EBQ:IST-3

Complete Journal Club Article

IST-3 collaborative group. "The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.". Lancet. 2012. 379(9834):2352 - 2363.
PubMed Full text

Clinical Question

Can use of fibrinolytics for acute ischemic stroke be extended to a wider range of patients up to 6 hours?

Conclusion

Thrombolysis within 6 hours improved functional outcome even though there were early hazards. This applies to the population of patients recruited for IST-3, benefits appear to be seen in the elderly as well.

Major Points

• IST-3 was the largest randomized trial of IV alteplase for acute ischemic stroke, including patients >80 years old
• The primary outcome (alive and independent at 6 months, Oxford Handicap Score 0-2) did not reach statistical significance (OR 1.13, 95% CI 0.95-1.35, p=0.181)
• Ordinal analysis showed a significant shift toward better functional outcomes with alteplase (OR 1.27, 95% CI 1.10-1.47)
• Early hazard: significantly more symptomatic intracranial hemorrhage within 7 days in the alteplase group (7% vs 1%)
• The trial extended the evidence base for thrombolysis in patients aged >80 years, where prior trials had limited enrollment

Study Design

• International, randomized controlled trial
• open treatment

Inclusion Criteria

• Signs and symptoms of acute stroke
• Known time of stroke onset
• Treatment could be started within 6 hours of onset
• CT or MRI excluded ICH and brain lesion
• Patient and clinician felt the treatment was "promising but unproven"
• If patient had indication for IV thrombolysis- treated with local guidelines

Interventions

• IV alteplase (0.9 mg/kg, max 90 mg; 10% bolus, remainder over 60 minutes) within 6 hours of stroke onset
• Control group: standard care without alteplase (open-label)
• Aspirin was withheld for 24 hours after alteplase administration
• All patients received standard stroke unit care

Outcomes

Primary Outcome

• Alive and independent at 6 months (OHS 0-2): alteplase 554/1515 (37%) vs control 534/1520 (35%)
• Adjusted OR 1.13 (95% CI 0.95-1.35, p=0.181) - not statistically significant

Secondary Outcomes

• Ordinal shift analysis favored alteplase: common OR 1.27 (95% CI 1.10-1.47, p=0.001)
• Symptomatic intracranial hemorrhage within 7 days: 7% alteplase vs 1% control
• Mortality at 6 months: 27% alteplase vs 27% control (no difference)
• Deaths within 7 days: 11% alteplase vs 7% control (higher early mortality with alteplase)

Criticisms

• Open-label design introduces potential for bias in post-stroke care decisions
• Extended treatment window up to 6 hours included patients where benefit of thrombolysis is less established
• Primary endpoint did not reach statistical significance; the positive ordinal analysis was a secondary outcome
• Higher rate of symptomatic intracranial hemorrhage raises safety concerns, particularly in elderly patients
• The trial was underpowered for its original primary outcome due to slower than expected recruitment

Funding

UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.