Molyneux, Andrew et al. “International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial.” Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association vol. 11,6 (2002): 304-14
Intracranial aneurysms occur in about 5–8% of the population (1). Aneurysmal rupture often leads to catastrophic outcomes, including substantial mortality (2). Treatment modalities aim to achieve complete occlusion of the aneurysm while ensuring continued blood flow to the parent vessel, its branches, and perforating vessels.
In his 1933 report, Norman Dott described a 53-year-old man who presented with recurrent episodes of subarachnoid hemorrhage (3). Through a left frontal approach, the culprit aneurysm was identified close to the bifurcation of the internal carotid artery. The vessel was cleared of clots all around and the aneurysm was wrapped with thin strips of muscle obtained from the patient’s leg. In 1938, the legendary Walter Dandy, one of the founding fathers of neurosurgery, performed the first obliterative clipping of an intracranial aneurysm on a 43-year-old man who presented with a ruptured aneurysm of the internal carotid artery (4). He described how the narrow aneurysmal neck offered an easy “surgical attack”. A flat silver clip was placed on the neck of the aneurysm and tightly compressed, leading to complete obliteration. The aneurysm softened and ceased to pulsate almost instantaneously, heralding the era of surgical clipping.
The inherent complicity of surgical procedures paved the way for the genesis of endovascular techniques of aneurysm treatment. The quest for less invasive techniques led to the introduction of the detachable platinum coil device (5). The aneurysm is densely packed with multiple coils, leading to thrombus and granulation tissue formation, thereby limiting blood flow to the lumen. The endovascular coiling technique gained wide acceptance, considering its relative simplicity and applicability in patients too sick to undergo major surgery.
Hand in hand, surgical interventions too were performed with increasing finesse, with the advent of the operating microscope, improved microsurgical techniques, and the development of vascular neurosurgery as a stand-alone specialty. However, by 1995, endovascular coiling was being increasingly employed as the preferred treatment modality for intracranial aneurysms. Robust evidence on the ideal modality of treatment remained elusive, with only a small randomized controlled trial (RCT) that compared neurosurgical clipping with endovascular coiling. This RCT included 109 patients who presented with subarachnoid hemorrhage following a ruptured aneurysm (6). Patients were randomized to undergo surgical ligation or coil embolization. This study revealed more favorable angiographic results with surgical intervention in patients with anterior cerebral artery aneurysm, while endovascular treatment appeared more optimal among those with aneurysms in the posterior circulation. The need for an adequately powered RCT that compared endovascular coiling with neurosurgical clipping was sorely felt, leading to the study by the International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group.
Population and design
The ISAT multicentric RCT was conducted between Sept 12, 1994, and May 1, 2002, across 43 centers in Europe and North America (7). Patients with ruptured intra-cranial aneurysms were randomized to conventional neurosurgical or endovascular treatment if they were considered suitable for both therapies. All participating sites were major neurosurgical centers, treating between 60–100 cases per year, with expertise in both treatment modalities.
Subarachnoid hemorrhage was proven by CT or lumbar puncture within 28 days preceding randomization. A causative intracranial aneurysm had to be demonstrated by conventional or CT angiography. Patients were deemed to require treatment by neurosurgical intervention or endovascular technique; either treatment modality was considered appropriate based on angiographic anatomy.
Patients were excluded if >28 days had elapsed since the occurrence of subarachnoid hemorrhage or considered ineligible for one or both treatment modalities.
Randomization and procedure
Patients were randomized to craniotomy and micro-neurosurgical clipping or endovascular treatment using detachable platinum coils. A minimization algorithm was employed aiming to balance both groups based on age, gender, clinical grade, location of the culprit aneurysm, and the extent of hemorrhage on the CT scan. Post-procedure angiography was mandated for endovascular procedures unless specifically contraindicated. Angiography was also recommended for patients who underwent clipping, but not mandated if it meant a change in practice for the center where the procedure was performed. Following the initial procedure, further interventions could be performed on the target lesion or other lesions as appropriate.
The authors assumed a reduction in the number of patients dead or dependent at 1 year from 24% in the surgical clipping group to 19% in the endovascular treatment arm. This represented a 25% relative reduction in unfavorable outcomes at 1 year. The trial aimed to recruit 2500 patients, providing the study with 90% power at a level of significance of 0.01.
Recruitment was ceased following a planned interim analysis in May 2002. During the study period, 9559 patients were admitted with proven subarachnoid hemorrhage; following exclusion of 7416 patients, 2143 were randomized. Nearly all aneurysms (97.3%) involved the anterior circulation – most common locations were anterior cerebral, internal carotid, and middle cerebral arteries. The assigned modality of treatment was performed in 95.3% of patients. Nine patients who were randomized to the endovascular treatment group crossed over to surgical clipping, while 38 allocated to the surgical arm received endovascular treatment. Among patients randomized to the endovascular arm, the mean duration between randomization and performance of the procedure was 1.1 days; it was significantly longer in the neurosurgical group (1.7 days). The WFNS grade, size of the target aneurysm, and the number of aneurysms identified were similar in both groups. The endovascular procedure was successful in 92.5% of patients; the neurosurgical procedure was completed in 97.8% patients.
Clinical outcomes at 2 months
Among 1918 patients who were eligible for analysis at 2 months, data were available on 1906 patients. Clinical outcomes were evaluated based on the modified Rankin scale. The primary objective was to evaluate the proportion of patients who were dead or dependent, defined as score of 3–6. At 2 months, there were significantly more patients who were dead or dependent in the neurosurgical group compared to the endovascular treatment group. In the endovascular treatment group, 254/959 (25.4%) patients were dead or dependent compared with 345/947 (36.4%) in the neurosurgery group (relative risk, 0.698; [95% CI: 0.609-0.801], p = 0.0001).
Clinical outcomes at 1 year
At one year, data were available on 1594 of 1624 patients who were eligible for analysis. Similar to outcomes at 2 months, patients who underwent endovascular treatment fared better compared with those who underwent neurosurgical procedures. Among 801 patients assigned to endovascular treatment, 190 (23.7%) were dead or dependent at 1 year, compared with 243/793 (30.6%) patients who were allocated to undergo neurosurgery (relative risk, 0.774; [95% CI: 0.658-0.911], p = 0.0019). This represented a relative risk reduction of 22.6% and an absolute risk reduction of 6.9% for patients who underwent endovascular procedures. The case fatality rate at 1 year did not differ significantly between the two groups (endovascular treatment: 8.1% vs. neurosurgery: 10.1%).
Rebleeding before the assigned procedure occurred in 14 (7%) in the endovascular treatment group and 23 (16%) patients in the neurosurgical group. Rebleeding in the first 30 days after the procedure was more common in the endovascular treatment group (20 [10%] vs. 6 [3%] patients).
Among the 20 patients who rebled in the endovascular group, the aneurysm could not be occluded in five patients while occlusion was incomplete in seven. In three patients, the aneurysm was considered fully occluded. The remaining five patients developed a thromboembolic complication following the endovascular procedure. They went on to receive thrombolytic therapy; however, there were no survivors.
Among the six patients in the neurosurgery group who rebled, occlusion of the aneurysm was incomplete in three patients, while the other three had undergone complete neurosurgical clipping.
The total incidence of rebleeding from initial rupture up to one year was similar in both groups. The risk of rebleeding after 1 year was low – two per 1276 patient-years in the endovascular treatment group and 0 per 1081 patient-years in the neurosurgical group.
The ISAT trial demonstrated that in patients with ruptured intracranial aneurysms, disability-free survival is significantly greater with endovascular treatment using detachable platinum coils compared with neurosurgical intervention to clip the neck of the aneurysm. Early rebleeding was more common with endovascular coiling; however, the long-term risk of rebleeding was low with both therapies. The results of the trial apply to patients who are deemed to be appropriate for either intervention by the treating team. The case fatality rate at 1 year did not differ between the two groups.
The ISAT trial addressed an important, but largely unanswered clinical question regarding the optimal modality of therapy in ruptured intracranial aneurysms. It was a multicentric trial with central randomization, providing external validity. Short and long-term follow-up was rigorous and unbiased.
Although multicentric by design, most patients (77%) were recruited from the UK. A large number of patients were excluded, casting doubts on the generalizability of the study. Although 9559 patients were assessed for eligibility, only 2143 (22.4%) patients were randomized. The trial was ceased prematurely as interim analysis revealed the likelihood of more favorable outcomes with endovascular coiling compared with neurosurgical intervention. Follow-up data were collected by a postal questionnaire, which may have been liable to subjective bias and misinterpretation. The outcomes from neurosurgical intervention were less favorable than observed in previous studies. Although endovascular operators were required to meet pre-set experience criteria, no such eligibility rules were applied to neurosurgeons. Questions were raised as to whether lack of experience with the surgical procedure may have resulted in suboptimal outcomes. Most centers were proficient with endovascular treatment; however, centers with adequate neurosurgical expertise were fewer. The study reported 92.5% of endovascular procedures as “completed”; however, the authors failed to provide angiographic data to substantiate this result. There was no report of procedure-related complications.
Rebleeding frequently occurred among patients who were awaiting neurosurgical intervention following the failure of endovascular treatment, suggesting that follow-up interventions must be carried out expeditiously unless contraindicated. The study did not suggest that neurosurgical intervention should be totally dispensed with; there are many patients who may not be amenable to endovascular treatment due to anatomical features or the clinical setting. Thrombolytic therapy was clearly shown to cause rebleeding and death; hence, antiplatelet agents are preferred for ischemic complications.
Complete 1-year follow-up (2005)
The first ISAT study had complete 1-year follow-up data only for 1594 of 2143 patients who were randomized. In a later study, the ISAT authors reported on 1-year outcomes of 2118/2143 patients who were enrolled (8). This included 1063 of 1073 patients originally allocated to endovascular treatment, and 1055 of 1070 patients assigned to neurosurgical treatment. Clinical outcomes were significantly more favorable in the endovascular treatment group at 1-year follow-up. In the endovascular treatment group, 250/1063 (23.5%) were dead or dependent at 1-year compared with 326/1055 (30.9%) in the neurosurgical treatment group. This represented an absolute risk reduction of 7.5% (95% CI, 3·6–11·2; p = 0·0001). The survival advantage following endovascular treatment was sustained for up to 7 years. Furthermore, the risk of epileptic seizures was lower among patients who underwent endovascular treatment.
Aneurysm recurrence and retreatment (2007)
Although long-term clinical outcomes were more favorable with endovascular treatment, concerns were raised regarding aneurysm recurrence due to inadequate initial occlusion or late reopening after coiling. In a follow-up report, retreatment was more often required with endovascular treatment compared with neurosurgical intervention (17.4% vs. 3.8%) (9). Late retreatment was 6.9 times more frequent after endovascular intervention. Risk factors for late retreatment included younger age, larger lumen, and incomplete initial occlusion. Short-term follow-up imaging was insufficient to identify aneurysm recurrence.
The 6–14 year follow-up (2009)
This follow-up report of the ISAT trial evaluated the risk of recurrent subarachnoid hemorrhage, death, and dependence based on data available from 2004 patients (10). Rebleeding occurred in 24 patients more than 1 year after treatment – 13 were from the originally treated aneurysm. Among these 13 rebleeds from the originally treated aneurysm, 10 occurred in the endovascular treatment group and 3 in the neurosurgical group. At 5 years of follow-up, mortality was higher in the neurosurgical compared to the endovascular group (14% vs. 11%, p = 0.03). Disability-free survival at 5 years was similar – 83% in the endovascular and 82% in the neurosurgical group.
The 18-year follow-up (2014)
In a later study, the ISAT investigators reported on the follow-up of 1644 patients enrolled in 22 UK neurosurgical centers for clinical outcomes between 10·0–18·5 years (11). At 10 years of follow-up, 674/809 (83%) of patients in the endovascular coiling group and 657/835 (79%) patients in the neurosurgical group were alive; the difference was not statistically significant (odds ratio 1·35; 95% CI 1·06–1·73). Among 1003 subjects who answered the questionnaire at 10 years, 82% of patients in the endovascular coiling group and 78% of patients in the neurosurgical group were independent; the difference was not significant. Patients who underwent endovascular treatment were more likely to be alive and independent at 10 years (odds ratio 1·34; 95% CI 1·07–1·67). Although the overall incidence was low, rebleeding from the originally targeted aneurysm occurred more frequently in the endovascular treatment group (13 vs. 4 cases).
The ISAT RCT aimed to compare the safety and efficacy of endovascular coiling with neurosurgical clipping for aneurysms considered suitable for both modalities of treatment. The investigators enrolled 2143 patients – 1073 were assigned to endovascular treatment and 1073 to neurosurgical clipping. Trial recruitment was ceased following a planned interim analysis that showed likely benefit with endovascular treatment. Significantly more patients were dead or dependent at 1-year follow-up in the neurosurgical compared with the endovascular treatment group. The risk of rebleeding after 1 year was low; however, it was marginally higher with endovascular treatment. The study established that disability-free survival was higher with endovascular treatment compared with neurosurgical intervention among patients who were considered appropriate for either modality of treatment.
It is important to point out that both neurosurgical clipping and endovascular coiling remain effective treatment modalities for intracranial aneurysms. Refinements in technique have shifted the preference to endovascular treatment in recent years, especially considering the reduced procedural time and tolerability in sicker patients. However, not all aneurysms are amenable to intervention by the endovascular route; neurosurgical treatment using bypass techniques to direct the flow away from the aneurysm are still required in complex clinical situations.
1. Lee KS, Zhang JJY, Alalade AF, Vine R, Lanzino G, Park N, et al. Radiological surveillance of small unruptured intracranial aneurysms: a systematic review, meta-analysis, and meta-regression of 8428 aneurysms. Neurosurg Rev. 2021 Aug;44(4):2013–23.
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8. Molyneux AJ, Kerr RSC, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. 2005;366.
9. Campi A, Ramzi N, Molyneux AJ, Summers PE, Kerr RSC, Sneade M, et al. Retreatment of Ruptured Cerebral Aneurysms in Patients Randomized by Coiling or Clipping in the International Subarachnoid Aneurysm Trial (ISAT). Stroke. 2007 May;38(5):1538–44.
10. Molyneux AJ, Kerr RS, Birks J, Ramzi N, Yarnold J, Sneade M, et al. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol. 2009 May;8(5):427–33.
11. Molyneux AJ, Birks J, Clarke A, Sneade M, Kerr RSC. The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT). The Lancet. 2015 Feb;385(9969):691–7.
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