IST-3: Thrombolysis for Ischemic Stroke within 6 Hours (2012)

“For patients with ischaemic stroke, the early hazards of thrombolysis are substantial, but are offset by later benefits. For every 1000 patients given alteplase within 6 h of stroke, despite about ten extra early deaths, about 30 more will be alive and independent at 6 months.”

  • The IST-3 Collaborative Group

1. Publication Details

  • Trial Title: The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischaemic stroke (IST-3): a randomised, open-treatment trial
  • Citation: The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischaemic stroke (IST-3): a randomised, open-treatment trial. Lancet. 2012;379(9834):2352-2363. DOI: 10.1016/S0140-6736(12)60768-5
  • Published: June 23, 2012, in The Lancet
  • Author: The IST-3 (Third International Stroke Trial) collaborative group
  • Funding: UK Medical Research Council; The Health Foundation; The Stroke Association; and others.

2. Keywords

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

3. The Clinical Question

  • In adult patients with acute ischemic stroke within 6 hours of onset, for whom the treating clinician was uncertain about the balance of risks and benefits of thrombolysis (Population), does treatment with intravenous alteplase (Intervention) compared to standard care (Comparison) increase the proportion of patients who are alive and independent at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Intravenous thrombolysis with alteplase (t-PA) was a proven therapy for acute ischemic stroke, but its benefit had only been definitively established within a 3-hour window (NINDS trial, 1995) and, with more restrictions, up to 4.5 hours (ECASS III trial, 2008). A key area of uncertainty was its safety and efficacy in patients over 80 years old, who were largely excluded from previous trials.
  • Knowledge Gap: A very large, pragmatic trial was needed to determine the risk-benefit balance of thrombolysis in a broader range of patients and time windows encountered in routine clinical practice, especially in the elderly.
  • Proposed Hypothesis: The authors hypothesized that intravenous alteplase would be superior to standard care in improving the proportion of patients who were alive and independent at 6 months.

5. Study Design and Methods

  • Design: A very large, international, multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 156 hospitals in 12 countries.
  • Trial Period: Enrollment ran from May 2000 to July 2011.
  • Population:
    • Inclusion Criteria: Adult patients with acute ischemic stroke who were within 6 hours of symptom onset and for whom the treating clinician was substantially uncertain about the appropriateness of thrombolysis. A key feature was the inclusion of patients over 80 years old.
    • Exclusion Criteria: Included patients with a clear indication for or contraindication to thrombolysis.
  • Intervention: Patients received intravenous alteplase at a standard dose of 0.9 mg/kg.
  • Control: Patients received standard care without thrombolysis.
  • Management Common to Both Groups: All patients received best medical management for acute ischemic stroke according to local guidelines, including aspirin.
  • Power and Sample Size: The trial was designed to be large enough to detect a small but clinically important difference in the primary outcome with a high degree of statistical certainty.
  • Outcomes:
    • Primary Outcome: The proportion of patients who were alive and independent (defined as an Oxford Handicap Scale [OHS] score of 0-2) at 6 months.
    • Secondary Outcomes: Included mortality at 7 days, symptomatic intracranial hemorrhage (sICH), and an ordinal analysis of the full range of OHS scores.

6. Key Results

  • Enrollment and Baseline: 3035 patients were randomized (1515 to alteplase and 1520 to control). A key feature was that over half the patients (53%) were older than 80 years. The groups were well-matched.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no statistically significant difference in the primary outcome. 554 of 1515 patients (37%) in the alteplase group were alive and independent at 6 months, compared with 534 of 1520 patients (35%) in the control group (p=0.181).
  • Secondary Outcomes: There was a significant increase in early mortality at 7 days in the alteplase group (11% vs. 7%; p=0.001). However, by 6 months, there was no difference in overall mortality. The rate of symptomatic intracranial hemorrhage was significantly higher in the alteplase group (7% vs. 1%). A key positive finding was in the ordinal analysis, which showed a significant shift towards better functional outcomes across the entire range of the OHS in the alteplase group.
  • Adverse Events: The primary adverse event was symptomatic intracranial hemorrhage, which was significantly more common in the alteplase 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. The ordinal analysis used a shift analysis model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who were alive and independent between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for being alive and independent (OHS 0-2): 1.13 (95% CI, 0.95 to 1.35; P-value: 0.181).
  • 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 1.13.
      • Clinical Meaning: An OR of 1.13 suggests a non-significant 13% higher odds of a favorable outcome in the alteplase group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.95 to 1.35.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. The true effect could range from a 5% harm to a 35% benefit.
    • P-value: The p-value of 0.181 is higher than the 0.05 threshold, indicating the result is not statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the primary outcome was not met, ARR and NNT are not directly applicable. However, the authors’ analysis concluded that for every 1000 patients treated, 30 more would be alive and independent at 6 months.
  • Subgroup Analyses: The benefit of alteplase appeared to be greater when given earlier, but there was no evidence that the effect was different in patients older than 80 years.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized design provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design with very broad inclusion criteria, particularly the inclusion of a large number of elderly patients, makes the findings highly generalizable to the real-world population of stroke patients.
  • Statistical Power: The enormous sample size provided definitive power to evaluate the effects of thrombolysis in this broad population.
  • Patient-Centered Outcomes: The primary outcome of functional status at 6 months is a robust and highly relevant patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable due to the pragmatic design.
  • Other: The primary outcome was technically negative, which makes the interpretation of the positive secondary outcomes (like the ordinal analysis) more complex.

10. Conclusion of the Authors

  • The authors concluded that despite an increase in early deaths, thrombolysis within 6 hours of stroke improved long-term functional outcomes, and that this benefit was not diminished in older patients.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. Despite its neutral primary outcome, the robust evidence from the ordinal analysis and the clear demonstration of benefit in patients over 80 years old provided the evidence needed to confidently offer thrombolysis to a much wider range of patients than was previously thought safe.
  • Specific Recommendations:
    • Patient Selection: For a broad population of adult patients with acute ischemic stroke within 6 hours of onset, including those over 80 years old.
    • Actionable Intervention: Administer intravenous alteplase (0.9 mg/kg).
  • What This Trial Does NOT Mean: This trial does NOT mean that the time to treatment is not important. The benefit was still greatest when treatment was given earlier.
  • Implementation Caveats: The key takeaway is the trade-off between an early risk of harm (bleeding and death) and a later, larger benefit in functional independence. This trade-off must be discussed with patients and families.

12. Context and Related Studies

  • Building on Previous Evidence: The IST-3 trial (2012) was designed to provide a definitive answer on the utility of thrombolysis in the elderly and in the extended 3-6 hour time window, questions that were left unanswered by the earlier NINDS (1995) and ECASS III (2008) trials.
  • Influence on Subsequent Research: The definitive findings of this trial have been highly influential in shaping international stroke guidelines, which now strongly support the use of thrombolysis in eligible patients over 80 and have a more nuanced approach to the 4.5-6 hour time window.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal patient selection for thrombolysis in the 4.5-6 hour window remains an area of investigation.
  • Future Directions: The success of this trial in a broad population has shifted the focus of stroke research towards even later time windows (guided by advanced imaging) and, most importantly, towards the now-dominant therapy of mechanical thrombectomy for large-vessel occlusions.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, addressing major areas of clinical uncertainty (the elderly, the extended time window) for a time-sensitive therapy.
  • Methods: The very large, multicenter, pragmatic RCT design was a major strength, providing highly generalizable data. The main methodological weakness is the open-label design.
  • Results: The study was technically “negative” for its primary dichotomous outcome. However, the statistically significant positive result in the pre-specified ordinal analysis (which looks at the full spectrum of outcomes) is a powerful and more nuanced finding. The clear evidence of early harm (bleeding, death) balanced by later functional benefit is the key result.
  • Conclusions and Applicability: The authors’ conclusion, which emphasizes the net long-term benefit despite early hazards, is a fair interpretation of the totality of the data. The trial is a classic example of how a “negative” primary outcome can still be profoundly practice-changing when the secondary and ordinal analyses provide a more complete picture of the treatment’s effects.

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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