Top Things to Know: Expansion of the Time Window for Treatment of Acute Ischemic Stroke
Published: May 28, 2009
- A majority of patients with ischemic stroke are not treated with rtPA, largely because they arrive after the currently approved 3-hour time limit for administration of the medication.
- In order to optimize the reach of effective treatment, researchers have studied potential approaches which would allow for designation of a longer time window for treatment.
- Published in 2008, the European Cooperative Acute Stroke Study (ECASS-3) compared rtPA 0.9 mg/kg versus placebo in persons eligible for thrombolytic treatment between 3.0 to 4.5 hours from the onset of ischemic stroke symptoms.
- The primary study endpoint of ECASS-3 was defined using the modified Rankin Scale (mRS) to assess the level of post stroke disability at 90 days. Fifty-two percent of the rtPA treated group and 45.2% of the placebo group achieved a 0 to 1 mRS (p=0.04).
- The point estimate for the degree of benefit in ECASS-3 (Odds Ratio [OR] for a global favorable outcome was 1.28 (95% CI, 1.00 to 1.65; p<0.05) indicating a 28% better chance of having a positive outcome in patients who were treated with rt-PA as compared to placebo.
- The odds ratio from the ECASS-3 study was found to be comparable to the OR of 1.4 from a single pooled analysis derived from combining results of several studies in which participants received rtPA in the 3.0 to 4.5 hour window.
- In comparison, the National Institute of Neurological Disorders and Stroke (NINDS) study results reflected an OR of 1.9 which was estimated from a pooled analysis in patients who received rtPA in the 0 to 3.0 hour time frame. Indicating odds for a more favorable outcome when rtPA is administered early in ischemic stroke.
- Symptomatic intracranial hemorrhage (ECASS-3 SICH definition) was confirmed in 10 subjects treated with rt-PA (2.4%) and in 1 subject who was administered placebo (0.2%) (OR 9.85, 95% CI 1.26-77.32, p = 0.008).
- Implications for clinical practice:
*In the context of an expanded time window in ischemic stroke, delays in evaluation and initiation of therapy should be avoided, because the opportunity for improvement is greater with earlier treatment.
- Patients with ischemic stroke arriving in the hospital between 3 to 4.5 hours after symptom onset may be eligible for rt-PA, and if eligible should be treated.
- ECASS-3 study findings are not generalizable in ischemic stroke patients greater than 80 years of age, those taking oral anticoagulants, having a baseline NIH Stroke Scale>25, or those with both a history of stroke and diabetes.
- Guideline recommendations (see below), which are based on peer-reviewed publications should be reevaluated after the results of regulatory agency review of detailed, nonpublicly available data are known.
Guideline recommendations (extracted from the advisory):
rt-PA should be administered to eligible patients who can be treated in the time period of 3.0 to 4.5 hours after stroke (Class I, Level of Evidence B). The eligibility criteria for treatment in this time period are similar to those for persons treated at earlier time periods, with any one of the following additional exclusion criteria: patients older than 80 years, those taking oral anticoagulants with an INR ≤ 1.7, those with a baseline NIH Stroke Scale score greater than 25, or those with both a history of stroke and diabetes. Therefore, for the 3.0 to 4.5 hour window all patients receiving an oral anticoagulant are excluded whatever their INR. It should be noted that the relative utility of rt-PA in this time window in comparison to other methods of thrombus dissolution or removal has not been established. The efficacy of intravenous treatment with rt-PA within 3.0 to 4.5 hours after stroke in patients with these exclusion criteria is not well-established (Class IIb,, Level of Evidence C) and requires further study.
Citation
del Zoppo GJ, et al.; on behalf of the American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009: published online before print May 28, 2009, 10.1161/STROKEAHA.109.192535.