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Foundational Trials

ISAT

Image: Shutterstock / MD Habibur Rahman anis

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;360:1267-1274.

Context & Rationale

  • Background
    • Aneurysmal subarachnoid haemorrhage (aSAH) causes high early mortality and substantial long-term disability among survivors.
    • Microsurgical clipping had been the established definitive treatment to prevent rebleeding, but it carries operative morbidity.
    • Endovascular detachable coil embolisation emerged as a less invasive alternative, with rapidly increasing uptake, but comparative effectiveness and safety versus clipping were uncertain.
    • Observational series were confounded by anatomical selection, clinical grade, centre expertise, and outcome ascertainment method.
  • Research Question/Hypothesis
    • In patients with ruptured intracranial aneurysms judged suitable for either technique, does a policy of endovascular coiling (vs neurosurgical clipping) reduce the proportion of patients who are dead or dependent (modified Rankin Scale 3–6) at 1 year?
    • Hypothesis: endovascular coiling would reduce 1-year death/dependency by 25% relative (from 24% to 19%).
  • Why This Matters
    • For aSAH, the treatment decision is time-critical and has lifelong functional implications.
    • Even modest absolute improvements in disability-free survival would translate into large population-level gains.
    • Evidence was required to guide patient counselling, multidisciplinary pathway design, and service planning (including 24/7 endovascular capability).

Design & Methods

  • Research Question: In patients with ruptured intracranial aneurysms suitable for either approach, does allocation to a policy of endovascular coiling reduce 1-year death or dependency (mRS 3–6) compared with allocation to a policy of neurosurgical clipping?
  • Study Type: Pragmatic, multicentre, randomised clinical trial in major neurosurgical centres (international; 43 participating centres); central 24-hour telephone randomisation using minimisation for key prognostic factors; open-label treatment delivery; outcomes collected by validated postal questionnaire and rebleeding adjudicated by trial staff and clinicians.
  • Population:
    • Setting: Acute aSAH cared for in large regional neurosurgical centres (typically serving 1–3 million population per centre).
    • Key inclusion criteria: definite SAH (CT or lumbar puncture) within 28 days; intracranial aneurysm identified as responsible; clinical state justifying treatment by either approach; aneurysm anatomy judged by both neurosurgeon and interventional neuroradiologist to be suitable for either technique; uncertainty regarding best treatment; informed consent (or relative assent when permitted).
    • Key exclusion criteria: SAH >28 days before randomisation; patient unsuitable for one or both treatments; refused consent; concurrent enrolment in another randomised trial of SAH treatment.
    • Baseline profile (randomised n=2143): median age 52 years (range 18–87); 37% male; WFNS grade 1–2: 943/1073 (88%) vs 941/1070 (88%); target aneurysm ≤10 mm: 990/1073 (92%) vs 998/1070 (93%); posterior circulation target aneurysm: 33/1073 (3%) vs 25/1070 (2%).
  • Intervention:
    • Policy: endovascular treatment with detachable platinum coils (coil embolisation) of the target aneurysm.
    • Operator requirements: endovascular operators required minimum experience of 30 aneurysm treatment procedures to treat trial patients.
    • Imaging follow-up: follow-up angiography required in endovascular patients unless clinically contraindicated.
  • Comparison:
    • Policy: craniotomy and microneurosurgical clipping of the target aneurysm neck (wrapping permitted when clipping not achieved).
    • Operator requirements: accredited neurosurgeons with aneurysm surgery experience.
    • Imaging follow-up: angiography requested but not mandatory in neurosurgical patients (to avoid forcing a change in local practice).
  • Blinding: Unblinded (procedural nature precluded masking); primary outcome obtained via validated postal questionnaire (patient or proxy) with standardised mapping to the modified Rankin Scale; rebleeding events adjudicated after review of clinical forms and imaging.
  • Statistics: Planned sample size 2500 to detect a 25% relative reduction in 1-year death/dependency (from 24% to 19%) with 90% power at a two-sided significance level of 0.01; outcomes analysed by randomised allocation among patients expected to have reached the relevant follow-up time point (2 months or 1 year), with effect estimates presented as relative risks with 95% confidence intervals.
  • Follow-Up Period: Outcomes at 2 months and 1 year (index publication), with annual follow-up thereafter planned for at least 5 years (and extended follow-up reported subsequently in later publications).

Key Results

This trial was stopped early. Recruitment was halted by the steering committee after a planned interim analysis (2143 patients randomised).

Outcome Endovascular coiling Neurosurgical clipping Effect p value / 95% CI Notes
Primary outcome: death or dependency (mRS 3–6) at 1 year 190/801 (23.7%) 243/793 (30.6%) RR 0.774 95% CI 0.658 to 0.911; P=0.0019 Analysed in patients expected to have 1-year data (randomised before 1 Feb 2001); data available for 1594/1624 (98.2%).
Absolute risk reduction in death/dependency at 1 year 6.9% — ARR 6.9% 95% CI 2.5 to 11.3 Relative risk reduction 22.6% (95% CI 8.9 to 34.2) reported.
Death or dependency (mRS 3–6) at 2 months 244/959 (25.4%) 345/947 (36.4%) RR 0.698 95% CI 0.609 to 0.801; P<0.0001 Analysed in patients expected to have 2-month data (randomised before 1 Dec 2001); data available for 1906/1918 (99.4%).
Case fatality at 1 year 65/801 (8.1%) 80/793 (10.1%) Not reported Endovascular 95% CI 6.3 to 10.2; Neurosurgery 95% CI 8.1 to 12.4 Mortality difference not statistically significant (as reported).
Target aneurysm rebleeding after randomisation but before first procedure 14 (7 deaths) 23 (16 deaths) Not reported Not reported Counts; numbers in parentheses are deaths.
Target aneurysm rebleeding after procedure up to 30 days 20 (10 deaths) 6 (3 deaths) Not reported Not reported Includes failures/incomplete occlusion and rebleeding after thrombolysis for procedural complications (reported within trial).
Target aneurysm rebleeding 30 days to 1 year 6 (5 deaths) 4 (2 deaths) Not reported Not reported Counts; numbers in parentheses are deaths.
Target aneurysm rebleeding after 1 year (events accrued at time of report) 2 (0 deaths) 0 Not reported Not reported Reported as 2 per 1276 patient-years vs 0 per 1081 patient-years (rates; no new calculation shown here).
Further procedure on the target aneurysm during first year 121 patients 33 patients Not reported Not reported Includes additional endovascular and/or neurosurgical procedures; clinical outcome incorporated into 1-year endpoint.
Time from randomisation to first procedure Mean 1.1 days (IQR 0–1) Mean 1.7 days (IQR 0–2) Not reported P<0.0001 Difference reported as statistically significant.
  • At 1 year, allocation to endovascular coiling reduced death/dependency from 30.6% to 23.7% (RR 0.774; 95% CI 0.658 to 0.911; P=0.0019), an absolute reduction of 6.9% (95% CI 2.5 to 11.3).
  • Case fatality at 1 year was similar (8.1% vs 10.1%), indicating the primary difference was driven by functional outcome among survivors.
  • Trade-offs were evident: more target-aneurysm rebleeding in the early post-procedure period after coiling (20 vs 6 up to 30 days) and a substantially higher need for further target-aneurysm procedures within 1 year (121 vs 33).

Internal Validity

  • Randomisation and Allocation: Central 24-hour telephone randomisation with baseline data recorded before allocation; minimisation used for age, sex, WFNS grade, CT blood burden, and aneurysm size/location (supports allocation concealment and baseline balance).
  • Drop out or exclusions: Outcome data completeness was high in the time-eligible cohorts (2 months: 1906/1918, 99.4%; 1 year: 1594/1624, 98.2%); missing/awaited data at 1 year were 12 (coiling allocation) and 18 (clipping allocation).
  • Performance/Detection Bias: Treatment was unblinded; functional outcome (mRS) was obtained via postal questionnaire (patient or proxy) which reduces assessor variability but does not eliminate expectation or reporting effects.
  • Protocol Adherence: 2042/2143 (95.3%) received the allocated treatment as the first procedure; crossovers occurred (coiling→surgery: 9; surgery→coiling: 38).
  • Separation of the Variable of Interest: Coiling pathway had shorter time to first procedure (mean 1.1 vs 1.7 days) and greater retreatment burden (further target-aneurysm procedure within 1 year: 121 vs 33), indicating materially different treatment strategies and downstream care.
  • Technical success (first procedure performed): Endovascular procedures (n=1086): completed coiling 1005 (92.5%), failed to catheterise 29 (2.7%), catheterised but anatomy unsuitable 36 (3.3%), not attempted 16 (1.5%); neurosurgical procedures (n=1004): clipped 968 (96.4%), wrapped 14 (1.4%), not completed 14 (1.4%), not attempted 8 (0.8%).
  • Baseline Characteristics: Groups were closely matched (median age 52 years in both; WFNS 1–2: 88% in both; anterior circulation: 97% overall; aneurysm ≤10 mm: 92–93%).
  • Heterogeneity: No evidence of heterogeneity of treatment effect between the six largest recruiting centres versus the remainder (as reported in the index paper).
  • Timing: Median time from SAH to randomisation was 2 days (IQR 1–4 vs 1–5); intervention was delivered promptly after randomisation in both arms, but earlier in the endovascular arm.
  • Dose: Not applicable (procedural intervention); however, evolving coil technology during the recruitment era may have influenced procedural completeness and complication profiles within the “endovascular policy” arm.
  • Outcome Assessment: Primary outcome (mRS 3–6) was clearly defined; post-randomisation target-aneurysm rebleeds were systematically classified (preprocedural, procedural, postprocedural) and adjudicated with imaging review.
  • Statistical Rigor: Effect estimates were presented with relative risks and 95% confidence intervals; early stopping after interim analysis introduces potential for overestimation of benefit, but follow-up completeness in the analysed cohorts was high.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong due to robust central randomisation, excellent follow-up in the time-eligible cohorts, and clear outcome definitions, but is tempered by open-label delivery, early stopping, and the inherent susceptibility of patient-reported functional outcomes to expectation and measurement effects.

External Validity

  • Population Representativeness: Of 9559 SAH patients assessed for eligibility, 2143 (22.4%) were randomised; the cohort was predominantly good-grade (WFNS 1–2: 88%), with small aneurysms (≤10 mm: 92–93%) and overwhelmingly anterior circulation targets (97%).
  • Under-represented subgroups: Posterior circulation aneurysms were uncommon (58/2143, 2.7%); middle cerebral aneurysms were a minority (303/2143, 14.1%); poor-grade SAH (WFNS 4–5) comprised ~4–5% of randomised participants.
  • Applicability: Most applicable to systems with high-volume neurosurgical and endovascular expertise available emergently; less applicable where coiling capacity is limited, or for aneurysms with morphology unsuitable for coiling (wide neck, complex bifurcation anatomy) or clinical situations where equipoise is absent.
  • Temporal considerations: Coils and endovascular techniques evolved during and after ISAT; contemporary device iterations and peri-procedural antithrombotic strategies may alter both safety and durability compared with the original era.

Conclusion on External Validity: Generalisability is high for patients resembling the ISAT cohort (good-grade aSAH with small anterior circulation aneurysms suitable for either modality in high-volume centres), but limited for posterior circulation aneurysms, complex middle cerebral aneurysms, and poor-grade presentations where equipoise and suitability for both approaches are uncommon.

Strengths & Limitations

  • Strengths: Large, pragmatic randomised trial; central randomisation with prognostic-factor minimisation; clinically meaningful functional endpoint; near-complete follow-up in analysed cohorts; detailed capture and adjudication of rebleeding; multicentre design across high-volume specialist units.
  • Limitations: Markedly selected population (only ~22% of assessed SAH patients randomised); open-label intervention; early stopping at interim analysis; time-truncated primary analysis (restricted to patients expected to have 1-year follow-up at time of reporting); evolving endovascular technology and peri-procedural practice during recruitment; key secondary outcomes (e.g., neuropsychological and health-economic analyses) not fully reported in the index publication.

Interpretation & Why It Matters

  • Clinical practice impact
    For ruptured aneurysms suitable for either treatment, an endovascular-first policy improved 1-year disability-free survival (death/dependency 23.7% vs 30.6%).
  • Risk–benefit trade-offs
    Coiling conferred a higher early post-procedural rebleeding burden (20 vs 6 up to 30 days) and higher retreatment within 1 year (121 vs 33), reinforcing the need for surveillance imaging and prompt rescue strategies when occlusion is incomplete or fails.
  • Systems and workforce
    The results supported major service redesign towards 24/7 endovascular capability and integrated neurovascular decision-making, while preserving an essential role for microsurgical expertise for aneurysms less amenable to coiling.

Controversies & Other Evidence

  • Selection and generalisability: The randomised cohort represented a highly selected subgroup of aSAH; contemporaneous commentary emphasised that results should be applied primarily to good-grade patients with small anterior circulation aneurysms suitable for either approach, and not extrapolated to all ruptured aneurysms.1
  • Outcome measurement and clinical meaning of the effect: Commentary highlighted that between-group differences were concentrated around adjacent mRS strata (notably mRS2 vs mRS3) without a mortality difference, raising concerns about the discriminatory precision of postal questionnaires for moderate disability and the absence (in the index report) of broader functional and cognitive measures.1
  • Durability, retreatment, and late haemorrhage: The index trial demonstrated substantially higher retreatment after coiling, and early post-procedural rebleeding events (including after incomplete/failed occlusion and after thrombolytic rescue for thromboembolic complications); longer follow-up publications subsequently addressed whether early functional benefit persists and how late rebleeding risks compare over years to decades.23
  • Interpretive debate in later correspondence/commentary: Discussion continued regarding whether ISAT should be considered “settling” the coiling-versus-clipping debate versus defining a narrower evidence-based indication (and the clinical importance of small absolute late rebleeding differences).45
  • Subsequent syntheses: Systematic reviews and meta-analyses (including Cochrane) broadly support a functional outcome advantage for endovascular coiling in eligible ruptured aneurysms, while emphasising retreatment/durability considerations and uncertainty for subgroups under-represented in ISAT (e.g., poor-grade SAH, complex aneurysm morphology).6
  • Guidelines: Contemporary guideline recommendations generally support endovascular treatment when aneurysm anatomy is suitable, with neurosurgical clipping remaining essential for aneurysms less amenable to coiling and within multidisciplinary decision-making frameworks.7

Summary

  • ISAT randomised 2143 patients with ruptured intracranial aneurysms suitable for either approach to an endovascular coiling policy (n=1073) or neurosurgical clipping policy (n=1070) and stopped early after interim analysis.
  • At 1 year, death or dependency (mRS 3–6) was lower with coiling (23.7%) than clipping (30.6%): RR 0.774; 95% CI 0.658 to 0.911; P=0.0019; absolute reduction 6.9% (95% CI 2.5 to 11.3).
  • Mortality at 1 year was similar (8.1% vs 10.1%), implying the main benefit was reduced disability among survivors.
  • Coiling was associated with greater early post-procedural target-aneurysm rebleeding (20 vs 6 up to 30 days) and substantially more retreatment within 1 year (121 vs 33).
  • Findings are most applicable to good-grade patients with small anterior circulation aneurysms suitable for either modality; posterior circulation and poor-grade patients were under-represented.

Notes

  • ISAT used a validated postal questionnaire (patient or proxy) to map functional status to the modified Rankin Scale, and systematically adjudicated rebleeding using clinical records and imaging.

Overall Takeaway

ISAT reshaped modern neurovascular practice by demonstrating that, in carefully selected patients with ruptured aneurysms suitable for either approach, an endovascular coiling policy improves 1-year disability-free survival compared with neurosurgical clipping. The trial also clarified a core trade-off: better early functional outcome with coiling at the expense of higher early post-procedural rebleeding and a substantially greater retreatment burden, motivating long-term surveillance strategies and sustained microsurgical capability for anatomically unsuitable lesions.

Overall Summary

  • Endovascular coiling reduced 1-year death/dependency (23.7% vs 30.6%) in eligible ruptured aneurysms.
  • Mortality was similar; the benefit was predominantly reduced disability among survivors.
  • Coiling increased early post-procedural rebleeding events and retreatment within 1 year, emphasising durability and follow-up.

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