ISAT: Endovascular Coiling vs. Neurosurgical Clipping for Ruptured Aneurysms (2002)

“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.”

  • The ISAT Collaborative Group

1. Publication Details

  • Trial Title: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial
  • Citation: Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360(9342):1267-1274. DOI: 10.1016/s0140-6736(02)11314-6
  • Published: October 26, 2002, in The Lancet
  • Author: Andrew Molyneux, on behalf of the ISAT collaborative group
  • Funding: UK Medical Research Council; and others.

2. Keywords

  • Subarachnoid Hemorrhage, Cerebral Aneurysm, Endovascular Coiling, Neurosurgical Clipping, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with a ruptured intracranial aneurysm deemed suitable for either treatment (Population), does a strategy of endovascular coiling (Intervention) compared to standard neurosurgical clipping (Comparison) improve the rate of survival free of significant disability at 1 year (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Surgical clipping was the established gold standard for treating ruptured cerebral aneurysms to prevent re-bleeding. Endovascular coiling was a newer, less invasive technique, but its long-term effectiveness and durability compared to the gold standard were unknown.
  • Knowledge Gap: There was no high-quality evidence from a large randomized trial to determine if the less invasive coiling procedure was as good as, or superior to, surgical clipping in terms of patient-centered functional outcomes.
  • Proposed Hypothesis: The authors hypothesized that the clinical outcome of patients treated with endovascular coiling would not be substantially worse than that of patients treated with neurosurgical clipping.

5. Study Design and Methods

  • Design: A multicenter, international, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 42 neurosurgical centers, primarily in the UK and Europe.
  • Trial Period: Enrollment ran from September 1994 to August 2002.
  • Population:
    • Inclusion Criteria: Adult patients with subarachnoid hemorrhage from a ruptured intracranial aneurysm, where the treating neurosurgeon and interventional radiologist agreed that the aneurysm was suitable for treatment with either coiling or clipping.
    • Exclusion Criteria: Included patients where only one treatment was deemed feasible, or those with a very poor clinical grade.
  • Intervention: Patients were randomized to undergo endovascular coiling.
  • Control: Patients were randomized to undergo standard neurosurgical clipping.
  • Management Common to Both Groups: All other aspects of care for subarachnoid hemorrhage were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 2500 patients would provide 80% power to detect a 6% absolute difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The proportion of patients who were either dead or dependent on others for daily activities (defined as a modified Rankin Scale [mRS] score of 3-6) at 1 year.
    • Secondary Outcomes: Included mortality at 1 year and the risk of re-bleeding.

6. Key Results

  • Enrollment and Baseline: 2143 patients were randomized (1073 to coiling and 1070 to clipping). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the steering committee after a planned interim analysis showed a clear and significant benefit in the endovascular coiling group.
  • Primary Outcome: The risk of death or dependency at 1 year was significantly lower in the endovascular coiling group. 250 of 1063 patients (23.5%) in the coiling group had a poor outcome, compared with 326 of 1055 patients (30.9%) in the clipping group (p=0.0001).
  • Secondary Outcomes: All-cause mortality at 1 year was also lower in the coiling group. However, the risk of late re-bleeding, although low, was higher in the coiling group.
  • Adverse Events: The risk of seizures was lower in the coiling group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients with a poor outcome between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death or dependency: 0.77 (95% CI, 0.67 to 0.89; P-value: 0.0002).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the adjusted result as 0.77.
      • Clinical Meaning: The RR of 0.77 means that patients in the coiling group had a 23% lower relative risk of being dead or dependent at 1 year compared to the clipping group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.67 to 0.89.
      • Clinical Meaning: Since this entire range is well below the line of no effect (1.0), it confirms that the result is highly statistically significant.
    • P-value: The p-value of 0.0002 is extremely low, indicating the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 30.9% – 23.5% = 7.4%.
      • Clinical Meaning: For every 100 patients treated with coiling instead of clipping, about 7 were saved from death or severe disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.074 = 13.5, which is rounded up to 14.
      • Clinical Meaning: You would need to treat 14 patients with coiling instead of clipping to prevent one additional case of death or dependency at 1 year.
  • Subgroup Analyses: The benefit of coiling was consistent across subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design, including a large number of diverse international centers, increases the applicability of the findings.
  • Statistical Power: The study was large and adequately powered, and found a clear, significant effect.
  • Patient-Centered Outcomes: The primary outcome of functional status at 1 year is a robust and highly relevant patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is an unavoidable limitation for this type of procedural trial.
  • External Validity (Generalizability): The trial only included patients who were deemed suitable for both coiling and clipping by the treating physicians. This represents a highly selected population (only about 20% of all patients with subarachnoid hemorrhage at the participating centers were randomized), so the results cannot be generalized to all patients with ruptured aneurysms.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The long-term durability of coiling and the risk of late re-bleeding was an important unanswered question at the time of publication.

10. Conclusion of the Authors

  • The authors concluded that in patients with a ruptured intracranial aneurysm who are suitable for both treatments, the outcome in terms of survival free of disability at 1 year is significantly better with endovascular coiling.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial that established endovascular coiling as the first-line treatment for ruptured cerebral aneurysms whenever it is technically feasible.
  • Specific Recommendations:
    • Patient Selection: For adult patients with a ruptured intracranial aneurysm that is anatomically suitable for both coiling and clipping.
    • Actionable Intervention: Endovascular coiling should be the preferred treatment strategy.
    • Expected Benefit: This strategy can be expected to prevent one additional case of death or severe disability for every 14 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that surgical clipping is obsolete. It remains a crucial therapy for aneurysms that are not amenable to coiling.
  • Implementation Caveats: The success of this strategy is dependent on having a high-volume center with experienced interventional neuroradiologists and neurosurgeons.

12. Context and Related Studies

  • Building on Previous Evidence: The ISAT trial (2002) was the first large, multicenter RCT to provide high-quality evidence comparing the new technology of coiling against the established gold standard of clipping.
  • Influence on Subsequent Research: The definitive positive result of this trial led to a rapid and major shift in practice worldwide. It also spurred a great deal of further research, including long-term follow-up of the ISAT cohort, which has shown that while the risk of re-bleeding is slightly higher after coiling, the initial survival and functional benefit is maintained at 10 years.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal management of aneurysms not suitable for coiling, and the best strategies for long-term surveillance after coiling to detect recurrence, remain areas of investigation.
  • Future Directions: The success of coiling has driven the development of even more advanced endovascular techniques, such as flow-diverting stents and other devices, for treating complex aneurysms.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, directly comparing a new, less invasive technology against the established gold standard for a life-threatening condition.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological limitation is the highly selected patient population, which is a critical factor in interpreting the applicability of the results.
  • Results: The study reported a statistically significant and clinically important benefit for its primary outcome (NNT of 14). The trial was appropriately stopped early for efficacy.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data for the population studied. The trial is a landmark in neurovascular care and a classic example of how a new technology can be proven superior to an established standard. Its findings are highly applicable, but only to the specific group of patients who are good candidates for both procedures.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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