Is It Time to Be Dis-ENCHANTED with Low Dose Alteplase in Acute Ischemic Stroke?

Published - Written by Bhavna Seth, M.D.

2016-06-13_13-00-21Ms. M, is hustled in to your emergency room, a septuagenarian with a history of hypertension. She was last noted to be well and playing with her grandchildren 1 hour ago, when her family noticed she began to slur her words, her face drooped to the left and she felt a heaviness & inability to lift her left arm. You activate the stroke team and in minutes a stat head CT rules out a cerebral hemorrhage. With evidence of an acute ischemic stroke a decision for thrombolysis with intravenous alteplase is made. However, with her co-morbidities, and the risk of hemorrhage, one pauses to consider low-dose alteplase as a therapeutic avenue: Would a lower dose 0.6mg/kg intravenous alteplase be more beneficial compared to the standard 0.9mg/kg dose? How would it impact her immediate and eventual risk for death and disability?

Despite the lack of high quality evidence, many Asian centers have adopted low-dose alteplase as a therapeutic alternative to limit the risks of intracranial hemorrhage. The Enhanced Control of Hypertension and Thrombolysis Stroke (ENCHANTED) takes on this complex problem and through a well-designed trial endeavors to fulfill this gap.

The study, published in this week’s NEJM, was designed as a non-inferiority trial, with the goal to prove that the low-dose alternative was no worse than the standard regimen. It recruited 3310 eligible stroke patients from 111 clinical centers in 13 countries. Patients were randomly assigned to receive either the standard regimen or the low-dose alteplase, within 4.5 hours of suffering from stroke. The primary outcome was to determine death or disability at 90 days based on the modified Rankin scale (scores 2-6). Secondary outcomes included any intracranial hemorrhage, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, health-related quality of life, length of hospital stay, need for permanent residential care, and serious adverse events.

The study failed to show non-inferiority of the low-dose strategy as the primary outcome was observed in 53.2% of the low-dose recipients, and 51.1% of those who received the standard dose regimen (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.95 – 1.25). The non-inferiority margin was set at  1.14; and the P value for non-inferiority was 0.51). This outcome was consistent across all sub-group analyses, thus this study did not establish that low-dose is non-inferior to standard dose and perhaps suggests that it is not the time to make seismic shifts in treatment guidelines in favor of the low-dose strategy.

The authors note possible limitations of their study to be interobserver variability for the administration of the modified Rankin scale via telephone, the high percentage of Asian participants and a concurrent intensive blood pressure control arm precluding generalizability. Additionally, compared to other stroke trials, patients in this trial included those with mild neurological impairment who were treated at a later time point than symptom onset compared to other stroke trials, thus, leading to an element of selection bias.

However, the study did have some interesting findings, which may affect clinical decision-making. Patients in the low-dose group suffered from significantly fewer major, symptomatic intracranial hemorrhages, at 1% with low-dose vs. 2.1% with standard dose (OR 0.48, 95% CI 0.27-0.86, p= 0.01). Although in an accompanying editorial, it is noted the rates of hemorrhage in both arms were low. This trial does however provide some evidence in support of the low-dose strategy to treat patients of acute ischemic stroke who may have elevated risk of suffering from intracranial hemorrhage.

As this trial failed to demonstrate non-inferiority based on the authors’ pre-specified criterion, the results of ENCHANTED are unlikely to change current clinical practice. However, it does open the debate about considering a lower dose regimen in certain risk groups but future research would be necessary to determine whether low-dose alteplase is preferable in some patients.

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bhavna_croppedBhavna Seth is a Resident in Internal Medicine at Boston University Medical Center.

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