NINDS

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Marler JR, et al. "Tissue Plasminogen Activator for Acute Ischemic Stroke". The New England Journal of Medicine. 1995. 333(24):1581-1587.
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Clinical Question

In patients with ischemic stroke, does the administration of tPA reduce morbidity and mortality?

Bottom Line

In patients with ischemic stroke within 3 hours, tPA administration significantly improved NIHSS scores but did not confer survival benefit.

Major Points

Prior pilot studies suggested that tPA was beneficial when treatment was begun within 3 hours of stroke onset, but the 1995 National Institute of Neurological Disorders and Stroke rt-PA Stroke Study (NINDS) was the first to establish efficacy of thrombolysis within a 3-hour time frame for ischemic stroke. The NINDS trial demonstrated improvements in functional outcomes at 3 months if thrombolysis was administered within 3 hours of symptom onset, with the greatest benefit seen within 90 minutes. Despite a tenfold increase in symptomatic intracranial hemorrhage (ICH), there was no significant difference in mortality among those receiving tPA. These results were confirmed in ATLANTIS A[1] (2002).

The subsequent ECASS III trial (2008), demonstrated a benefit of IV alteplase beyond the conventional 3-hour window, effectively extending the window for alteplase to 4.5 hours. A 2014 meta-analysis found a benefit for tPA therapy up to 4.5 hours, though there was a higher rate of a low Modified Rankin score with tPA administration <3 hours (NNT 9; 95% CI 6-18) than between 3-4.5 hours (NNT 20; 95% CI 11-97). There was no benefit of tPA administration later than 4.5 hours.[2]

Guidelines

AHA/ASA Early management of acute ischemic stroke (2013, adapted) [3]

  • Intravenous tPA for selected patients up to 3 hours after onset of ischemic stroke (class I level A)
  • Eligible patients should receive tPA as quickly as possible, ideally within 60 minutes of hospital arrival (class I level A)
  • Intravenous tPA for selected patients between 3-4.5 after onset of ischemic stroke (class I level B)

Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines (2015, adapted) [4]

  • Eligible patients: those who can receive IV tPA within 4·5 h of the onset of stroke symptoms (ECASS III) in accordance with criteria adapted from NINDS [Evidence Level A]
  • All eligible patients should receive IV tPA ASAP after presentation [Evidence Level A]
    • target time door-to-needle <60 min
    • median time in 90% of treated patients of 30 min [Evidence Level B]
  • tPA dosing following the American Stroke Association guidelines:
    • 0.9 mg/kg (max 90 mg total dose): 10% (0.09 mg/kg) IV bolus over 1min, remaining 90% (0.81 mg/kg) as IV infusion over 60 min [Evidence Level A]

Design

  • Double-blinded, randomized, placebo-controlled trial
  • N=624
    • Part 1: N=291, tPA (n=144) vs. placebo (n=147)
    • Part 2: N=333, tPA (n=168) vs. placebo (n=165)
  • Setting: 8 US centers
  • Enrollment: 1991-1994
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Improvement by >4 points on NIHSS or complete resolution at 24 hours
    • Proportion after stroke with favorable outcomes at 90 days

Population

Inclusion Criteria

  • Ischemic stroke with:
    • Clearly defined time of onset
    • Deficit measurable on NIHSS
    • Baseline CT scan of brain that showed no evidence of ICH

Exclusion Criteria

  • Stroke or serious head trauma within previous 3 months
  • Major surgery within 14 days
  • History of ICH or symptoms suggestive of SAH
  • SBP >185mmHg or DBP >110mmHg; or aggressive treatment required to reduce BP to specified limits
  • Rapidly improving or minor symptoms
  • Symptoms suggestive of SAH
  • GI or GU bleeding within previous 21 days
  • Arterial puncture at noncompressible site within previous 7 days
  • Seizure at onset of stroke
  • Anticoagulants or antithrombotics within 48 hours preceding onset of stroke
  • Elevated PTT/PT or platelets <100k
  • Glucose <50 or >400 mg/dl

Baseline Characteristics

  • Mean age: 67 years
  • Female: 41%
  • Race or ethnic group
    • White, non-Hispanic: 62%
    • Black: 30%
  • Weight: 78 kg
  • NIHSS score: median 14
  • Stroke etiology:
    • Small-vessel occlusive: 15%
    • Cardioembolic 43%
    • Large-vessel occlusive: 37%
  • Mean SBP: 154 mmHg
  • Mean DBP: 85 mmHg

Interventions

  • Permuted-block design with patients stratified according to time from stroke onset to start of treatment
  • Randomized to placebo or intravenous alteplase (0.9 mg/kg up to maximum 90 mg; 10% as bolus, then remaining 90% as 60 minute infusion)
  • No anticoagulants or antiplatelets to be given for 24 hours after treatment
  • Study divided into two parts:
    • Part 1 tested tPA activity, indicated by complete resolution or improvement in NIHSS by ≥4 points within 24h. Groups divided by time from symptom onset to tPA delivery:
      • 0-90 mins
      • 91-180 mins
      • 0-180 mins
    • Part 2 investigated benefits of tPA at 90 days based upon several indices:
      • Bartel index measures ability to perform ADLs. Score of 95-100 indicates favorable outcome.
      • Modified Ranking scale: 0 indicates absence of symptoms, 5 indicates severe disability
      • Glasgow outcome scale: 1 = good recovery, 2 = moderate disability, 3 = severe disability, 4 = vegetative state, 5 = death
      • NIHSS, 42-point scale that quantifies neurologic deficits in 11 categories

Outcomes

Comparisons are tPA vs. placebo.

Primary Outcomes

Improvement by >4 points on NIHSS or complete resolution at 24 hours
47% vs. 39% (RR 1.2; 95% CI 0.9-1.6; P=0.21)
Proportion after stroke with favorable outcomes at 90 days
Barthel index: 50% vs. 38% (OR 1.6; 95% CI 1.1-2.5, P=0.026)
Modified Rankin scale: 39% vs. 26% (OR 1.7; 95% CI 1.1-2.6; P=0.019)
Glasgow outcome scale: 44% vs. 32% (OR 1.6; 95% CI 1.1-2.5; P=0.025)
NIHSS: 31% vs. 20% (OR 1.7; 95% CI 1.0-2.8; P=0.033)

Secondary Outcomes

90-day mortality
17% vs. 21% (P=0.30)

Adverse Events

ICH within 36 hours of stroke treatment
6.4% vs. 0.6% (P<0.001), of which 45% were fatal
ICH within 3 months of stroke treatment
7.7% vs. 1.3% (P<0.001), of which 61% were fatal
New ischemic strokes
5.8% vs. 5.4% (P not stated)

Subgroup Analysis

tPA improved all outcome measures at 90 days regardless of age, stroke subtype, severity of stroke, and use of aspirin before stroke.

Funding

Supported by the National Institute of Neurological Disorders and Stroke.

Further Reading

  1. Albers, Gregory W., et al. "ATLANTIS trial results for patients treated within 3 hours of stroke onset." Stroke 33.2 (2002): 493-496.
  2. Emberson J, et al. "Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials." The Lancet. 2014;384:1929-1935.
  3. PDF file - Jauch EC, et al. "Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association." Stroke. 2013;44:870-947.
  4. Casaubon, L. K., Boulanger, J.-M., Blacquiere, D., Boucher, S., Brown, K., Goddard, T., Gordon, J., Horton, M., Lalonde, J., LaRivière, C., Lavoie, P., Leslie, P., McNeill, J., Menon, B. K., Moses, B., Penn, M., Perry, J., Snieder, E., Tymianski, D., Foley, N., Smith, E. E., Gubitz, G., Hill, M. D., Glasser, E., Lindsay, P. and Heart and Stroke Foundation of Canada Canadian Stroke Best Practices Advisory Committee (2015), Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015. International Journal of Stroke [1]