NINDS: t-PA for Acute Ischemic Stroke (1995)

“Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.”

  • The NINDS rt-PA Stroke Study Group

1. Publication Details

  • Trial Title: Tissue Plasminogen Activator for Acute Ischemic Stroke
  • Citation: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. DOI: 10.1056/NEJM199512143332401
  • Published: December 14, 1995, in The New England Journal of Medicine
  • Author: The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group
  • Funding: The National Institute of Neurological Disorders and Stroke (NINDS).

2. Keywords

  • Ischemic Stroke, Thrombolysis, Alteplase, t-PA, Tissue Plasminogen Activator, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute ischemic stroke treated within 3 hours of symptom onset (Population), does treatment with intravenous recombinant tissue plasminogen activator (t-PA) (Intervention) compared to placebo (Comparison) improve the rate of favorable functional outcome at 3 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Ischemic stroke is a leading cause of death and long-term disability. The underlying cause is a thrombus occluding a cerebral artery. It was hypothesized that rapidly dissolving this clot with a fibrinolytic agent could restore blood flow and salvage brain tissue.
  • Knowledge Gap: While physiologically plausible, there was no definitive evidence from a large randomized controlled trial to prove that thrombolysis was safe and effective in improving patient-centered outcomes after stroke. The risk of causing a fatal intracranial hemorrhage was a major concern.
  • Proposed Hypothesis: The authors hypothesized that intravenous t-PA administered within 3 hours of stroke onset would be superior to placebo in improving functional outcomes at 3 months.

5. Study Design and Methods

  • Design: A multicenter, prospective, two-part, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: Multiple academic and community hospitals in the United States.
  • Trial Period: Enrollment ran from January 1991 to October 1994.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with a clinical diagnosis of ischemic stroke who could be treated within 3 hours of symptom onset.
    • Exclusion Criteria: Included evidence of hemorrhage on CT scan, rapidly improving symptoms, recent surgery or trauma, and uncontrolled hypertension.
  • Intervention: Patients received intravenous alteplase (t-PA) at a dose of 0.9 mg/kg (maximum 90 mg).
  • Control: Patients received a matching intravenous placebo.
  • Management Common to Both Groups: All patients received standard supportive care for acute stroke, including aspirin after 24 hours.
  • Power and Sample Size: The trial was designed to have sufficient power to detect a clinically meaningful difference in the primary outcome across its two parts.
  • Outcomes:
    • Primary Outcome: A global measure of functional outcome at 3 months, defined as the proportion of patients with minimal or no disability. This was assessed using a combination of four scales: the modified Rankin Scale (mRS), the Barthel Index, the Glasgow Outcome Scale, and the National Institutes of Health Stroke Scale (NIHSS).
    • Secondary Outcomes: Included mortality and the incidence of symptomatic intracranial hemorrhage (sICH).

6. Key Results

  • Enrollment and Baseline: 624 patients were randomized (312 to t-PA and 312 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Patients in the t-PA group were significantly more likely to have a favorable neurologic outcome at 3 months. Across all four scales, the odds of a favorable outcome were at least 30% higher in the t-PA group. For example, using the mRS, 39% of the t-PA group had a score of 0-1 (no or minimal symptoms), compared to 26% of the placebo group.
  • Secondary Outcomes: There was no significant difference in 90-day mortality between the groups (17% in the t-PA group vs. 21% in the placebo group).
  • Adverse Events: The incidence of symptomatic intracranial hemorrhage within 36 hours was significantly higherin the t-PA group (6.4% vs. 0.6%; p<0.001).

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 global statistical test combining the four outcome scales.
  • Primary Outcome Analysis: The primary outcome was a comparison of the overall distribution of functional outcomes between the two groups.
  • Key Statistic(s) Reported: The odds ratio for a favorable outcome.
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR): The OR for a favorable outcome (minimal or no disability) was consistently between 1.7 and 2.1 across the different scales, indicating a strong and significant benefit for t-PA.
    • P-value: The p-values for the primary outcome analyses were all highly statistically significant (p<0.05), indicating the benefit was very unlikely to be due to chance.
  • Clinical Impact Measures (for functional independence, mRS 0-1):
    • Absolute Risk Reduction (ARR) (for the adverse outcome of disability/death):
      • Formula: ARR = (Risk of Poor Outcome in Control Group) – (Risk of Poor Outcome in Intervention Group)
      • Calculation: ARR = (100% – 26%) – (100% – 39%) = 74% – 61% = 13%.
      • Clinical Meaning: For every 100 patients treated with t-PA within 3 hours, about 13 were saved from death or significant disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.13 = 7.7, which is rounded up to 8.
      • Clinical Meaning: You would need to treat 8 patients with t-PA to achieve one additional case of functional independence at 3 months.
  • Subgroup Analyses: The benefit of t-PA was consistent across all major subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard and was essential for proving the efficacy of this high-risk therapy.
  • Generalizability: The inclusion of both academic and community hospitals increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 3-month functional status 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 findings are specific to treatment administered within a strict 3-hour time window.
  • Other: The significant risk of intracranial hemorrhage is a major trade-off that requires careful patient selection.

10. Conclusion of the Authors

  • The authors concluded that despite an increased risk of symptomatic intracranial hemorrhage, treatment with intravenous t-PA within 3 hours of the onset of ischemic stroke improves clinical outcomes at 3 months.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It was the first study to demonstrate a clear benefit for any therapy in acute ischemic stroke and single-handedly established intravenous thrombolysis as the global standard of care.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute ischemic stroke who present within 3 hours of symptom onset and have no contraindications.
    • Actionable Intervention: Administer intravenous alteplase (0.9 mg/kg).
    • Expected Benefit: This intervention can be expected to result in one additional patient being alive and independent for every 8 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that t-PA is without risk. The significant risk of intracranial hemorrhage underscores the importance of strict adherence to the inclusion and exclusion criteria.
  • Implementation Caveats: The key takeaway is that “time is brain.” The benefit of t-PA is highly time-dependent, and hospital systems must be organized for rapid patient evaluation and treatment.

12. Context and Related Studies

  • Building on Previous Evidence: The NINDS trial (1995) was the landmark study that provided the definitive evidence for a practice that was based on the “open artery” hypothesis but was unproven in stroke.
  • Influence on Subsequent Research: The definitive positive result of this trial led to a revolution in acute stroke care. It spurred the development of organized “stroke systems of care” worldwide and led directly to the design of subsequent trials (e.g., ECASS III (2008), IST-3 (2012)) that successfully extended the time window for thrombolysis.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not answer whether the benefit of thrombolysis extends beyond 3 hours or to patients over 80 years old.
  • Future Directions: The success of this trial spurred decades of research into optimizing reperfusion therapy, leading to the current era of extended time windows and mechanical thrombectomy for large-vessel occlusions.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a novel therapy for a devastating disease with no effective treatments at the time.
  • Methods: The multicenter, double-blind RCT design was of high quality and was essential for providing a definitive answer for this high-risk therapy. The use of a global functional outcome was a major strength.
  • Results: The study reported a statistically significant and clinically profound benefit for its primary outcome (NNT of 8). The clear evidence of harm (intracranial hemorrhage) was also reported, allowing for a transparent assessment of the risk-benefit trade-off.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in medicine that established the first effective therapy for acute ischemic stroke and became the model for how to conduct high-quality, practice-changing research in neurology and critical care.

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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