Alteplase given within 6 hours of stroke did not improve clinical outcomes at 90 days
ACP J Club. 1999 Mar-April;130:34. doi:10.7326/ACPJC-1999-130-2-034
Hacke W, Kaste M, Fieschi C, et al., for the Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998 Oct 17;352:1245-51.
In patients with moderate-to-severe ischemic hemispheric stroke, can alteplase given within 6 hours of onset of symptoms improve clinical outcomes?
Randomized, double-blind, placebo-controlled trial with follow-up of 90 days (European Cooperative Acute Stroke Study [ECASS II]).
108 centers in 14 European countries, Australia, and New Zealand.
800 patients (median age 68 y, 59% men) with a clinical diagnosis of moderate-to-severe ischemic hemispheric stroke who could be treated within 6 hours of onset of symptoms and who had no or minor signs of infarction on the initial computed tomography scan. Exclusion criteria were extensive brain swelling, hemorrhage, unknown time of stroke onset, coma, stupor, hemiplegia plus fixed-eye deviation, minor stroke symptoms, uncontrolled hypertension, recent traumatic brain injury or seizures, recent surgery, heparin use, bleeding diathesis, lactation, recent or current pregnancy, and abnormal laboratory values. All patients included in the final analysis.
409 patients were allocated to alteplase, 0.9 mg/kg of body weight up to 90 mg given in a 10% bolus and then in an intravenous infusion. 391 patients were allocated to placebo. Low-dose subcutaneous heparin and osmotic agents were allowed.
Main outcome measures
A favorable outcome at 90 days (score of 0 or 1 on the modified Rankin scale [MRS]). Secondary outcomes were death, neurologic deficit using the National Institutes of Health Stroke Scale (NIHSS) and the Scandinavian Stroke Scale, activities of daily living using the Barthel Index, mental and physical status, length of hospital stay, quality of life at 90 days, and adverse effects.
5 patients in the placebo group and 2 patients in the alteplase group did not receive their allocated therapy. Analysis was by intention to treat. The groups did not differ for rates of favorable outcome at 90 days (40.3% in the alteplase group vs 36.6% in the placebo group, P = 0.28) or any other outcome (death, neurologic deficit, activities of daily living, length of hospital stay, or mental or physical status). NIHSS scores were improved at 30 days with alteplase (P = 0.035), and by using MRS scores of 0 to 2, more patients in the alteplase group were independent (54% vs 46%, P = 0.024). Symptomatic intracranial hemorrhage was more common in the alteplase group (8.8% vs 3.4%, P = 0.001).
Alteplase given within 6 hours of onset of symptoms of acute ischemic stroke did not increase favorable outcomes at 90 days.
Source of funding: Not stated.
For correspondence: Professor W. Hacke, Department of Neurology, University of Heidelberg Medical School, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. FAX 49-6221-565348.
ECASS II, like its predecessor, ECASS I (1), was technically neutral: Alteplase had no effect on the predefined primary end point of a "favorable outcome" (MRS score 0 to 1). In contrast, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study was positive for the same outcome (2). Meta-analysis of thrombolytic trials in acute ischemic stroke suggests that this therapeutic approach increases independence (3). Furthermore, in post hoc analyses, ECASS II was positive using an MRS score of 0 to 2, whereas ECASS I was positive with an MRS score of 0 to 1 (4). Why then, if all 3 studies were essentially positive, is this not reflected in their primary results?
First, the trials were medium-sized, involving 624 to 800 patients. Therefore, they were too small to reliably detect their declared aims of improving outcome by an absolute difference of 10% to 24% (2). Such improvements are probably unrealistic, and it might be better to design studies that detect smaller differences of 4% to 8%. Second, different outcomes of MRS scores of 0 to 1 or 0 to 2 were used, although most trials in acute stroke have used the latter, which may be more appropriate to patients and society and more statistically efficient. Other differences between the trials may partly explain their disparate results. The NINDS Stroke Study only recruited patients up to 3 hours after stroke, whereas both ECASS studies included patients up to 6 hours. However, ECASS II found no time-dependent effects on outcome, which suggests that thrombolysis may be effective if given between 3 to 6 hours after onset of symptoms.
It is evident that one last and much larger (approximately 2400 patients) trial should be done to determine the role of thrombolysis in the management of patients with acute ischemic stroke.
Philip Bath, MD
University of NottinghamNottingham, England, UK
1. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study. JAMA. 1995;274:1017-25.
4. Hacke W, Bluhmki E, Steiner T, et al. Dichotomized efficacy end points and global end-point analysis applied to the ECASS intention-to-treat data set: post hoc analysis of ECASS I. Stroke. 1998;29:2073-5.