EBQ:Tissue Plasminogen Activator for Acute Ischemic Stroke

incomplete Journal Club Article

Neurological Disorders and Stroke Stroke Study Group. "Tissue Plasminogen Activator for Acute Ischemic Stroke". The New England Journal of Medicine. 1995. 333(24):1581-1587.
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Clinical Question

• Two part study
• tPA versus placebo
  1. Does tPA have clinical activity which was measured as improvement of 4 points on the NIHSS or resolution of neurologic deficit within 24 hours of onset?
  2. What are the clinical outcomes at 3 months based on Barthel index, modified Rankin scale, Glasgow outcome scale and NIHSS?

Conclusion

• No significant differences in neurologic improvement at 24 hours between two groups.
• At three months, improved neurologic outcome in tPA group
• At three months patients with tPA were 30% more likely to have minimal or no disability compared to placebo.
• Increased risk of intracranial hemorrhage (ICH) within 36 hours in patients treated with tPA (6.8%) versus placebo (0.6%) p<0.001
• No significant difference in mortality at 3 months between groups.

Major Points

• tPA has greater risk of hemorrhagic transformation however, in patients who received tPA they were more likely to have less of a neurologic disability at 3 months.

Study Design

• Permutated- block design for randomization stratified based on clinical center and time from onset of stroke to start of treatment
• Multicenter clinical trial
• patient assessed at baseline with NIHSS and head CT
• patients were randomized to placebo or intervention group with two groups of time straum (0-90 minutes or 91-180 minutes after the onset of stroke)
• Received either placebo or alteplase at dose of 0.9mg/kg of body weight (max of 90 mg) with 10% given as bolus and 90 % given as infusion over 60 minutes
• no anticoagulants or antiplatelets given 24 hrs after treatment
• specific BP controls
• repeat NIHSS at 24 hours
• outcome at 3 months by certified examiners not present during initial evaluation **Barthel index- ability to perform ADLs 95-100 is favorable and 0 is severe dysfunction
  • Modified Rankin scale- 0 no symptoms and 5 severe disability
  • Glasgow outcome scale- 1 is good recovery and 5 is death
  • NIHSS- 42 point scale assessing the extent of neurologic deficits across 11 categories

Population

• all patients with ischemic stroke with clearly defined onset, deficit measured on NIHSS and baseline CT with no evidence of ICH
• 624 patients from January 1991 through October 1994 who presented to one of the eight geographically diverse academic centers in the United States

Patient Demographics

No differences were detected between treatment groups in baseline characteristics

Characteristics	Part I t-PA N=144	Part I Placebo N=147	Part 2 t-PA N=168	Part 2 Placebo N=165
Age	67 (57-77)	66 (55-77)	69 (57-81)	66 (53-79)
Female	42%	40%	43%	42%
Race – White	62%	61%	69%	66%
Race - Black	29%	31%	23%	26%
Race - Hispanic	8%	5%	5%	7%
Race - Asian	1%	0%	3%	1%
NIHSS score- Median	14	14	14	15
Stroke Subtype- Small-Vessel Occlusive	19%	11%	14%	9%
Stroke Subtype- Cardioembolic	42%	44%	45%	44%
Stroke Subtype- Large-Vessel Occlusive	35%	42%	39%	45%

Inclusion Criteria

• ischemic stroke with clearly defined onset
• deficit measured on NIHSS
• baseline CT with no evidence of ICH

Exclusion Criteria

• stroke or serious head trauma within preceding 3 months
• major surgery in preceding 14 days
• history of ICH
• SBP>185 or DBP>110
• rapidly improving or minor symptoms
• symptoms suggestive of subarachnoid hemorrhage
• hx of GI or urinary hemorrhage in preceding 21 days
• arterial puncture at a noncompressible site in preceeding 21 days
• had seizure at the onset of stroke
• (patients who received heparin in preceding 48 hours with elevated PTT
• PTT>15 seconds
• platelets<100000
• glucose < 50 or >400

Interventions

• tPA IV 0.9 mg/kg with 10% given as a bolus and 90% given over 60 minutes after the bolus

Outcomes

Primary Outcome

• Part 1: > 4 point improvement in NIHSS at 24 hours

N = 291 tPA – 47% (67/144) Placebo 39% (57/147) At 24 hours, no statistically significant difference

• Part 2: Improvement in stroke scale (Barthel Index, modified Rankin Scale, Glasgow Outcome Score and NIHSS) at 3 months

Minimal to no disability 95 or 100 on Barthel index at 90 days 38% placebo and 50% t-PA (12% absolute benefit) NNT=8

• similar results with modified Rankin scale, Glasgow outcome scale, NIHSS

Secondary Outcomes

• Lower rate of hemorrhage compared to trials with streptokinase and t-PA
• recommend to mimized blood pressure elevations

• Symptomatic ICH with a mortality of 45-50%
  • tPA: 6.4% (20/312)
  • Placebo: 0.64% (2/312)

• Asymptomatic ICH
  • tPA 4.4% (14/312)
  • Placebo 2.9 % (9/312)

Number Needed to harm was 17

Criticisms & Further Discussion

• Imbalance in the stroke subtypes
• Placebo had more large vessel occlusive strokes than tPA
• fragility index of 3 which is the number of outcomes that could be changed which causes a loss of statistical significance which is a very low number

External Links

https://emcrit.org/emcrit/tpa-for-ischemic-stroke-debate/

Funding

National Institute of Neurological Disorders and Stroke