ESCAPE: Endovascular Treatment for Ischemic Stroke (2015)

“We conclude that in patients with acute ischemic stroke, rapid endovascular treatment improves functional outcome and reduces mortality.”

  • The ESCAPE Trial Investigators

1. Publication Details

  • Trial Title: Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke
  • Citation: Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019-1030. DOI: 10.1056/NEJMoa1414905
  • Published: March 12, 2015, in The New England Journal of Medicine
  • Author: Mayank Goyal, M.D.
  • Funding: Covidien; The Heart and Stroke Foundation of Canada; and others.

2. Keywords

  • Ischemic Stroke, Mechanical Thrombectomy, Endovascular Therapy, t-PA, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute ischemic stroke from a large-vessel occlusion in the anterior circulation (Population), does rapid endovascular thrombectomy (Intervention) compared to standard medical care (including intravenous t-PA where eligible) (Comparison) improve functional outcomes at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Intravenous thrombolysis (t-PA) was the established standard of care for acute ischemic stroke, but its efficacy was limited, especially for large-vessel occlusions. Early, small trials of endovascular therapy (thrombectomy) had been neutral, but newer stent-retriever devices showed much higher rates of successful revascularization.
  • Knowledge Gap: It was a critical and unanswered question whether the superior rates of vessel opening with modern thrombectomy devices would translate into better patient-centered functional outcomes compared to standard medical care alone.
  • Proposed Hypothesis: The authors hypothesized that rapid endovascular thrombectomy would be superior to standard medical care in improving functional outcomes at 90 days.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial with blinded outcome assessment (used to test the effectiveness of interventions).
  • Setting: 22 comprehensive stroke centers worldwide (primarily in Canada).
  • Trial Period: Enrollment ran from March 2013 to February 2015.
  • Population:
    • Inclusion Criteria: Adult patients with acute ischemic stroke who could be treated within 12 hours of symptom onset, had a proximal large-vessel occlusion in the anterior circulation confirmed by CT angiography, and had a small infarct core with good collateral circulation on imaging.
    • Exclusion Criteria: Included a large established infarct or poor baseline functional status.
  • Intervention: Patients received mechanical thrombectomy using available stent-retriever devices plus standard medical care.
  • Control: Patients received standard medical care alone.
  • Management Common to Both Groups: All eligible patients in both groups received intravenous alteplase (t-PA) as part of standard care.
  • Power and Sample Size: The authors calculated that a sample size of 500 patients would provide 80% power to detect a 20% absolute difference in the rate of favorable outcomes. (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 distribution of functional outcomes on the modified Rankin Scale (mRS) for disability at 90 days.
    • Secondary Outcomes: Included the rate of functional independence (mRS score of 0-2) at 90 days and 90-day mortality.

6. Key Results

  • Enrollment and Baseline: 316 patients were randomized (165 to thrombectomy and 151 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after a pre-planned interim analysis showed a clear and overwhelming benefit in the thrombectomy group.
  • Primary Outcome: The distribution of functional outcomes on the mRS at 90 days was significantly better in the thrombectomy group (p<0.001).
  • Secondary Outcomes: The rate of functional independence at 90 days was dramatically higher in the thrombectomy group (53.0% vs. 29.3%; p<0.001). 90-day mortality was significantly lower in the thrombectomy group (10.4% vs. 19.0%; p=0.04).
  • Adverse Events: The incidence of symptomatic intracranial hemorrhage was low and not significantly different between the groups.

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 proportional-odds model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the overall distribution of mRS scores between the two groups.
  • Key Statistic(s) Reported: The key statistics were the rate of functional independence and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <0.001 for both the primary and key secondary outcomes is extremely low, indicating a highly statistically significant result that is very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for the outcome of functional dependence):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = (100% – 29.3%) – (100% – 53.0%) = 70.7% – 47.0% = 23.7%.
      • Clinical Meaning: For every 100 patients treated with thrombectomy, about 24 were saved from death or severe disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.237 = 4.2, which is rounded down to 4.
      • Clinical Meaning: You would only need to treat 4 patients with thrombectomy in this selected population to achieve one additional case of functional independence.
  • Subgroup Analyses: The benefit was consistent across all subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design with blinded outcome assessment provided high-quality evidence. The emphasis on rapid treatment times (“time is brain”) was a key strength.
  • Generalizability: The inclusion of 22 diverse centers increases the applicability of the findings.
  • Statistical Power: The study showed such a large treatment effect that a benefit was clear even with early termination.
  • Patient-Centered Outcomes: The primary outcome of the mRS distribution is a robust and highly patient-centered endpoint that captures the full spectrum of disability.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias. However, the primary outcome was assessed by blinded adjudicators, which mitigates this concern.
  • External Validity (Generalizability): The findings are only applicable to patients who meet the specific imaging criteria (small core, good collaterals) and are treated at comprehensive stroke centers capable of rapid thrombectomy.
  • Other: The trial was stopped early for benefit, which can sometimes lead to an overestimation of the true treatment effect. The trial was partly funded by the manufacturer of a thrombectomy device.

10. Conclusion of the Authors

  • The authors concluded that in patients with acute ischemic stroke with a small infarct core and a proximal large-vessel occlusion, rapid endovascular thrombectomy was associated with significantly better functional outcomes and lower mortality than standard care alone.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. As one of five major positive thrombectomy trials published in 2015, it definitively established mechanical thrombectomy as the standard of care for eligible patients with large-vessel occlusion stroke.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute ischemic stroke from a proximal large-vessel occlusion who present within 12 hours and have a favorable imaging profile.
    • Actionable Intervention: Proceed with emergent mechanical thrombectomy.
    • Expected Benefit: This intervention has a very large effect, with an NNT of only 4 to achieve one additional good outcome.
  • What This Trial Does NOT Mean: This trial does NOT mean that all stroke patients benefit from thrombectomy. The benefit is limited to those with a confirmed large-vessel occlusion and a small infarct core.
  • Implementation Caveats: The success of this strategy is entirely dependent on having a well-organized system of care for rapid patient identification, imaging, and transfer to a comprehensive stroke center.

12. Context and Related Studies

  • Building on Previous Evidence: The ESCAPE trial (2015) was one of the pivotal “first wave” of positive thrombectomy trials (along with MR CLEAN, EXTEND-IA, SWIFT PRIME, and REVASCAT) that overturned the neutral results of earlier trials that had used older devices.
  • Influence on Subsequent Research: The definitive positive result of this trial and its contemporaries led to a rapid and major revision of international stroke guidelines. It also spurred the next wave of research into extending the time window for thrombectomy, which led to the DAWN (2018) and DEFUSE 3 (2018) trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not answer whether patients with larger infarct cores or those presenting beyond 12 hours could benefit from thrombectomy.
  • Future Directions: The results of this trial directly led to the design of the DAWN and DEFUSE 3 trials to investigate the benefit of thrombectomy in an extended time window (up to 24 hours).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a promising but unproven therapy for a devastating disease.
  • Methods: The multicenter RCT design with blinded outcome adjudication was of high quality. The use of a pragmatic but imaging-based inclusion criterion was a key strength that allowed for the selection of patients most likely to benefit.
  • Results: The study reported a very large and statistically overwhelming benefit for the intervention, with an extremely low p-value and a very impressive NNT of 4. The trial was appropriately stopped early for efficacy.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in stroke care and a classic example of how technological advances (new stent-retriever devices) combined with better patient selection can transform a previously ineffective therapy into a highly effective one.

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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