What are the mortality benefits of thrombolysis with tissue plasminogen activator (tPA) for acute ischemic stroke?

Mortality Benefits of Thrombolysis for Acute Ischemic Stroke

Thrombolysis with IV tPA does not reduce 90-day mortality in acute ischemic stroke, but it significantly improves functional outcomes, which is the primary reason to administer this treatment. 1

Evidence on Mortality Outcomes

The most robust guideline evidence consistently demonstrates that IV tPA does not alter 90-day mortality when administered for acute ischemic stroke, regardless of the treatment time window 1. This finding has been replicated across multiple high-quality trials:

• Within 3 hours: The landmark NINDS trial showed no mortality difference between tPA-treated patients and placebo controls, despite significant functional improvements 1
• Within 3-4.5 hours: The ECASS III trial and subsequent meta-analyses confirmed no mortality benefit (OR 1.04; 95% CI 0.75-1.43; P=0.83) 2
• Intra-arterial thrombolysis: Similarly shows no mortality benefit (RR 0.86; 95% CI 0.56-1.33), with 29 fewer deaths per 1,000 patients but confidence intervals crossing the line of no effect 1

Why Thrombolysis is Still Strongly Recommended

Despite the absence of mortality reduction, the American College of Emergency Physicians and American Heart Association strongly recommend IV tPA (Grade 1A) within 3 hours because it dramatically improves functional outcomes 1, 3:

• Number Needed to Treat (NNT) = 8 for achieving excellent functional recovery (modified Rankin Scale 0-1) within 3 hours 1
• NNT = 14 for functional independence when treated between 3-4.5 hours 1
• Patients achieve 30% greater odds of favorable functional outcome at 90 days (OR 1.7; 95% CI 1.2-2.6) 1

The Trade-off: Hemorrhagic Risk

The lack of mortality benefit must be understood in context of the hemorrhagic complications:

• Symptomatic intracranial hemorrhage (sICH) occurs in 6.4% of tPA-treated patients versus 0.6% of placebo patients 4
• Number Needed to Harm (NNH) = 17 for sICH within 3 hours 1
• NNH = 23 for sICH in the 3-4.5 hour window 1

The mortality from hemorrhagic complications appears to offset any potential mortality reduction from preventing stroke progression, resulting in neutral mortality outcomes 1. However, survivors who avoid hemorrhage experience substantially better functional recovery, which is why the treatment remains beneficial overall.

Clinical Algorithm for Decision-Making

Within 0-3 Hours of Symptom Onset:

• Strongly recommend IV tPA (Grade 1A) if eligibility criteria are met 1, 3
• Counsel patients that mortality is unchanged, but functional recovery improves significantly 1
• Accept the 6% risk of symptomatic hemorrhage for the substantial functional benefit 4

Within 3-4.5 Hours of Symptom Onset:

• Conditionally recommend IV tPA (Grade 2C) with more stringent exclusion criteria 1, 3
• Exclude patients >80 years, NIHSS >25, diabetes plus prior stroke, or any anticoagulant use 5
• Mortality remains neutral, but functional benefit is more modest (NNT=14) 1

Beyond 4.5 Hours:

• Recommend against IV tPA (Grade 1B) as mortality actually increases (OR 1.49; 95% CI 1.0-2.21) with no functional benefit 6
• Consider mechanical thrombectomy if large vessel occlusion is present 3

Key Pitfall to Avoid

Do not withhold tPA based solely on concerns about mortality—the decision should prioritize quality of life and functional independence, which are dramatically improved despite neutral mortality effects 1. The American College of Emergency Physicians explicitly states that "IV tPA does not alter 90-day mortality" but still strongly recommends treatment because functional outcomes are what matter most to stroke survivors 1.