Effect of Delayed Thrombolysis on Stroke Outcomes
The benefit of thrombolysis decreases progressively with treatment delay, with the greatest functional benefit occurring within 3 hours (154 additional favorable outcomes per 1,000 patients), diminishing to 69 additional favorable outcomes per 1,000 patients in the 3-4.5 hour window, and showing potential harm beyond 4.5 hours. 1
Time-Dependent Treatment Efficacy
Within 3 Hours (Optimal Window)
- High-quality evidence demonstrates that IV tPA administered within 3 hours produces 154 more excellent outcomes (mRS 0-1) per 1,000 patients compared to placebo 1
- Mortality remains unchanged (RR 1.00,95% CI 0.76-1.33), with no increase in deaths despite a 10-fold increase in symptomatic intracerebral hemorrhage (6.4% vs 0.6%) 1, 2
- This represents the strongest evidence base with a relative risk of 1.44 (95% CI 1.21-1.72) for achieving good functional outcome 1
Between 3 and 4.5 Hours (Reduced Benefit)
- The treatment effect diminishes substantially, producing only 69 more excellent outcomes per 1,000 patients 1
- Evidence quality remains high for functional outcomes (OR 1.34,95% CI 1.06-1.68), but mortality data shows low quality with wide confidence intervals suggesting possible harm (OR 1.22,95% CI 0.87-1.71) 1
- Symptomatic ICH rates increase to 8.4% versus 2.5% in placebo (OR 3.34,95% CI 2.4-4.7) 1
Beyond 4.5 Hours (Harm Without Benefit)
- Treatment after 4.5 hours shows moderate-quality evidence of increased mortality (OR 1.49,95% CI 1.0-2.21) with 49 more deaths per 1,000 patients and no significant functional benefit 1
- The confidence interval for good functional outcome crosses unity (OR 1.22,95% CI 0.96-1.54), indicating inability to demonstrate benefit 1
- Fatal ICH risk remains significantly elevated across all time windows up to 6 hours (OR 3.70,95% CI 2.36-5.79) 1
Long-Term Outcome Data
Recent nationwide cohort data demonstrates that treatment delay affects not just immediate outcomes but long-term survival and recurrent stroke risk 3
- Patients treated within 90 minutes had 19.0% absolute 3-year risk of death or recurrent stroke 3
- This increased to 23.3% for treatment at 91-180 minutes (adjusted HR 1.25,95% CI 1.06-1.48) and 23.8% for 181-270 minutes (adjusted HR 1.35,95% CI 1.12-1.61) 3
- The rate of adverse outcomes increased progressively with time and plateaued after 138 minutes 3
Clinical Algorithm for Time-Based Decision Making
0-3 Hours: Strong Recommendation for Treatment
- Administer IV tPA 0.9 mg/kg (maximum 90 mg) with 10% bolus over 1 minute, 90% infused over 60 minutes 4
- Blood pressure must be reduced to ≤185/110 mm Hg before treatment 4
- Accept the 6.4% symptomatic ICH risk given the substantial functional benefit 1, 2
3-4.5 Hours: Conditional Recommendation for Treatment
- Treatment remains beneficial but with diminished effect size 1, 4, 5
- More careful patient selection warranted given narrower benefit-risk ratio 1
- Mortality signal becomes less favorable in this window 1
Beyond 4.5 Hours: Contraindicated
- Do NOT administer IV tPA due to evidence of harm without benefit 1, 6
- Initiate aspirin 160-325 mg instead (after excluding hemorrhage) 4, 6
- Consider intraarterial thrombolysis for proximal vessel occlusions within 6 hours if IV tPA ineligible 1, 6
Critical Pitfalls to Avoid
The most common error is treating patients beyond 4.5 hours based on outdated protocols or misunderstanding of the evidence 1, 6
- Early trials (ECASS I, ECASS II, ATLANTIS) that extended treatment windows to 6 hours showed increased mortality without functional benefit 1
- Protocol violations in early trials (17.4% in ECASS I) led to 42% mortality in violators who received tPA 1
- Performing additional imaging (angiography, perfusion studies) doubles in-hospital delays and should be avoided when it delays treatment 7