Evidence-Based Medicine
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Extending the window for t-PA (alteplase) thrombolysis in acute ischemic stroke within 4.5 hours of symptom onset is not associated with an increased risk of symptomatic intracranial hemorrhage or death and does improve good outcomes at 90-days.
 
The Case
A 75-year-old female with a history of hypertension and a left-sided stroke 10-years ago presents 2.5 hours after the onset of left arm and leg weakness while playing bridge. After obtaining her head CT, labs, and history you note no contraindications to thrombolytic therapy (Table). Unfortunately, 3.5 hours have now passed since her symptoms began. Her husband, a retired Pediatrician, astutely notes recent professional organizations and newswire reports advocating thrombolysis for acute ischemic stroke at up to 4.5 hours.

Table ECASS III Exclusion Criteria
While awaiting Radiology’s CT interpretation, you notify your Neurologist who concurs with the decision to administer t-PA (alteplase 0.9mg/kg IV with 10% IV over 1- to 2-minutes and the remaining 90% as an IV drip over 60-minutes – maximum dose 90 mg) as per the ECASS III and NINDS protocol.

Table 1
ECASS III Exclusion Criteria

  • Age 80 years
  • Onset of stroke > 4.5 hours before drug administration or symptom onset unknown
  • Stroke symptoms present < 30 minutes or significantly improving before treatment
  • Intracranial hemorrhage
  • Severe stroke as defined by NIHSS > 25 or imaging (CT or MRI) displaying > 1/3 of middle cerebral artery territory involved
  • Seizure at the onset of stroke
  • Stroke or serious head trauma within the previous 3-months
  • Combination of previous stroke and diabetes mellitus
  • Heparin within the preceding 48 hours with PTT above normal limit
  • Platelet count < 100,000 mm3
  • Systolic blood pressure > 185 mm Hg or diastolic > 110 mm Hg or aggressive treatment (intravenous medication) to reduce blood pressure to these limits
  • Glucose 400 mg/dL
  • Symptoms suggestive of subarachnoid hemorrhage even if CT normal
  • Oral anticoagulation therapy
  • Major surgery or severe trauma within 3-months
  • Other major disorders with an increased risk of bleeding

The Evidence
Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke, N Engl J Med 2008; 359: 1317-1329.

Background
In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) study group reported that select acute ischemic stroke patients receiving t-PA within 3-hours of symptom onset were significantly more likely to display minimal to no disability at 3-months than similar patients treated with placebo and routine post-stroke care. Meanwhile, the European Cooperative Acute Stroke Study (ECASS) had conducted two alteplase trials (ECASS I and ECASS II) with a treatment window extending to 6-hours after symptom onset, but failed to demonstrate a benefit. The ATLANTIS trial also demonstrated no benefit for ischemic stroke patients treated between 3-5 hours after symptom onset. Each of these trials reported a significant proportion of protocol violations (range 5-17%) and per-protocol analysis suggested a trend towards benefit when appropriate patients were selected. In a subsequent meta-analysis of all subjects in six randomized trials totaling 2775 patients, a favorable outcome was observed for the subset treated within 3 to 4.5 hours of symptom onset. Since only 1.1% of stroke patients are currently receiving thrombolytic therapy, extending the treatment window from 3-hours to 4.5-hours may benefit a substantial number of stroke patients.

The Study
ECASS III, an industry sponsored trial, recruited 821 adult acute ischemic stroke patients from July 2003 through November 2007 from 130 hospitals in 19 European countries. Potential subjects had to receive t-PA within 3- to 4.5-hours of symptom onset while lacking any of the exclusion criteria enumerated above. Patients, clinicians, and outcome assessors were unaware of whether t-PA or placebo had been administered. During the first 24-hours after drug administration, IV heparin, oral anticoagulants, aspirin, and volume expanders were prohibited. Clinical reevaluations occurred at 1, 2, and 24-hours as well as days 7, 30, and 90. CT or MRI were obtained prior to randomization and at 22- to 36-hours post-treatment. The primary outcome was a favorable outcome as measured by the modified Rankin Scale (mRS, 0 = no deficit; 1 = minimal non-disabling deficit). A secondary outcome measure also assessed various other post-stroke disability parameters using the NIH Stroke Scale (NIHSS), Barthel Index, and Glasgow Outcome Scale. Finally, the investigators performed a statistical analysis of their results following the completion of data collection to adjust for the initial NIHSS and time-to-treatment, the two strongest prognostic variables for a favorable outcome. To assess safety of t-PA in this population the investigators evaluated 90-day mortality, any intracranial hemorrhage, symptomatic intracranial hemorrhage (ICH), and symptomatic cerebral edema.

The Results
Thrombolytic therapy, administered a median of 3 hours 59 minutes after symptom onset, was associated with a significantly favorable outcome: 219/418 (52.4%) compared with 182/403 (45.2%) in the placebo group which translates into a Number Needed to Treat (NNT) of 14 individuals (95% CI 7 - 255) to produce one functionally independent outcome that would not otherwise have occurred.

Alteplase was also associated with a favorable outcome for the secondary global outcomes measure (Odds Ratio 1.28, 95% Confidence Interval 1.00-1.65). Thrombolysis remained an independent variable for favorable outcome when adjusted for initial NIHSS and time-to-treatment in the post hoc analysis. Although t-PA was associated with significantly more symptomatic ICH events than the placebo group (27% vs. 17.6%, p = 0.001, Number Needed to Harm = 47; 95% CI 39-161), these complications were not more common than the traditional 3-hour NINDS protocol reported adverse event rate. Death occurred within 90-days at equal rates (t-PA 7.7%, placebo 8.4%).

Summary
Intravenous alteplase administered from 3- to 4.5-hours after symptom onset for ischemic stroke in select patients (see extensive exclusion criteria above) in a research environment is associated with a clinically significant improvement in the proportion of patients with functionally independent favorable outcomes (NNT=14) without increasing mortality. Patients who can be treated within 3-hours should not have their treatment delayed since earlier time-to-treatment is consistently associated with a higher proportion of subjects with favorable outcomes.

Table 2
                                                        t-PA       Placebo    NNT    NNH
Good Recovery at 90 Days              52.4%     45.2%       14        N/A
Symptomatic ICH                           
2.4%       0.3%         N/A     47
Death    
                                          7.7%       8.4%         N/A     N/A

Christopher R. Carpenter, MD, MSc Assistant Professor, Washington University in St. Louis, Director, Evidence Based Medicine
 
 

Comments   

# Dir. Emergency Cardiac/Neuro Services St. Luke's HospitalMike Klevens, MD FAAEM 2009-09-29 04:02
Dr. Carpenter lays out a nice summary. However, I am still concerned about the ability to bleed. I would really like to see this in a cates plot which would allow me to easily speak to my patient and their family the pros and cons of this therapy.
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