Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke

A noninferiority trial comparing two doses of thrombolytic therapy with the tissue plasminogen activator (tPA) alteplase has failed to demonstrate that low-dose therapy is as effective as standard-dose treatment for reducing the risk of death and disability in patients with acute ischemic stroke.

Major symptomatic intracerebral hemorrhage was significantly less common among patients treated with low-dose alteplase, however. In the low-dose treatment arm—where alteplase was administered at a dose of 0.6 mg/kg of body weight—the rate of symptomatic intracerebral hemorrhage was 1.0%. In the standard-dose arm—where alteplase was given at a dose 0.9 mg/kg of body weight—the rate was 2.1% (P = 0.01).

Known as the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), the trial was presented earlier this week at the European Stroke Organisation Conference in Barcelona, Spain, and published simultaneously online in the New England Journal of Medicine.

In an editorial accompanying the study, Cathy Sila, MD (University Hospitals Case Medical Center, Cleveland, OH), says the trial provides more robust data to guide care, noting that previous recommendations were based on registry data. The bottom line: “ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes,” states Sila.

In their paper, lead investigator Craig Anderson, MD (University of Sydney Medical School, Australia), said the study “was driven by concern about high risks of intracerebral hemorrhage with alteplase, particularly among Asians, because preliminary studies have had differing results with respect to the effectiveness and risks of this treatment.”

In the United States, Australia, and Europe, alteplase (Activase, Genentech) is approved as thrombolytic therapy for acute ischemic stroke at a dose of 0.9 mg/kg of body weight. In Japan, however, alteplase is approved at a dose of 0.6 mg/kg of body weight because there are concerns about an increased risk of bleeding in this population. As the ENCHANTED researchers point out, the lower dose was approved by Japanese regulators on the basis of an uncontrolled, open-label study showing equivalent outcomes—and a lower risk of intracerebral hemorrhage—compared with the standard dose.

Designed as a noninferiority study, ENCHANTED included 3,310 patients with acute ischemic stroke eligible for thrombolytic therapy, of whom 63% were Asian. All patients underwent randomization to either low-dose or standard-dose alteplase within 4.5 hours after the onset of stroke. The primary endpoint of the trial was death or disability, defined by scores 2 through 6 on the modified Rankin scale, at 90 days. Symptomatic intracerebral hemorrhage was assessed according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria.

Criteria for the noninferiority of low-dose alteplase for the primary endpoint were not met (P = 0.51).

In the editorial, Sila argues that while the study was not sufficiently powered to detect differences in outcomes among Asian and non-Asian patients, the low rate of hemorrhage and lack of significant interaction with ethnicity “argue against a substantially increased risk that would preclude standard-dose therapy.”

Sila points out that intravenous thrombolysis with tPA in patients with acute ischemic stroke “has driven the infrastructure development for acute stroke care in the United States, Europe, and Australia for the past 20 years.”

Early adoption was initially slow and cautious given the concerns about intracerebral hemorrhage, and while cost wasn’t particularly an initial issue, it may well become one given that the average cost of a standard dose increased 111% in the past decade, writes the editorialist. However, using less effective therapies, such as low-dose alteplase, to save short-term costs will only increase the costs of long-term care for stroke survivors, she writes.

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