ECASS III: Thrombolysis for Stroke at 3 to 4.5 Hours (2008)

“In patients with acute ischaemic stroke, intravenous alteplase administered between 3 h and 4.5 h after symptom onset significantly improved clinical outcomes.”

  • The ECASS III Investigators

1. Publication Details

  • Trial Title: Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke
  • Citation: Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med. 2008;359(13):1317-1329. DOI: 10.1056/NEJMoa0804656
  • Published: September 25, 2008, in The New England Journal of Medicine
  • Author: Werner Hacke, M.D., Ph.D.
  • Funding: Boehringer Ingelheim.

2. Keywords

  • Ischemic Stroke, Thrombolysis, Alteplase, t-PA, Extended Time Window, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute ischemic stroke who present between 3 and 4.5 hours after symptom onset (Population), does treatment with intravenous alteplase (Intervention) compared to placebo (Comparison) improve the rate of favorable neurologic outcome at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark NINDS trial (1995) had established that intravenous alteplase (t-PA) was an effective therapy for acute ischemic stroke, but its benefit had only been proven when administered within a narrow 3-hour window from symptom onset.
  • Knowledge Gap: A large proportion of stroke patients present to the hospital after the 3-hour window has closed. It was a critical and unanswered question whether the time window for this highly effective therapy could be safely extended.
  • Proposed Hypothesis: The authors hypothesized that intravenous alteplase would be superior to placebo in improving functional outcomes when administered in the 3-to-4.5-hour time window.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: Multiple academic and community hospitals across Europe.
  • Trial Period: Enrollment ran from March 2003 to September 2007.
  • Population:
    • Inclusion Criteria: Adult patients (18-80 years) with acute ischemic stroke who could be treated between 3 and 4.5 hours after the onset of symptoms.
    • Exclusion Criteria: Included a combination of very severe stroke (NIHSS score > 25) and older age (>80 years), a history of both previous stroke and diabetes, and patients taking oral anticoagulants.
  • Intervention: Patients received intravenous alteplase at a standard dose of 0.9 mg/kg.
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All patients received standard medical care for acute ischemic stroke according to European guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 800 patients would provide 80% power to detect an 8% 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: Favorable neurologic outcome at 90 days, defined as a score of 0 or 1 on the modified Rankin Scale (mRS) for disability.
    • Secondary Outcomes: Included a global outcome analysis (distribution of mRS scores) and the incidence of symptomatic intracranial hemorrhage (sICH).

6. Key Results

  • Enrollment and Baseline: 821 patients were randomized (418 to alteplase and 403 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: A significantly higher proportion of patients in the alteplase group had a favorable neurologic outcome at 90 days. 219 of 418 patients (52.4%) in the alteplase group had an mRS score of 0-1, compared with 182 of 403 patients (45.2%) in the placebo group (p=0.04).
  • Secondary Outcomes: The global outcome analysis also significantly favored the alteplase group.
  • Adverse Events: The incidence of symptomatic intracranial hemorrhage was significantly higher in the alteplase group (2.4% vs. 0.2%; p=0.008), but this did not negate the overall net benefit of the treatment.

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 favorable outcome between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for a favorable outcome (mRS 0-1): 1.34 (95% CI, 1.02 to 1.76; P-value: 0.04).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Favorable Outcome in Intervention Group) / (Odds of Favorable Outcome in Control Group).
      • Calculation: The paper reports the result as 1.34.
      • Clinical Meaning: The OR of 1.34 means that the odds of having a favorable outcome were 34% higher in the alteplase group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.02 to 1.76.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is statistically significant.
    • P-value: The p-value of 0.04 is below the 0.05 threshold, indicating the result is 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) (for the adverse outcome of disability/death):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = (100% – 45.2%) – (100% – 52.4%) = 54.8% – 47.6% = 7.2%.
      • Clinical Meaning: For every 100 patients treated with alteplase in this extended window, about 7 were saved from death or disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.072 = 13.9, which is rounded up to 14.
      • Clinical Meaning: You would need to treat 14 patients with alteplase in the 3-to-4.5-hour window to achieve one additional favorable outcome.
  • Subgroup Analyses: The benefit appeared consistent across most subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of a large number of diverse centers across Europe increases the external validity of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of functional status at 90 days is a robust and highly relevant patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The trial had a number of important exclusion criteria (e.g., age > 80, severe stroke, prior stroke + diabetes) that are not present in the original <3-hour indication. This means the findings are not applicable to all stroke patients in this time window.
  • Other: The trial was funded by the manufacturer of alteplase, which represents a potential conflict of interest.

10. Conclusion of the Authors

  • The authors concluded that in patients with acute ischemic stroke, intravenous alteplase administered between 3 and 4.5 hours after symptom onset significantly improved clinical outcomes.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided the definitive evidence needed to extend the time window for intravenous thrombolysis from 3 hours to 4.5 hours, making this life-changing therapy available to a much larger population of stroke patients.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute ischemic stroke who present between 3 and 4.5 hours from symptom onset and who do not have any of the specific ECASS III exclusion criteria.
    • Actionable Intervention: Administer intravenous alteplase (0.9 mg/kg).
    • Expected Benefit: This intervention can be expected to result in one additional patient having a good functional recovery for every 14 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that it is safe to delay treatment. The benefit of thrombolysis is still highly time-dependent, and earlier treatment is always better.
  • Implementation Caveats: It is critical to adhere to the stricter exclusion criteria of the ECASS III trial when treating patients in the 3-to-4.5-hour window.

12. Context and Related Studies

  • Building on Previous Evidence: The ECASS III trial (2008) was a direct follow-up to the landmark NINDS trial (1995), which had established the benefit of alteplase within 3 hours.
  • Influence on Subsequent Research: The positive result of this trial led to its rapid incorporation into international stroke guidelines. It also spurred further research into even more extended time windows for thrombolysis, guided by advanced imaging (e.g., the WAKE-UP trial).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The trial did not answer whether the benefit of thrombolysis extends beyond 4.5 hours in unselected patients.
  • Future Directions: Subsequent research has focused on using advanced imaging (MRI mismatch) to select patients for thrombolysis in even later time windows or when the time of onset is unknown (e.g., “wake-up strokes”).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a major clinical need to expand the treatment window for a proven therapy.
  • Methods: The multicenter, double-blind RCT design was of high quality. A key methodological point is the more restrictive set of exclusion criteria compared to the original <3-hour trials, which is critical for the safe application of these findings.
  • Results: The study reported a statistically significant and clinically meaningful benefit for its primary outcome (NNT of 14). The increased risk of symptomatic intracranial hemorrhage was noted but was outweighed by the overall functional benefit.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in stroke care that provided the evidence to change a fundamental aspect of acute stroke management worldwide. Its findings are highly applicable, provided that clinicians carefully adhere to the specific inclusion and exclusion criteria.

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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