BY SARAH OWENS
A low dose (0.6 mg/kg) of alteplase was no more effective than the standard dose (0.9 mg/kg) at reducing rates of death and disability among patients with acute ischemic stroke (AIS) who were eligible for thrombolysis, according to a new study published online on October 2 in JAMA Neurology.
The treatment effects of both dose groups were consistent across key subgroups of patients with AIS, including older, Asian, and severely affected patients, researchers found.
Low-dose alteplase was approved in Japan on the basis of a single-arm study that showed it was just as safe and effective as a standard dose, but evidence from randomized trials is lacking. Additionally, recent studies have suggested that patients aged 80 and older or with severe neurological deficits may derive the same benefit from a low dose as a standard dose but have a lower risk of adverse events, such as intracerebral hemorrhage, but those effects have not been demonstrated in a randomized trial.
The current findings show that "the effects of low-dose alteplase were not clearly superior to the effects of standard-dose alteplase on death or disability in key demographic subgroups of patients with AIS," the study authors, led by Xia Wang, PhD, of the University of Sydney in Sydney, New South Wales, Australia, wrote.
For the study, researchers performed a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial, an international, randomized, open-label, blinded, endpoint clinical trial of low-dose vs standard-dose intravenous alteplase for patients with AIS. The ENCHANTED trial enrolled 3,310 patients who were diagnosed with AIS by brain imaging and who fulfilled local criteria for thrombolysis in the trial's alteplase-dose arms.
The patients were randomly assigned to receive a low dose of alteplase (0.6mg/kg; 15 percent as bolus and 85 percent as infusion over 1 hour) or a standard dose (0.9mg/kg; 10 percent as bolus and 90 percent as infusion over 1 hour). The researchers compared outcomes between the low-dose and standard-dose groups. Their primary outcome measure was a poor outcome, defined as a score from 2 to 6 on the modified Rankin scale (mRS, a measure of post-stroke disability, with higher scores indicating worse disability and 6 indicating death) at 90 days.
They found no significant differences in treatment effects between low- and standard-dose alteplase for poor outcomes by age, ethnicity, or stroke severity (all were p>0.37 for interaction). Similarly, the treatment effects of low- vs. standard-dose alteplase on functional outcomes (as measured by an ordinal analysis of the full range of mRS scores) were similar between Asians (odds ratio, 1.05;95%CI, 0.90-1.22) and non-Asians (odds ratio,0.93; 95%CI,0.76-1.14; p=0.32 for interaction).
In addition, reductions in rates of symptomatic intracerebral hemorrhage were generally consistent with low-dose alteplase, but the reduction was not statistically significant according to age, ethnicity, or severity of AIS.
The findings, the study authors concluded, "suggest that decisions about the dose of alteplase used in thrombolysis-eligible patients with AIS should not be based solely on age, ethnicity, or stroke severity."
The researchers noted a few limitations to their study. Among them, interobserver variability in mRS scoring may have caused imprecise estimates of the treatment effect; and the trial included patients who had mild neurological severity and had a longer delay from symptom onset compared to patients in other trials of alteplase for ischemic stroke, which may raise concern over the findings' external validity.
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