Background Endovascular treatment is the first line therapy for the management of ruptured and unruptured intracranial aneurysms, but delayed aneurysm rupture leading to bleeding/rebleeding can occur subsequently. ARETA (Analysis of Recanalization after Endovascular Treatment of intracranial Aneurysm) is a prospective, multicenter study conducted to analyze aneurysm recanalization. We analyzed delayed bleeding and rebleeding in this large cohort.
Methods 16 neurointerventional departments prospectively enrolled patients treated for ruptured and unruptured aneurysms between December 2013 and May 2015 (ClinicalTrials.gov: NCT01942512). Participant demographics, aneurysm characteristics and endovascular techniques were recorded. Data were analyzed from participants with ruptured or unruptured aneurysms treated by coiling or balloon-assisted coiling. Rates of bleeding and rebleeding were analyzed and associated factors were studied using univariable and multivariable analyses.
Results The bleeding rate was 0.0% in patients with unruptured aneurysms and 1.0% (95% CI 0.3% to 1.7%) in patients with ruptured aneurysms. In multivariate analysis, two factors were associated with rebleeding occurrence: incomplete aneurysm occlusion after initial treatment (2.0% in incomplete aneurysm occlusion vs 0.2% in complete aneurysm occlusion, OR 10.2, 95% CI 1.2 to 83.3; p=0.03) and dome-to-neck ratio (1.5±0.5 with rebleeding vs 2.2±0.9 without rebleeding, OR 0.2, 95% CI 0.04 to 0.8; p=0.03). Modalities of management of aneurysm rebleeding as well as clinical outcomes are described.
Conclusions Aneurysm coiling affords good protection against bleeding (for unruptured aneurysms) and rebleeding (for ruptured aneurysms) at 1 year with rates of 0.0% and 1.0%, respectively. Aneurysm occlusion and dome-to-neck ratio are the two factors that appear to play a role in the occurrence of rebleeding.
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Since the initial publication of the International Subarachnoid Aneurysm Trial (ISAT), endovascular treatment (EVT) in the management of intracranial aneurysms (IA) has progressively become the first-line treatment.1–3 Several limitations of aneurysm coiling were rapidly identified by interventional neuroradiologists, such as the difficulty of treating wide-neck aneurysms and the relatively high risk of aneurysm recurrence, leading to the development of new endovascular techniques and devices, for example, balloon-assisted coiling, stent-assisted coiling, flow diversion and flow disruption.4 5
The primary and most important role of aneurysm treatment is to prevent aneurysm rebleeding in cases of ruptured intracranial aneurysms (RIA) and bleeding in cases of unruptured intracranial aneurysms (UIA). Based on initial analyses of the ISAT population, the number of patients suffering from rebleeding in the first year after treatment was slightly higher in the endovascular group (26/801, 3.2%) compared with the surgical group (10/793, 1.3%).1 The risk of rebleeding after 1 year was also analyzed in subsequent ISAT publications, showing a progressive decrease over time.6 In contrast to ruptured aneurysms, relatively little is known regarding the protection afforded by aneurysm coiling in preventing bleeding in unruptured aneurysms. This phenomenon was not analyzed in the Analysis of Treatment by Endovascular Approach of Non Ruptured Aneurysms (ATENA) study, where 1 year and long-term follow-up was not available, and in the meta-analysis conducted by Naggara et al. 2 7
The Analysis of Recanalization after Endovascular Treatment of intracranial Aneurysm (ARETA) study is a French, prospective, multicenter study, which aims to determine the factors that affect aneurysm recanalization after endovascular treatment.8 Several baseline patient and aneurysm characteristics were collected as well as complications that occurred during and after treatment .9 10 Given the large sample (n=1289), this study offers the opportunity to conduct a detailed analysis of intra- and postoperative events occurring in relation to endovascular treatment of intracranial aneurysms (ruptured or unruptured). Findings from analyses of intraoperative complications in the ARETA study occurring during aneurysm treatment have already been published.10 However, several complications occur after endovascular treatment of intracranial aneurysms, including: delayed aneurysm rupture inducing rebleeding in ruptured aneurysms, bleeding in unruptured aneurysms, thromboembolic events, and delayed remote hematomas.4 While delayed bleeding of UIA is rare during the year following aneurysm treatment, rebleeding of RIA can occur within 3 days (acute bleeding), 30 days (early rebleeding), or later (late rebleeding) following aneurysm treatment.11 The goal of the present analysis is to determine the rate of postoperative bleeding or rebleeding after coiling (including balloon-assisted coiling) of unruptured and ruptured aneurysms, the clinical outcome of these events, and factors associated with these complications.
The ARETA study
ARETA was primarily designed to analyze factors that affect aneurysm recanalization after endovascular treatment. The French Ministry of Health in a PHRC (Programme Hospitalier de Recherche Clinique, No. 12-001-0372) provided funding. ARETA was registered on www.clinicaltrials.gov (NCT01942512), and received national regulatory authorization from the Consultative Committee of Information Processing in Healthcare Research Program and the National Commission for Data Processing and Freedom. The study objective and its protocol, including inclusion and exclusion criteria, have previously been described.8 According to French law, the study did not require approval by institutional review board, nor written informed consent.
Inclusion criteria were: age >18 years, saccular IA, ruptured or unruptured IA, and IA treated by any endovascular technique (coiling, balloon-assisted coiling (BAC), stent-assisted coiling (SAC), flow diversion, flow disruption). Exclusion criteria included dissecting or fusiform IA, IA associated with a brain arteriovenous malformation, and IA already treated by clips or coils.
Sample size was calculated based on a potential association between tobacco use and recanalization at 12 months. Based on estimated tobacco use in 40% of participants without recanalization, and 55% with recanalization, a recanalization rate of 25%, with an alpha of 5%, power of 95%, and a two-sided test, the number of participants required was 760 (NQuery software version 4.0, Cork, Ireland).3 Assuming an estimated 40% rate of loss to follow-up or death at 12 months, a sample size of 1275 participants was considered necessary.
Four ARETA manuscripts have been previously published. One described study background and protocol.8 The remaining three studies described the population and modalities of treatment, analyzed patient and aneurysm risk factors associated with aneurysm rupture, and analyzed intraoperative complications occurring during aneurysm coiling (including BAC).9 10 12
The study objectives were as follows:
Determine the rate of aneurysm bleeding in the year following coiling among patients with unruptured aneurysms
Determine the rate of aneurysm rebleeding in the year following coiling among patients with ruptured aneurysms
Determine the factors that are associated with the risk of bleeding/rebleeding
Analyze the management used and clinical outcome in cases of bleeding/rebleeding.
Participating centers reported participant, aneurysm and treatment characteristics, and complications on a standardized form. Clinical research assistants controlled the accuracy of the collected data. A core laboratory centrally adjudicated the aneurysm characteristics, treatment modalities and complications of all the participants.
Rebleeding or bleeding was suspected when sudden changes in clinical status occurred and were confirmed by the detection of fresh blood on CT in the vicinity of the aneurysm initially treated. Clinical outcome of bleeding/rebleeding was evaluated by modified Rankin Scale (mRS) at hospital discharge. Poor clinical outcome was defined by mRS 3–6 at hospital discharge.
Centers also collected preoperative digital subtraction angiography (DSA) and immediate postoperative DSA, and transferred anonymized results to Reims Hospital. Aneurysm characteristics, treatment modalities and complications of all participants were reviewed, checked for accuracy and, if necessary, revised by the core laboratory.
The participants were prospectively enrolled in 16 centers in France between December 2013 and May 2015. Within the overall ARETA cohort, participants with at least one IA treated with a technique other than coiling or BAC (ie, stent-assisted coiling, flow diversion, flow disruption) were excluded from analysis. Participating study sites reported the following baseline participant characteristics: age, sex, current use of cigarettes, regular consumption of alcohol, diabetes mellitus (glycemia >6 mmol/L), elevated blood pressure (defined as blood pressure >140/90 mmHg uncorrected by medical treatment), polycystic kidney disease, and familial history of aneurysm. Family history of aneurysm was defined as the presence of two or more family members among first- and second-degree relatives with proven aneurysmal subarachnoid hemorrhage or incidental aneurysms. Clinical status before treatment was evaluated based on World Federation of Neurosurgical Societies (WFNS) grade for participants with RIA, and mRS for participants with UIA.
Recorded aneurysm characteristics were: aneurysm sac diameter (dichotomized into <7 mm and ≥7 mm); neck size and dome-to-neck ratio (wide neck defined as neck size ≥4 mm and/or dome to neck ratio <2); aneurysm location (extradural internal carotid artery (ICA), intradural ICA including the posterior communicating artery, middle cerebral artery (MCA), anterior communicating/anterior cerebral artery (ACA/Acom) or vertebrobasilar (VB)); aneurysm rupture status (ruptured or unruptured); aneurysm shape (regular or irregular); and number of IA (single or multiple). Aneurysm was classified as regular when there was a single sac with a smooth margin, and irregular if it was a single sac with an irregular margin or a daughter sac or a multilobulated aneurysm.
Treatment modalities including perioperative medications were at the discretion of the treating interventional neuroradiologist. Treatment modalities were categorized into coils, BAC, SAC, flow diversion, intrasaccular flow disruption, and parent vessel sacrifice. According to the primary objective of ARETA, postoperative medications were not collected in the database.
The Department of Research and Public Health of Reims Hospital was responsible for data management and statistical analysis. Data were described using mean±SD for continuous variables and number and percentage for categorical variables. Patient and aneurysm factors associated with aneurysm bleeding/rebleeding in the year following treatment were assessed using univariate analysis (Wilcoxon tests or Fisher exact tests, as appropriate) and multivariate analysis (logistic regressions with stepwise selection, with an exit threshold of 0.20 and variables significant at p=0.10 included). A p value <0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC, USA).
After applying study inclusion criteria to the overall cohort of 1289 participants (harboring 1761 aneurysms), the study population for this analysis consisted of 1140 participants (53.8±12.8 years, 757 women (66.4%)) with 1195 aneurysms (figure 1). In this population, 794 patients (69.6%) presented with at least one RIA (54.0±13.1 years, 520 women (65.5%)) and 346 patients (30.4%) presented only UIA (53.3±12.1 years, 237 women (68.5%)) (table 1). Among the 794 patients with at least one RIA, 753 had a single treated IA and 41 had multiple treated IAs, corresponding to a total of 838 treated IAs (817 RIAs and 21 UIAs). Among the 346 patients with only UIA, 335 had a single treated IA and 11 had multiple treated IAs, corresponding to a total of 357 treated UIAs. Thus, among the 1195 IAs, 817 (68.4%) were RIAs treated by coiling (461/817, 56.4%) or BAC (356/817, 43.6%) during the initial procedure, while 378 (31.6%) were UIAs treated by coiling (187/378, 49.5%) or BAC (191/378, 50.5%) during the initial procedure (table 1).
Rate of bleeding in patients with unruptured aneurysms
At 12 month follow-up (mean follow-up 14.2±5.2 months), we observed no episodes of bleeding (0.0%) in the cohort of 346 patients treated only for unruptured aneurysms.
Rate and delay of rebleeding in patients with ruptured aneurysms
At 12 month follow-up (mean follow-up 12.2±6.3 months), rebleeding was observed in 8/794 patients treated for at least one RIA (1.00%, 95% CI 0.3% to 1.7%). Among the RIAs, 8/817 aneurysms (0.98%) rebled (table 2).
Rebleeding occurred within 30 days (early rebleeding) following the initial procedure in five patients (1, 3, 8, 13 and 26 days, respectively), and after 30 days (late rebleeding) in three patients (151, 207 and 296 days, respectively).
Characteristics of patients with ruptured aneurysms and rebleeding
Six of the eight patients with ruptured aneurysms who experienced rebleeding were female. Age was between 18 and 40 years in two patients, between 41 and 60 years in four patients, and above 61 years in two patients. Two patients were current smokers and one patient regularly consumed alcohol. Aneurysm location was supraclinoid ICA in four patients, ACA/Acom in two patients, MCA in one patient, and VB in one patient. Aneurysm size (maximum diameter) was <7 mm in six patients and ≥7 mm in two patients. The aneurysm neck was narrow (<4 mm) in five patients and wide (≥4 mm) in three patients. The dome-to-neck ratio was between 0.7 and 2.2 (mean 1.5±0.5). All aneurysms had an irregular shape. Aneurysm occlusion after the initial procedure was complete aneurysm occlusion in one patient, neck remnant in six cases, and aneurysm remnant in one patient. At the time of rebleeding, one patient (patient 8) rebled from the coiled Acom aneurysm 3 days post-procedure and quickly clinically deteriorated leading to death before any retreatment. One patient (patient 5) was treated by surgery (without DSA before treatment) due to a compressive parenchymal hematoma, and the aneurysm was clipped. The patient subsequently died. Six patients had DSA, which was not collected for analysis in one patient. In the five remaining patients, aneurysm occlusion at the time of rebleeding was neck remnant in one patient and aneurysm remnant in four patients (table 2).
Management and outcome of rebleeding in patients with ruptured aneurysms
Modalities of retreatment included clipping in one patient (large temporal hematoma) and EVT in six patients (additional coiling with BAC in one patient, SAC in four patients, and flow diversion in one patient). One patient was left untreated due to rapid clinical deterioration and died before any retreatment. At hospital discharge after rebleeding, clinical outcome was good (mRS 0 to 2) in three patients and poor (mRS 3 to 6) in five patients, including death in two patients. At 12 month follow-up (mean follow-up 11.1±5.6 months), clinical outcome was good in six patients (mRS 0 in four patients, mRS 1 in two patients) and two patients died (table 2).
Patient factors associated with the risk of rebleeding in patients with ruptured aneurysms
We found no significant association between age (p=0.48), sex (p=0.72), elevated blood pressure (at the time of the initial procedure) (p=0.99), current smoking (p=0.46), regular alcohol consumption (p=0.99), diabetes mellitus (p=0.99), polycystic kidney disease (p=0.99), family history (p=0.99) and risk of rebleeding in patients with at least one treated ruptured aneurysm (table 3).
Aneurysm factors associated with the risk of rebleeding in treated ruptured aneurysms
In univariate analysis, aneurysm location (p=0.31) and size (p=0.80) were not significantly associated with rebleeding in treated ruptured aneurysms. Mean neck size was larger in treated ruptured aneurysms that rebled than in those that did not rebleed (4.3±2.1 mm vs 3.0±1.3 mm, respectively; p=0.049). Dome-to-neck ratio was smaller in treated ruptured aneurysms that rebled than in those that did not rebleed (1.5±0.5 vs 2.2±0.9, respectively; p=0.03). Risk of rebleeding was not associated with aneurysm shape (0.0% in regular aneurysms vs 1.0% in irregular aneurysms; p=0.37). Postoperative complete occlusion was less frequent in treated ruptured aneurysms that rebled than in those that did not rebleed (0.2% vs 2.0%, respectively; p=0.02). Risk of rebleeding was not significantly different between aneurysms with wide neck and aneurysms without wide neck (1.4% and 0.5%, respectively; p=0.30). In multivariate analysis, dome-to-neck ratio (OR 0.2, 95% CI 0.04 to 0.8; p=0.03) and incomplete occlusion (OR 10.2, 1.2 to 83.3; p=0.03) were significantly associated with rebleeding (table 4).
Our analysis of this recent, large, prospective, multicenter cohort shows that aneurysm coiling provides good protection against bleeding in UIAs (bleeding rate 0.0%) and rebleeding in RIAs (rebleeding rate 1.0%) in the year following the initial procedure. In this series, rebleeding occurred primarily in the month following the initial bleeding and aneurysm treatment (early rebleeding) in 5/8 patients, and between 1 month and 1 year after the initial procedure (late rebleeding) in 3/8 patients. Two factors potentially play a role in rebleeding based on our findings, namely, postoperative aneurysm occlusion and dome-to-neck ratio. Rebleeding is a severe clinical event, which was fatal in 2/8 patients in this series, and can be managed using several treatment modalities (including clipping).
Rate of bleeding (for UIA) and rebleeding (for RIA)
The main goal of IA treatment is to prevent bleeding in UIAs and rebleeding in RIAs. According to the present series, in the year following initial aneurysm treatment, no bleeding was observed after unruptured aneurysm treatment. Indeed, the risk of bleeding of coiled UIAs has to be evaluated in the long-term knowing the relatively low risk of rupture of untreated UIAs.13 In a recent analysis conducted using a nationwide retrospective cohort in South Korea (14 634 patients with UIA treated by EVT, and 11 777 treated by clipping), the adjusted probability of rupture at 7 years was very low (0.9% in the endovascular group and 0.7% in the surgical group).14
In RIAs, the risk of rerupture after aneurysm coiling has been evaluated in several studies. In ISAT, among the 801 patients with RIA treated by coiling, 40 (0.5%) presented with rebleeding, including 14 that occurred before aneurysm treatment, leading to a rate of rebleeding after the first EVT of 3.2% (26/801 patients). Early rebleeding (within 30 days of initial bleeding) was more frequent (20/801, 2.5%) than late rebleeding (31 days to 1 year; 6/801, 0.7%). In the large Sluzewski and van Rooij series (431 patients with RIA), the rate of early rebleeding was 1.4%.15 The same group also reported the occurrence of late rebleeding (after 30 days) in four patients, including two in the year following initial treatment (2/393, 0.5%).16 In two other large studies of patients with RIA treated by coiling, the rate of early rebleeding was 0.9% and 1.1%.17 18 In our series, the rate of early rebleeding was 0.6% (5/794 patients), whereas late rebleeding (31 days to 1 year) was 0.4% (3/794 patients), leading to an overall 1 year rebleeding rate of 1.0%. These findings highlight two important points: (1) there appears to have been a progressive decrease in the rate of early rebleeding from 2.5% in ISAT to 0.6% in our series, associated with a global decrease of aneurysm rebleeding in the first year (from 3.2% to 1.0%), which can potentially be attributed to technical improvement of the coils and adjunctive devices and improved physician skills (learning curve); and (2) rebleeding in the first year after initial treatment typically occurs early (<30 days), whereas late rebleeding can occur several weeks or months after initial treatment and is rare.
Risk factors for rebleeding of RIA
Identifying risk factors associated with rebleeding of coiled ruptured aneurysms is not easy due to low occurrence of events. In a recent meta-analysis, several risk factors were identified: incomplete aneurysm occlusion, dual antiplatelet therapy, presence of an adjacent intracranial hematoma, presence of an aneurysmal bleb, Acom aneurysm location, small aneurysms (<6 mm), and intraoperative rupture.19 In the univariate and multivariate analysis conducted in ARETA, no patient factors were associated with rebleeding, whereas two aneurysm factors were identified: dome-to-neck ratio and postoperative occlusion. Aneurysm morphology seems to play an important role in aneurysm rebleeding. If the neck size was significantly associated with rebleeding in univariate analysis (4.3±2.1 mm vs 3.0±1.3 mm; p=0.049), it is no longer the case in multivariate analysis. On the contrary, dome-to-neck ratio is significantly lower in patients with rebleeding compared with patients without rebleeding (1.5±0.5 vs 2.2±0.9; punivariate=0.03, pmultivariate=0.03). It probably shows that more than the neck size by itself, it is more the global morphology of the aneurysm that plays a role in the occurrence of rebleeding as previously reported.20 Postoperative aneurysm occlusion is an important factor to consider, as it can be important for the therapeutic strategy. The rate of rebleeding is 0.2% (1/465 patients) in postoperative complete occlusion, whereas it is 2.0% (7/348 patients) in postoperative incomplete occlusion (punivariate=0.02; pmultivariate=0.06). Interestingly, among seven patients with incomplete post-operative aneurysm occlusion, only two had an aneurysm remnant while the remaining five had a neck remnant. The Cerebral Aneurysm Rerupture After Treatment (CARAT) study has previously shown that the degree of aneurysm occlusion after initial coiling is a strong predictor of the risk of subsequent rupture, with a 2.9% risk in cases with 91–99% aneurysm occlusion (that can be considered as a neck remnant) and a higher risk when aneurysm occlusion is <90% (5.9% to 17.6%).21 The fact that 5/8 patients (three with early rebleeding and two with delayed rebleeding) in our series had a neck remnant immediately after the initial procedure suggests that this occlusion type is not really sufficient to completely prevent rebleeding. It has two consequences: (1) during the first procedure, the goal is to obtain complete aneurysm occlusion, which offers the best protection against rebleeding; and (2) when a neck remnant is the final occlusion of the initial procedure, a careful follow-up or even a retreatment must be considered.
Early and late rebleeding probably involves different mechanisms. According to Cho et al, early rebleeding can be related to intraprocedural administration of antiplatelet or thrombolytic medications, maintenance of anticoagulation after the procedure, incomplete treatment of the aneurysm, or presence of intracranial hematoma, while delayed rebleeding is likely related to aneurysm recanalization with increased aneurysm size and/or coil compaction.18
Management and clinical outcome of patients with rebleeding
Management of patients initially treated for RIA presenting with rebleeding depends on the clinical status of the patient after rebleeding and location of the rebleeding (brain parenchyma or subarachnoid space). In our series, one patient experienced rapid clinical deterioration and died without receiving treatment. Another patient had a large temporal hematoma and was treated surgically with removal of the hematoma, exploration and aneurysm clipping; despite this management, the patient died. Retreatment in the remaining six patients was performed by an endovascular approach using several techniques: BAC in one patient, SAC in four patients, and flow diversion in one patient. In the eight patients with rebleeding, clinical outcome at discharge was good (mRS 1) in 3/8 patients (37.5%), poor (mRS 3, 4 and 5) in 3/8 patients (37.5%), and death in 2/8 patients (25.0%). At 12-months follow-up, clinical status was better with good clinical outcome (mRS 0 in four patients and mRS 1 in two patients) in 6/8 patients (75.0%) and death in 2/8 patients (25.0%).
First, ARETA was designed to analyze recanalization after EVT of intracranial aneurysms, not intra- and postoperative complications. However, given that ARETA is, to the best our knowledge, the largest recent series of patients with aneurysm treated by EVT, the cohort offers the opportunity to analyze the rate of bleeding/rebleeding during 1 year follow-up. Second, in relation to the previous limitation, and according to the study’ primary objective (recanalization), postoperative medications were not collected in the database knowing that postoperative antiplatelet medication can potentially play a role in the occurrence of rebleeding in patients with ruptured aneurysms. Third, patients who died at home or were lost to follow-up after hospital discharge may have experienced undiagnosed rebleeding, leading to an underestimation of the rebleeding rate.
Aneurysm coiling affords good protection against bleeding (for unruptured aneurysms) and rebleeding (for ruptured aneurysms) at 1 year with rates of 0.0% and 1.0%, respectively. Aneurysm occlusion and dome-to-neck ratio are the two factors that appear to play a role in the occurrence of rebleeding. Consequently, the goal of initial treatment of a ruptured aneurysm is to obtain complete aneurysm occlusion. If this outcome is not possible, close monitoring needs to be undertaken.
Contributors All authors have: provided a substantial contribution to the conception and design of the studies and/or the acquisition and/or the analysis of the data and/or the interpretation of the data; drafted the work or revised it for significant intellectual content; approved the final version of the manuscript; agreed to be accountable for all aspects of the work, including its accuracy and integrity.
Funding The French Health Ministry has funded ARETA (Programme Hospitalier de Recherche Clinique, No. 12-001-0372).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The data related to this manuscript are available upon reasonable request.
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