ECASS III

Article Identification

Article Title: Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

Authors (Top 5): Werner Hacke, M.D., Markku Kaste, M.D., Erich Bluhmki, Ph.D., Miroslav Brozman, M.D., Antoni Dávalos, M.D.

Journal Name, Year, Volume, Issue: The New England Journal of Medicine, 2008, Vol. 359, No. 13

Type of Study: Randomized, placebo-controlled, phase 3 clinical trial

DOI/PMID: 10.1056/NEJMoa0804656

Quick Reference Summary

Intravenous alteplase administered between 3 and 4.5 hours after acute ischemic stroke significantly improved clinical outcomes compared to placebo (52.4% vs. 45.2%; P = 0.04). Alteplase treatment was associated with a modest increase in symptomatic intracranial hemorrhage (2.4% vs. 0.2%; P = 0.008) but did not significantly affect mortality rates.

Core Clinical Question

Does intravenous alteplase administered within 3 to 4.5 hours after the onset of acute ischemic stroke symptoms improve clinical outcomes compared to placebo without increasing mortality?

Background

Disease Overview:

Acute ischemic stroke is a leading cause of disability and death worldwide.

Prior Data:

• The NINDS study (1995) demonstrated that alteplase within 3 hours improves outcomes by ≥30%.
• European trials (ECASS I & II) investigating up to 6-hour windows did not show efficacy.

Current Standard of Care:

Alteplase is approved for use within 3 hours of stroke onset.

Knowledge Gaps Addressed by Study:

Efficacy and safety of alteplase when administered between 3 and 4.5 hours post-stroke.

Study Rationale:

Pooled analyses suggested potential benefits of extending the treatment window, necessitating a dedicated randomized trial.

Methods Summary

Study Design: Double-blind, placebo-controlled, randomized phase 3 trial.

Setting and Time Period: 130 centers across 19 European countries, July 29, 2003 – November 13, 2007.

Population Characteristics:

Adults aged 18-80 with acute ischemic stroke.

Inclusion/Exclusion Criteria:

• Inclusion: Diagnosed acute ischemic stroke, treatment initiated within 3 to 4.5 hours.
• Exclusion: Intracranial hemorrhage, severe stroke (NIHSS >25), recent surgery, uncontrolled hypertension, etc.

Intervention Details:

Alteplase at 0.9 mg/kg body weight (max 90 mg) administered intravenously.

Control/Comparison Group Details:

Placebo administered in a similar fashion to match the intervention.

Primary and Secondary Outcomes:

• Primary: Disability at 90 days (modified Rankin scale 0-1 favorable).
• Secondary: Global outcome analysis combining multiple neurologic and disability scores.

Statistical Analysis Approach:

Intention-to-treat analysis with chi-square tests; adjusted logistic regression post hoc.

Sample Size Calculations:

400 patients per group for 90% power to detect an odds ratio of 1.4.

Ethics and Funding Information:

Approved by institutional review boards; funded by Boehringer Ingelheim.

Detailed Results

Participant Flow and Demographics

Total Enrolled: 821 patients

• Alteplase Group: 418
• Placebo Group: 403

Excluded from Per-Protocol:

• Alteplase: 43
• Placebo: 48

Baseline Characteristics: Similar between groups except for initial stroke severity and history of stroke.

Primary Outcome Results

Favorable Outcome (mRS 0-1):

• Alteplase: 52.4% (219/418)
• Placebo: 45.2% (182/403)
• Odds Ratio: 1.34 (95% CI, 1.02 to 1.76)
• P-value: 0.04 **statistically significant**
• Absolute Risk Difference: 7.2 percentage points

Secondary Outcome Results

Global Odds Ratio for Favorable Outcome:

• Alteplase: 1.28 (95% CI, 1.00 to 1.65)
• Placebo: Reference
• P-value: <0.05 **statistically significant**

Subgroup Analyses

Significant favorability in specific functional endpoints (e.g., NIHSS score improvement).

Adverse Events/Safety Data

• Symptomatic Intracranial Hemorrhage:
  • Alteplase: 2.4% (10/418)
  • Placebo: 0.2% (1/403)
  • Odds Ratio: 9.85 (95% CI, 1.26 to 77.32)
  • P-value: 0.008 **statistically significant**
• Mortality:
  • Alteplase: 7.7%
  • Placebo: 8.4%
  • P-value: 0.68 (Not significant)

Results Tables

Authors’ Conclusions

Primary Conclusions:

Alteplase administered between 3 and 4.5 hours post-stroke significantly improved clinical outcomes compared to placebo.

Interpretation of Results:

The extended window is effective without increasing overall mortality, despite a higher rate of symptomatic intracranial hemorrhage.

Clinical Implications:

Extending the treatment window to 4.5 hours allows more patients to benefit from thrombolysis.

Future Research Recommendations:

Further studies to optimize patient selection and minimize hemorrhagic risks.

Literature Review

Comparison with Previous Studies:

• Consistent with NINDS (1995) findings on alteplase efficacy within 3 hours.
• Contrasts with ECASS I & II, which did not demonstrate efficacy within a 6-hour window.

Positioning Within Existing Evidence:

Confirms pooled analysis suggesting benefits up to 4.5 hours.

References to Guidelines:

Aligns with European guidelines recommending alteplase within extended windows under certain conditions.

Critical Analysis

A. Strengths

• Randomized, double-blind, placebo-controlled design enhances internal validity.
• Large, multicenter European cohort improves generalizability within similar healthcare settings.
• Detailed definition of outcomes and rigorous adjudication of hemorrhages ensures reliable safety and efficacy data.

B. Limitations

• Excluded patients with severe strokes (NIHSS >25), limiting applicability to all stroke severities.
• Higher incidence of symptomatic hemorrhage, though mortality was unaffected.
• Post hoc analyses were necessary to adjust for confounders, indicating initial imbalances.

C. Literature Context

• Consistent with NINDS and pooled analyses supporting extended thrombolysis window.
• Echoes findings from SITS-MOST on safety in real-world settings.
• Contrasts earlier ECASS trials by demonstrating efficacy within a narrower extended window.

Clinical Application

Findings support the use of alteplase up to 4.5 hours post-acute ischemic stroke, expanding the treatment eligibility window.

Most applicable to patients presenting within 3 to 4.5 hours without severe stroke criteria, considering the balance between improved outcomes and hemorrhage risks.

How to Use This Info In Practice

Clinicians should consider administering alteplase to eligible acute ischemic stroke patients within a 4.5-hour window to enhance functional outcomes, ensuring careful patient selection to mitigate hemorrhagic risks.

Additional Notes

• Confidence Intervals Included: Yes, for all key outcomes.
• Statistical Significance Highlighted: Outcomes with bold significance markers.
• Conflicts of Interest Noted: Yes, as reported in the article.
• Funding Sources: Supported by Boehringer Ingelheim.
• Areas of Uncertainty: Balancing extended treatment window benefits against increased hemorrhage risk.