteristics of the aneurysms (eg, detailed location, daughter sac, dome neck ratio, or calcification), the status of occlusion (eg, complete occlusion, remnant neck, or remnant aneurysm sac), or other clinical considerations (eg, symptoms, smoking status, or family history that are important when deciding on the treatment modality). Although we implemented propensity scoring and IPTW for ATT to control for covariates, other unmeasured covariates could not be adjusted because the propensity scoring method only handles observed covariates. Our data also had missing values concerning the size and location of aneurysms. However, we used multiple imputation to avoid reaching biased results, which may occur if analyses are performed with only the complete data, and we tried to confirm the robustness of our results after imputation through sensitivity tests under several scenarios under the assumption of MNAR.
In conclusion, this nationwide claims database retrospective cohort study found that mortality at 7 years was similar between the elective surgical clipping and endovascular coiling groups in patients with unruptured aneurysm who had no history of subarachnoid hemorrhage due to aneurysm rupture.
Contributors All named authors contributed substantially to the work described by actively participating in the study and the generation of the data and providing editorial evaluation or the manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Ethics approval Ministry of Health and Welfare.
Provenance and peer review Not commissioned; externally peer reviewed.