Two recently published studies have investigated new modalities for the treatment of acute ischemic stroke.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group1 recently reported the results of a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (TPA) for acute ischemic stroke. There were two parts to the overall study; a total of 624 patients were randomized in both parts. To qualify for inclusion in either of the two parts, patients had to (1) have had an ischemic stroke with a clearly defined time of onset; (2) have a deficit that was measurable according to the National Institutes of Health Stroke Scale (NIHSS), a 42-point serial measure of neurological deficit; and (3) have a baseline computed tomographic brain scan that showed no evidence of intracranial hemorrhage. Patients had to have treatment with study drug initiated within 3 hours of symptom onset. Exclusion criteria included another stroke or head trauma within the past 3 months, major surgery within the past 2 weeks, any history of intracranial hemorrhage, blood pressure either >185 mm Hg systolic or >110 mm Hg diastolic, rapidly improving or minor symptoms, symptoms suggestive of subarachnoid hemorrhage, and seizures at the onset of stroke. Other exclusion criteria included a recent history of gastrointestinal or genitourinary bleeding. Recombinant TPA was administered intravenously; the dose was 0.9 mg/kg (up to a maximum of 90 mg). Ten percent of the drug was given as a bolus, followed by a 60-minute infusion of the remaining 90% of the drug.
In part 1 (n=291), the clinical efficacy of TPA was assessed according to the NIHSS and the degree of neurological deficit at 24 hours. There was no significant difference between the TPA and placebo groups in the percentages of patients with neurological improvement at 24 hours. Despite the negative short-term results, at late (3-month) follow-up, there was significantly better improvement of NIHSS scores in the TPA group.
In part 2 (n=333), a global test statistic was used to assess clinical outcome at 3 months according to scores on the NIHSS, the Barthel index (an index of activity of daily living), the Glasgow outcome scale (a global assessment of function), and the modified Rankin scale (a simplified overall assessment of function). The odds ratio for a favorable outcome as measured by the global test statistic at 3 months was 1.7 (95% CI, 1.2 to 2.6). Compared with placebo, TPA treatment was associated with a 12% absolute (32% relative) increase in the number of patients with minimal or no disability on the Barthel index (38% with placebo and 50% with TPA). In the TPA group, there was also an 11% absolute (55% relative) increase in the number of patients with NIHSS scores of 0 or 1 (20% with placebo, 31% with TPA). The 36-hour incidence of symptomatic intracerebral hemorrhage was 6.4% in TPA-treated patients and 0.6% in placebo-treated patients. The overall mortality at 3 months was not significantly affected by treatment with TPA (17% in the TPA group, 21% in the placebo group; P=NS).
Kay and coworkers2 recently reported a study of the use of low-molecular-weight heparin for the treatment of acute ischemic stroke. They conducted a randomized, double-blind, placebo-controlled investigation that compared two doses of subcutaneous low-molecular-weight heparin (4100 IU BID and 4100 IU QD) with placebo in patients presenting with acute ischemic stroke symptoms within the past 48 hours (excluding patients with age >80 years, CT evidence of intracranial hemorrhage, transient deficits, sustained hypertension, current anticoagulation therapy, and patients with no motor deficit or patients in whom death was considered to be imminent). Four hospitals in Hong Kong participated in the study; study medication was administered for 10 days. The primary study end point was “poor outcome,” defined as death from any cause or dependency with respect to daily activities during the 6 months following the stroke. Secondary outcomes included death, hemorrhagic transformation of the infarct, other complications, and poor outcome at 3 months.
A total of 2750 patients were screened between October 1992 and July 1994; 308 were randomized and eligible for the study, and 306 of these had complete 6-month follow-up. During the 10 days of study drug treatment, 23 patients (7.5%) died; study medication was discontinued in 28 others (9.2%) because of complications. These outcomes did not differ among treatment groups. There were also no differences among groups in patients with hemorrhagic infarct transformations. By 3 months, there was a nonsignificant trend toward better outcome in the high-dose low-molecular-weight heparin group (poor outcome in 53% of the high-dose group, 60% of the low-dose group, and 64% of the placebo group; P=.12). By 6 months, the overall mortality in the study cohort was 16.2%. There was a significant favorable, dose-dependent effect of low-molecular-weight heparin on outcome at 6 months (poor outcome in 45% of the high-dose group, 52% of the low-dose group, and 65% of the placebo group; P=.005).
- Copyright © 1996 by American Heart Association