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Molyneux A, et al. "International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial". The Lancet. 2002. 360(9342):1267-1274.
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Clinical Question

In patients with intracranial aneurysms, is endovascular coiling a safer alternative to craniotomy and clipping?

Bottom Line

In patients with a ruptured intracranial aneurysm, for which endovascular coiling and neurosurgical clipping are therapeutic options, the outcome in terms of survival free of disability at 1 year is significantly better with endovascular coiling.

Major Points

Aneurysmal subarachnoid haemorrhage (SAH) is a significant cause of death and disability with an annual incidence of between 6 and 12 per 100,000 population in most western countries[1]. Nearly a third of patients die within 24 hours of the bleed and an additional 25-30% will die within a month without surgical intervention[2]. Conventional neurosurgical treatment involves a craniotomy and occlusion of the aneurysm with a metal clip to prevent further bleeding.

In 1995, the FDA approved the use of a detachable platinum coil for the treatment of intracranial aneurysms through less invasive endovascular techniques. This alternative to neurosurgical clipping raised the questions whether patients undergoing endovascular treatment would have better functional outcome compared with conventional treatment.

ISAT is a multicentered randomized trial involving 2143 patients with ruptured intracranial aneurysms from Europe and North America[3]. Participants were randomized into either a endovascular coiling or neurosurgical clipping group. Outcome was assessed by comparing the proportion of death or dependency in each treatment group after 1 year. Dependency was defined as a score of 3-6 on the modified Rankin Scale. At 1 year 190 of 801 (23·7%) in the endovascular treatment group were dependent or dead compared with 243 of 793 (30·6%) in the neurosurgery group (relative risk 0·774 [0·658–0·911], p=0·0019). The rate of re-bleed after 1 year was 2 per 1276 in the endovascular group compared with 0 per 1081 in the neurosurgical group.


AHA/ASA Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage

  • For patients with ruptured aneurysms judged to be technically amenable to both endovascular coiling and neurosurgical clipping, endovascular coiling should be considered (Class I; Level of Evidence B)


  • Multicenter, randomized, controlled trial
  • N=2,143
    • Endovascular coiling (n=1073)
    • neurosurgical clipping (n=1070)
  • Setting: 43 major neurosurgical centers in Europe and North America
  • Enrollment: 1994-2001
  • Mean follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: survival free disability at 1 year measured by Modified Rankin Scale


Inclusion Criteria

  • They had a definite subarachnoid haemorrhage, proven by computed tomography (CT) or lumbar puncture, within the preceding 28 days
  • They had an intracranial aneurysm, demonstrated by intra-arterial or by CT angiography, which was considered to be responsible for the recent subarachnoid haemorrhage (SAH)
  • They were in a clinical state that justified treatment, at some time, by either neurosurgical or endovascular means
  • The aneurysm was judged by both the neurosurgeon and the interventional neuroradiologist to be suitable for either technique on the basis of its

angiographic anatomy

  • There was uncertainty as to whether the ruptured aneurysm should be treated by neurosurgical or endovascular means
  • they gave appropriate informed consent, according to the criteria laid down by the local ethics committee, or if unable, assent from relatives

Exclusion Criteria

  • SAH occurred more than 28 days before randomization
  • The patient was regarded as unsuitable for one or both treatments
  • Consent was refused
  • The patient was participating in another randomized clinical trial of a treatment for SAH

Baseline Characteristics

Comparisons are from endovascular group vs. neurosurgery group

  • Male sex 400 (37%) 399 (37%)
  • Median age (years) 52 vs 52
  • Number of patients according to WFNS grade
    • 1: 674 (63%) vs 661 (62%)
    • 2: 269 (25%) vs 280 (26%)
    • 3: 66 (6%) vs 68 (6%)
    • 4: 38 (4%) vs 36 (3%)
    • 5: 11 (1%) vs 9 (1%)
    • 6: (not assessable)† 15 (1%) vs 16 (1%)
  • Maximum target aneurysm lumen size (mm)
    • 5: 552 (51%) vs 572 (53%)
    • 6–10: 438 (41%) vs 426 (40%)
    • 11: 83 (8%) vs 72 (7%)
  • Number of aneurysms detected
    • 1: 836 (78%) vs 850 (79%)
    • 2: 173 (16%) vs 170 (16%)
    • 3: 44 (4%) vs 35 (3%)
    • 4: 20 (2%) vs 15 (1%)
    • Median time between SAH and randomization (days) 2 vs 2


  • Random assignments were done through a 24-h telephone randomization service
    • 1073 were allocated to endovascular treatment vs 1070 allocated to neurosurgery
  • At 2 months and 1 year, patients were assessed using the following questionaires: Glasgow Outcome Scale, the Rankin Scale, the Oxford Handicap Scale and Euroqol
  • At 6 months, patients treated endovascularly had follow-up arterial angiography
  • All hospital admissions that occurred at any time after randomization were recorded and data collected on length of stay, any further procedures, and adverse events.


Comparisons are endovascular group vs neurosurgery group.

Primary Outcomes

proportion of patients with a moderate or poor functional outcome (defined by Rankin grade 3-6)

  • At 2 months, 244 of 959 (25·4%) were dependent or dead compared with 345 of 947 (36·4%) (relative risk 0·698 [95% CI 0·609–0·801], p<0·0001).
  • At 1 year 190 of 801 (23·7%) were dependent or dead compared with 243 of 793 (30·6%) (relative risk 0·774 [0·658–0·911], p=0·0019).
    • Relative risk reduction 22·6% (95% CI 8·9–34·2) absolute risk reduction 6·9% (2·5–11·3)

Secondary Outcomes

Risk of re-bleeding after 1 year

  • 2 per 1276 compared with 0 per 1081

Adverse Events

  • 20 patients allocated endovascular treatment rebled after the first procedure and before 30 days
    • In 5 the procedure had failed to occlude the aneurysm
    • In 7 there was incomplete coil occlusion of the aneurysm
    • In 3 the aneurysm was judged to be completely occluded
    • 5 patients received thrombolytic therapy to treat a thromboembolic event after treatment. All 5 died.
  • 6 patients allocated to neurosurgery who re-bled before discharge
    • 3 had incomplete aneurysm occlusion
    • 3 had clipping judged to be complete
  • 154 patients had a further procedure on the same aneurysm in the first year
    • 121 of these patients were of the endovascular treatment group compared with 33 in the neurosurgery group


  • Authors did not report on the rate of complete occlusion of aneurysm based on the 6-month angiography results in the endovascular coiling group
  • Lack of reference in text or tables to procedure-related complications
  • Although the study was published as an international trial, 77% of patients were recruited from the UK.
  • Question of expertise bias through patient recruitment. Some believed centers with expertise in endovascular treatment provided most of the patients, but centers with cerebrovascular surgical expertise provided a negligible amount.


Oxford Regional Health Authority Research and Development; Medical Research Council, UK; Programme Hospitalier de Recherche Clinique 1998 of the French Ministry of Health (AOM 98150), Assistance Publique, Hôpitaux de Paris (AP-HP); the Canadian Institutes of Health Research; and the Stroke Association of the UK for the Neuropsychological assessments.

Further Reading

1. Linn, F. H. H., et al. "Incidence of subarachnoid hemorrhage role of region, year, and rate of computed tomography: a meta-analysis." Stroke 27.4 (1996): 625-629. 2. Alvord, Ellsworth C., et al. "Subarachnoid hemorrhage due to ruptured aneurysms: a simple method of estimating prognosis." Archives of neurology 27.4 (1972): 273-284. 3. Molyneux, Andrew, and International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. "International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial." The Lancet 360.9342 (2002): 1267-1274. 4. Connolly, E. Sander, et al. "Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association." Stroke 43.6 (2012): 1711-1737. 5. Molyneux, Andrew J., 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." The Lancet Neurology 8.5 (2009): 427-433.