Publication

• Title: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial
• Acronym: ISAT
• Year: 2002
• Journal published in: The Lancet
• Citation: 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. Lancet. 2002;360:1267-74.

Context & Rationale

• Background

  • Neurosurgical clipping had been the dominant definitive treatment for ruptured intracranial saccular aneurysms, with improving outcomes over time due to advances in microscopy, microsurgical technique, anaesthesia, intensive care, and diagnostics.
  • The Guglielmi detachable coil (GDC) enabled endovascular aneurysm occlusion without craniotomy, with rapid international uptake but wide practice variation.
  • Comparative efficacy/safety evidence was minimal: only one small randomised trial (n=109) of detachable coils versus clipping had been published.
• Research Question/Hypothesis

  • In patients with aneurysmal subarachnoid haemorrhage (SAH) whose ruptured aneurysm was considered suitable for either procedure, does a policy of endovascular coiling (vs a policy of neurosurgical clipping) reduce the proportion of patients dead or dependent at 1 year?
  • Prespecified target effect: 25% relative reduction in death/dependence (mRS 3–6) at 1 year.
• Why This Matters

  • Ruptured aneurysms cause high mortality and long-term disability; even with modern care, many survivors do not return to premorbid function.
  • Adoption of a less invasive technology without robust randomised evidence risked large-scale practice change based on selection-biased case series.
  • The question is inherently policy-relevant: systems of care need to know which definitive strategy provides better patient-centred outcomes when both are feasible.

Design & Methods

• Research Question: Among patients with a ruptured intracranial aneurysm judged suitable for both procedures, does allocation to a policy of endovascular coiling reduce death or dependency (mRS 3–6) at 1 year compared with allocation to a policy of neurosurgical clipping?
• Study Type: Pragmatic, multicentre, randomised trial comparing two treatment policies (endovascular coiling vs neurosurgical clipping) in major neurosurgical centres with expertise in both modalities; central 24-hour telephone randomisation; minimisation to balance key prognostic variables.
• Population:
  • Setting: Major regional neurosurgical centres (each treating ~60–200 aneurysmal SAH cases annually); population served ~80 million.
  • Inclusion: Definite SAH within the preceding 28 days (CT or lumbar puncture); intracranial aneurysm shown by intra-arterial or CT angiography and judged responsible; clinical state justified treatment by either modality; aneurysm judged suitable for either technique by both neurosurgeon and interventional neuroradiologist; clinical uncertainty about best approach; informed consent (or assent if not competent).
  • Exclusion: SAH >28 days before randomisation; regarded as unsuitable for one or both treatments; consent refused; participation in another randomised trial of a SAH treatment.
  • Multiple aneurysms: A “target aneurysm” was nominated; additional aneurysms could be treated during the first procedure if suitable for both, and later by whichever technique was appropriate.
• Intervention:
  • Allocation to a policy of endovascular treatment using detachable platinum coils (GDC-era coiling), delivered by accredited endovascular operators (minimum 30 aneurysm treatment procedures before treating trial patients).
  • Follow-up angiography was required in endovascular patients unless clinically contraindicated.
• Comparison:
  • Allocation to a policy of neurosurgical treatment (craniotomy and aneurysm clipping, with wrapping/partial treatment where clipping not achieved), delivered by accredited neurosurgeons with aneurysm surgery experience.
  • Angiography was requested after neurosurgery but was not mandatory (to avoid forcing a change in local practice).
• Blinding: Not blinded (procedural allocation inherently unblindable); primary outcome collected via a validated postal questionnaire (modified Rankin scale), creating potential for response/assessment bias.
• Statistics: Planned sample size 2500 to detect a reduction in death/dependence at 1 year from 24% (surgical) to 19% (endovascular) with 90% power at a 0·01% level of significance (25% relative improvement target); primary analyses compared outcomes by original allocation (patients crossing over were analysed in their originally allocated group).
• Follow-Up Period: Modified Rankin scale assessed at 2 months, 1 year (primary timepoint), and annually thereafter; additional planned outcomes included rebleeding, EuroQol quality of life, epilepsy, cost-effectiveness, and a neuropsychology substudy (7 UK centres).

Key Results

This trial was stopped early. After a planned interim analysis reviewed by the Data Monitoring Committee (29 April 2002), the steering committee stopped recruitment (2 May 2002) after 2143 patients had been randomised; follow-up continued.

• On the primary endpoint, allocation to an endovascular policy reduced death/dependency at 1 year (23.7% vs 30.6%; RR 0.774; 95% CI 0.658 to 0.911; p=0.0019).
• Mortality at 1 year was similar (8.1% vs 10.1%); the observed advantage was mainly disability reduction rather than survival benefit.
• Endovascular allocation was associated with more post-procedure non-procedural rebleeding within 30 days (20 vs 6) and substantially more re-interventions during the first year (121 vs 33).

Internal Validity

• Randomisation and allocation: Central 24-hour telephone randomisation; baseline data recorded before allocation; minimisation algorithm balancing age, sex, WFNS grade, aneurysm size/location, and CT blood burden.
• Selection after randomisation / exclusions: 2143 randomised; primary 1-year analysis included those randomised before 1 Feb 2001 (801 vs 793 analysed); data awaited among those eligible: 12 vs 18.
• Protocol adherence / contamination: 2042/2143 (95.3%) received allocated treatment as the first procedure; crossovers: 9 (endovascular→neurosurgery) vs 38 (neurosurgery→endovascular); “no procedure” recorded: 16 vs 38.
• Performance/detection bias: Unblinded treatments; primary outcome (mRS) collected by postal questionnaire; co-interventions and post-acute rehabilitation were not protocolised and could vary by centre.
• Baseline comparability: Median age 52 in both groups; 37% male; good-grade predominance (WFNS 1–2: 943/1073 [87.9%] vs 941/1070 [87.9%]); aneurysm profile dominated by small anterior circulation lesions (97.3% anterior circulation; >90% <10 mm).
• Timing (treatment delivery): Mean interval from randomisation to first procedure 1.1 days (IQR 0–1; range 0–30) vs 1.7 days (IQR 0–2; range 0–41); p<0.0001.
• Technical delivery and separation: Endovascular procedure completed 1005/1086 (92.5%); failed catheterisation 29/1086 (2.7%); catheterised but anatomy unsuitable 36/1086 (3.3%); neurosurgical procedure clipped 968/1004 (96.4%) with wrapping/partial/non-completion in 36/1004 (3.6%).
• Outcome adjudication for rebleeding: Post-procedural rebleeds were individually adjudicated after review of case report forms, CT, and angiography, permitting classification by mechanism (e.g., target aneurysm vs other aneurysm vs thrombolysis-associated).
• Statistical rigour: Prespecified interim analysis and early stopping after achieving the primary trial objective; planned sample size 2500 but 2143 randomised, increasing vulnerability to “random high” estimates of effect size associated with early stopping.

Conclusion on Internal Validity: Overall, internal validity is moderate to strong due to central concealed randomisation, good baseline balance, high protocol adherence, and rigorous follow-up; key constraints are the unblinded outcome assessment and early stopping, plus the policy-design reality that treatment timing and re-intervention pathways differed between strategies.

External Validity

• Population representativeness: Only patients judged suitable for either technique and in whom equipoise existed were randomised; in trial screening logs, a large proportion of aneurysmal SAH patients were excluded for “other reasons” or lack of equipoise.
• Case-mix: Predominantly good-grade, small, anterior circulation aneurysms (posterior circulation, middle cerebral artery aneurysms, poor-grade, and elderly patients were under-represented).
• System context: Delivered in high-volume, regionally planned centres with established expertise in both neurosurgical and endovascular aneurysm management; outcomes may not translate to low-volume settings or systems without 24/7 endovascular capability.
• Pragmatic policy comparison: Reflects real-world pathways (including timing-to-treatment and need for retreatment) in centres that could operationalise both strategies.

Conclusion on External Validity: Generalisability is good for patients resembling those randomised (good-grade, small anterior circulation aneurysms in centres with mature endovascular and neurosurgical services), but limited for anatomically complex, posterior circulation, poor-grade, or elderly cohorts and for settings without comparable specialist infrastructure.

Strengths & Limitations

• Strengths:
  • Large, pragmatic randomised comparison of two definitive treatment policies in ruptured aneurysmal SAH.
  • Central 24-hour randomisation with minimisation to balance key prognostic factors.
  • Patient-centred primary endpoint (death/dependency) with high follow-up completeness among those eligible for timepoint analysis.
  • Structured adjudication of rebleeding events using clinical records and imaging.
• Limitations:
  • Highly selected cohort: only patients suitable for both modalities and in whom equipoise existed; under-representation of posterior circulation, MCA, poor-grade, and elderly patients.
  • Unblinded interventions; primary outcome collected via postal questionnaire (potential misclassification around the mRS 2/3 boundary).
  • Stopped early at interim analysis; planned sample size 2500 not reached (risk of overestimating treatment effect).
  • Material separation included treatment timing (1.1 vs 1.7 days) and higher retreatment burden with endovascular allocation, complicating purely “procedure-intrinsic” interpretation.

Interpretation & Why It Matters

• Clinical signal

  In patients suitable for either approach, an endovascular-first policy improved 1-year functional outcome (mRS 3–6: 23.7% vs 30.6%; RR 0.774; 95% CI 0.658 to 0.911; p=0.0019) without a clearly demonstrated mortality difference.
• Mechanistic reading

  The benefit appears to be disability avoidance rather than survival; this aligns with the less invasive nature of coiling, but must be balanced against higher early post-treatment rebleeding and substantially higher retreatment rates within the first year.
• System implication

  Adoption requires rapid access to experienced endovascular operators and clear protocols for failed/incomplete occlusion and surveillance imaging, because failed occlusion and delayed retreatment carried catastrophic rebleeding risk in this dataset.

Controversies & Subsequent Evidence

• Equipoise and selection: ISAT randomised a selected subgroup; the accompanying Lancet commentary emphasised that apparent lack of equipoise in the majority of assessed aneurysmal SAH cases limits extrapolation beyond patients with similar anatomy/grade profiles. ¹
• Outcome measurement granularity: The same commentary noted that the observed benefit was concentrated around the mRS 2 versus mRS 3 boundary and questioned how reliably a questionnaire differentiates “some restriction” from “significant restriction”, particularly without ADL or deficit-delineation scales. ¹
• Durability and retreatment burden: Endovascular allocation produced more re-intervention (121 vs 33 procedures during the first year) and more early post-procedure rebleeding events (20 vs 6 within 30 days), reinforcing that “less invasive” does not necessarily mean “more definitive” in the first year. The editorial framed this as an ongoing debate about what constitutes definitive aneurysm treatment and the need for long-term follow-up. ¹
• Subsequent evidence (ISAT follow-up): A later Lancet report from the ISAT investigators examined longer-term endpoints including survival, dependence, seizures, rebleeding, subgroup effects, and angiographic occlusion, extending the conversation from 1-year disability to durability/surveillance trade-offs. ²
• Guideline incorporation: Contemporary professional guidance reflects ISAT’s practice-shaping role by recommending endovascular coiling as the preferred strategy when both coiling and clipping are feasible in experienced centres, while maintaining the need for individualised, multidisciplinary decision-making in anatomically/clinically complex cases. ³

Summary

• ISAT randomised 2143 patients with ruptured aneurysms judged suitable for both approaches to endovascular-first vs neurosurgery-first policies; recruitment stopped early after a planned interim analysis.
• Primary outcome favoured endovascular allocation: death/dependency at 1 year 23.7% vs 30.6% (RR 0.774; 95% CI 0.658 to 0.911; p=0.0019).
• Mortality at 1 year was similar (8.1% vs 10.1%); the advantage was primarily disability reduction.
• Endovascular allocation carried higher early non-procedural rebleeding after treatment (20 vs 6 within 30 days) and substantially more re-interventions in the first year (121 vs 33).
• Findings generalise best to good-grade patients with small anterior circulation aneurysms treated in high-volume centres with mature endovascular and neurosurgical services.

Further Reading

Other Trials

• 2002International 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. Lancet. 2002;360:1267-74.
• 2005Molyneux AJ, Kerr RSC, Yu LM, 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, dependence, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005;366:809-17.
• 2002Endovascular coiling versus neurosurgical clipping: only the beginning. Lancet. 2002;360(9342):1260-1.
• 2002Endovascular versus surgical treatment of ruptured intracranial aneurysms: is the method validated? Lancet. 2002;360(9342):1261-2.
• 2002Nichols DA, Brown RD Jr, Meyer FB. Coils or clips in subarachnoid haemorrhage? Lancet. 2002;360(9342):1262-3.

Systematic Review & Meta Analysis

• Not reportedNot reported in the provided source set.

Observational Studies

• Not reportedNot reported in the provided source set.

Guidelines

• 2023Hoh BL, Ko NU, Amin-Hanjani S, et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Haemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2023;54(7):e314-e370.

Notes

• ISAT’s main report states additional outcomes (EuroQol quality of life, epilepsy, cost-effectiveness, neuropsychological substudy, and long-term follow-up) but does not report those results in the index publication.
• Further-reading entries are limited here to publications with verified DOI landing pages available within the current source set.

Overall Takeaway

ISAT is landmark because it provided the first large, pragmatic randomised evidence that, in carefully selected ruptured aneurysm patients suitable for either approach, an endovascular-first policy improves 1-year functional outcome compared with surgical-first care. The trial simultaneously highlighted durability and surveillance trade-offs (more early rebleeding and retreatment after coiling), anchoring modern multidisciplinary decision-making and subsequent guideline recommendations.

Bibliography

• 1.Nichols DA, Brown RD Jr, Meyer FB. Coils or clips in subarachnoid haemorrhage? Lancet. 2002;360(9342):1262-3.
• 2.Molyneux AJ, Kerr RSC, Yu LM, 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, dependence, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005;366:809-17.
• 3.Hoh BL, Ko NU, Amin-Hanjani S, et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Haemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2023;54(7):e314-e370.