Is alteplase safe and effective for acute stroke when given between 3 hours and 4.5 hours after the onset of symptoms?

Under careful clinical trial conditions with strict adherence to exclusion criteria, alteplase improves functional outcomes for patients with acute ischemic stroke if given up to 4.5 hours after the onset of symptoms. Of course, in real clinical practice adherence is often flawed, interpretation of CT and MRI scans is sometimes inaccurate, and outcomes are unlikely to be as good. For example, in a study of 70 patients in Cleveland, deviation from national treatment guidelines was seen in half the patients, and the risk of in-hospital mortality was higher in the thrombolysis group (16% vs 5%; JAMA 2000;283:1151-58). These results also differ from the ATLANTIS study (JAMA 1999;282:2019-26), which found increased 90-day mortality among patients receiving thrombolysis between 3 and 5 hours after the onset of symptoms. (LOE = 1b)

Hacke W, Kaste M, Bluhmki E, et al, for the ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317-1329.  [PMID:18815396]

Randomized controlled trial (double-blinded)

Industry

Concealed

Inpatient (any location)

Thrombolysis for acute stroke remains controversial and is only used in approximately 2% of patients with acute stroke in the United States. Proponents argue that the window for treatment should be expanded to increase the number of eligible patients. In this study, patients aged between 18 years and 80 years who were able to receive alteplase between 3 to 4.5 hours after the onset of symptoms were randomized to receive 0.9 mg/kg alteplase (n = 418) or matching placebo (n = 403). The researchers applied the usual contraindications to thrombolysis (ie, severe stroke, evidence of intracranial hemorrhage, oral anticoagulation, recent stroke or head trauma, seizures, low platelets or very high blood pressure). Outcomes were evaluated by an examiner masked to treatment assignment and groups were balanced at the start of the study. The mean age of study patient was 65 years, 60% were male, and the mean National Institutes of Health Stroke Severity score was 11 on a scale of 0 to 42 (where 25 or higher is a contraindication for thrombolysis). The authors report both per-protocol and intention-to-treat analyses, but only the latter should be used because a per-protocol analysis will overestimate the benefit seen in the real world. The primary outcome was a good outcome on the 6-point modified Rankin scale, defined as a score of 0 or 1. At 3 months, this was more likely in the alteplase group (52.4% vs 45.2%; P = .04; number needed to treat = 14). The outcome for other stroke scales was similar. Intracranial hemorrhage (27% vs 17.6%; P = .001; number needed to treat to harm [NNTH] = 11) and symptomatic hemorrhage (7.9% vs 3.5%; P = .006; NNTH = 23) were more likely among patients receiving alteplase, although all-cause mortality did not differ between groups (7.7% vs 8.4%).