Lower Dose of Stroke Drug Reduces Risk of Hemorrhage

A lower-than-standard dose of intravenous alteplase (Activase; Genentech) for the treatment of patients with acute ischemic stroke is noninferior to the standard dose and is associated with significantly reduced risk of intracerebral hemorrhage, according to new study findings.

Ischemic stroke results in loss of neurologic function caused by a sudden loss of blood circulation to an area of the brain. Acute ischemic stroke, specifically, is more common than hemorrhagic stroke and is caused by thrombotic or embolic occlusion of a cerebral artery.

Standard-dose alteplase used in the treatment of patients with acute ischemic stroke has been associated with high risk of intracerebral hemorrhage, particularly among Asian patients treated in the United States. Previous studies have suggested that a 0.6-mg/kg dose of alteplase, rather than the standard 0.9-mg/kg dose, resulted in equivalent clinical outcomes and a lower risk of intracerebral hemorrhage.

To confirm these results, an international, multicenter, prospective, randomized, open-label trial (the ENCHANTED [Enhanced Control of Hypertension and Thrombolysis Stroke] study) was conducted to compare the 2 doses of alteplase in patients with acute ischemic stroke. Noninferiority was defined by the combined endpoint of death or disability at 90 days.

A total of 3310 patients from 111 clinical centers in 13 countries eligible for thrombolytic therapy for acute ischemic stroke were randomized within 4.5 hours after stroke onset to receive low-dose alteplase (n=1654) or standard-dose alteplase (n=1643). Patients were mostly of Asian descent (63%) and had a median age of 67 years.

Of the 3206 patients available for analysis, 855 of 1607 (53.2%) patients treated with low-dose alteplase and 817 of 1599 (51.1%) patients treated with standard-dose alteplase died or were disabled at 90 days (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.95–1.25; P = .51). Based on a modified Rankin scale (with 0 indicating no symptoms and 6 indicating death), in which noninferiority was defined by scores of 2 to 6 to determine noninferiority, the lower was noninferior to the standard dose (unadjusted common OR, 1.00; 95% CI, 0.89–1.13; P = .04 for noninferiority).

Secondary outcomes of the study showed that significantly more patients in the standard dose group experienced a major symptomatic intracerebral hemorrhage compared with those in the low-dose group (2.1% vs 1.0%, P = .01). In addition, significantly more patients in the standard-dose group had a fatal event within 7 days (1.5% vs 0.5%, P = .01). No significant differences were seen in 90-day mortality between the 2 groups (10.3% vs 8.5%, respectively, P = .07).

The study’s findings suggest that alteplase 0.6 mg/kg may be associated with a reduced risk of intracerebral hemorrhage compared with alteplase 0.9 mg/kg.