The Lancet June 23, 2012

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

IST-3 collaborative group

Bottom Line

In the largest trial of thrombolysis for acute ischemic stroke, alteplase given within 6 hours did not significantly improve the binary outcome of independence at 6 months but showed a significant favorable shift in functional outcomes, notably demonstrating benefit in patients over 80 years old.

Key Findings

1. At 6 months, 37% (554/1515) of patients in the alteplase group versus 35% (534/1520) in the control group were alive and independent (OHS score 0-2), which was not statistically significant (adjusted OR 1.13, 95% CI 0.95-1.35; P=0.181).

2. A prespecified ordinal analysis of the Oxford Handicap Scale (OHS) showed a significant shift toward less disability in the alteplase group (adjusted common OR 1.27, 95% CI 1.10-1.47; P=0.001).

3. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days was significantly higher with alteplase (7%, n=104) compared to control (1%, n=16) (adjusted OR 6.94, 95% CI 4.07-11.8; P<0.0001).

4. Early mortality within 7 days was higher in the alteplase group (11% vs 7%; adjusted OR 1.60, 95% CI 1.22-2.08; P=0.001).

5. Overall mortality at 6 months did not differ between the groups (27% in both arms).

Study Design

Design

RCT

Open-Label

Sample

3,035

Patients

Duration

6 mo

Median

Setting

12 countries

Population Adults with acute ischemic stroke presenting within 6 hours of symptom onset where the clinical benefit of alteplase was considered unproven (notably, 53% of enrolled patients were older than 80 years).

Intervention Intravenous alteplase (rt-PA) 0.9 mg/kg (maximum 90 mg; 10% given as bolus, 90% as 1-hour infusion) plus standard medical care.

Comparator Standard medical care alone.

Outcome Proportion of patients alive and independent (Oxford Handicap Scale score 0-2) at 6 months.

Study Limitations

• The open-label design could introduce performance and detection bias, although steps were taken to evaluate long-term outcomes blindly.

• The primary binary efficacy endpoint (OHS 0-2) was not met, requiring reliance on the prespecified secondary ordinal shift analysis to confirm functional benefit.

• The enrollment of a heterogeneous cohort with treatment times up to 6 hours diluted the overall magnitude of benefit compared to strict early-window cohorts.

Clinical Significance

IST-3 decisively overturned the dogma that patients older than 80 are too frail or at too high a risk to benefit from systemic thrombolysis. By establishing that the elderly derive comparable or even greater relative benefit in long-term functional independence—despite an upfront risk of early intracranial hemorrhage—the trial and its concurrent meta-analysis prompted international guideline updates to remove absolute upper age limits for acute stroke thrombolysis.

Historical Context

Following the landmark NINDS (1995) and ECASS-III (2008) trials, intravenous alteplase became standard-of-care for acute ischemic stroke up to 4.5 hours from symptom onset. However, these foundational trials excluded or severely underrepresented patients over the age of 80. Consequently, regulatory licenses contraindicated tPA in the elderly. The IST-3 trial was specifically designed to evaluate tPA in these unproven populations up to 6 hours, randomizing over 3,000 patients, of which 53% were over age 80.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does recombinant tissue plasminogen activator (rt-PA) work at the molecular level, and what is the pathophysiological concept of the "ischemic penumbra" that justifies its use up to 6 hours after symptom onset?

Key Response

Alteplase binds to fibrin and converts plasminogen to plasmin, initiating local fibrinolysis. The penumbra is hypoperfused brain tissue at risk of infarction but salvageable if reperfusion occurs early, forming the core rationale for extending time windows in thrombolytic trials like IST-3.

Resident

Given the increased risk of early symptomatic intracranial hemorrhage (sICH) seen in IST-3, how do you clinically counsel a family regarding the administration of IV alteplase for an 85-year-old patient arriving 4 hours after stroke onset?

Key Response

IST-3 showed that despite an initial increase in early deaths and sICH within 7 days, there was no increase in mortality at 6 months, and patients over 80 had a significant shift toward functional independence. Residents must balance early procedural risks against long-term functional benefits during shared decision-making.

Fellow

IST-3 failed its primary dichotomous outcome for independence but showed benefit in an ordinal "shift" analysis. How does ordinal analysis of the Oxford Handicap Scale provide a more nuanced understanding of stroke recovery compared to a strict dichotomous cutoff?

Key Response

A dichotomous outcome misses clinically meaningful improvements within disabled categories (e.g., shifting from bedbound to wheelchair-bound but able to assist). Ordinal shift analysis captures treatment effects across the entire spectrum of disability, which is highly relevant in severe strokes and older populations.

Attending

Historically, many practitioners withheld thrombolytics from octogenarians due to perceived excessive hemorrhage risk. How do the results of IST-3 serve as a teaching point to dismantle ageism in acute stroke pathways?

Key Response

IST-3 was practice-changing because it specifically enrolled a large cohort of patients over 80 and demonstrated that this demographic actually experienced a substantial absolute benefit from thrombolysis, permanently altering stroke protocols to remove arbitrary upper age limits.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

IST-3 utilized an open-label, randomized design rather than a strict double-blind, placebo-controlled setup. How might this trial design introduce bias in functional outcome assessments at 6 months, and what methodological safeguards mitigate this?

Key Response

Open-label designs are prone to performance and detection biases, particularly for subjective functional scales. Using PROBE (Prospective Randomized Open, Blinded Endpoint) designs where 6-month assessors are strictly blinded to treatment allocation is crucial to protecting the validity of the trial outcomes.

Journal Editor

The IST-3 trial recruited patients over a prolonged period (2000-2011), during which stroke care and accepted time windows evolved significantly. As a reviewer, how does this prolonged recruitment phase and shifting background standard threaten the internal validity of the pooled results?

Key Response

Changes in background stroke care, such as widespread use of stroke units and the approval of the 3-4.5 hour window mid-trial, shifted the baseline "usual care." This introduces temporal confounding, making it difficult to isolate the pure treatment effect of alteplase as originally hypothesized without complex covariate adjustments.

Guideline Committee

Following IST-3, how should major stroke guidelines update recommendations regarding intravenous alteplase for patients older than 80 years presenting in the 3 to 4.5-hour window, considering previous guidelines treated age over 80 as an exclusion criterion?

Key Response

Prior to IST-3, the ECASS III trial excluded patients older than 80 from the 3-4.5 hour window, leading guidelines to list advanced age as a relative contraindication. IST-3 provided critical Level A evidence demonstrating safety and efficacy in this demographic, prompting AHA/ASA guidelines to update and recommend IV alteplase for eligible patients over 80, removing the age restriction.

Clinical Landscape

Noteworthy Related Trials

1995

NINDS Trial

n = 624 · NEJM

Tested

Alteplase (0.9 mg/kg) within 3 hours

Population

Acute ischemic stroke patients

Comparator

Placebo

Endpoint

Favorable functional outcome at 3 months

Key result: Alteplase administered within 3 hours of symptom onset improved clinical outcome at 3 months compared to placebo despite an increased risk of symptomatic intracranial hemorrhage.

2008

ECASS III Trial

n = 821 · NEJM

Tested

Alteplase (0.9 mg/kg) within 3 to 4.5 hours

Population

Acute ischemic stroke patients aged 18 to 80 years

Comparator

Placebo

Endpoint

Favorable outcome (mRS 0-1) at 90 days

Key result: Alteplase administered between 3 and 4.5 hours after symptom onset significantly improved clinical outcomes compared with placebo.

2019

EXTEND Trial

n = 225 · NEJM

Tested

Alteplase (0.9 mg/kg) within 4.5 to 9 hours or on awakening

Population

Acute ischemic stroke patients with salvageable brain tissue on perfusion imaging

Comparator

Placebo

Endpoint

Excellent functional outcome (mRS 0-1) at 90 days

Key result: Alteplase improved the proportion of patients achieving an excellent functional outcome when guided by perfusion imaging up to 9 hours after onset.

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