Lower Dose Alteplase Demonstrates Nonsuperiority in Treating Lacunar AIS

Craig Anderson, MD, PhD

Post-hoc analyses from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED; NCT01422616) found no evidence that low-dose, 0.6-mg/kg alteplase has advantages over the standard 0.9-mg/kg dose for patients with definite/probable acute ischemic stroke (AIS).

To determine any differential efficacy and safety of low- versus standard-dose intravenous (IV) alteplase, senior author Craig S. Anderson, MD, PhD, professor of neurology, University of South Whales Sydney, and colleagues collected data on 2588 participants defined as having either definite/probable lacunar (n = 490) or non-lacunar AIS (n = 2098) for primary analyses.

In the subgroup with definite lacunar AIS, there were no significant differences on the primary efficacy outcome of modified Rankin Scale (mRS) score 2-6 (low dose: 33.7%; high dose: 32.9%; adjusted odds ratio [OR], 0.96 [95% CI, 0.49-1.87]) or major disability or death (mRS 3-6; low dose: 20.2%; high dose: 15.3%; adjusted OR, 1.31 [95% CI, 0.54-3.19]) between low-dose and standard-dose alteplase groups.

Anderson and colleagues also found that despite not showing a differential effect on functional outcomes, low-dose alteplase did a better job of reducing the risk of symptomatic intracranial hemorrhage (sICH). These reductions were evident using notable criteria such as the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), National Institutes of Neurological Diseases and Stroke (NINDS), and the European-Australian Cooperative Acute Stroke Study (ECASS).

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Anderson et al. noted, however, that “given the low rate of sICH, with fewer than 5 events in the primary analysis for definite or probable lacunar AIS, we are limited in the conclusions that can be drawn as to whether a lower dose of IV alteplase should be preferred because of the good prognosis for lacunar AIS.”

Patients with lacunar AIS had better 90-day functional outcomes, whether defined by the outcome of the mRS scores 2-6 (unadjusted OR, 0.26 [95% CI, 0.21-0.33]), mRS scores 3-6 (unadjusted OR, 0.20 [95% CI, 0.15-0.36]), ordinal shift in the full range of scores (unadjusted OR, 0.27 [95% CI, 0.23-0.33]), or death alone (unadjusted OR, 0.04 [95% CI, 0.01-0.12]) compared to those with definitely non-lacunar AIS.

The data also showed no heterogeneity of treatment effects on all outcomes for definite/probable lacunar versus non-lacunar AIS after adjustment for baseline covariables (all Pinteraction ≥.07).

There was 1 case of sICH (0.9%) meeting NINDS and the third International Stroke Trial (IST-3) criteria in participants with definite lacunar AIS treated by low-dose alteplase, but no cases of sICH were observed after use of standard-dose alteplase. A total of 3 participants with definite lacunar AIS who received low-dose alteplase had adjudicated ICH and 1 more was reported by a site investigator, while any ICH occurred in 2 (2.2%) participants with definite lacunar AIS in the standard-dose group.

Anderson and colleagues also observed a small subset population of patients with definite lacunar AIS identified at baseline with the size <15 mm and no adjudicated large vessel occlusion (LVO). Four of the 9 participants (44.4%) in the low-dose group within this analysis and 2 of the 7 participants (28.6%) in the standard-dose group had mRS 2-6 at 90 days post-randomization, with no ICH occurring in either group.

Anderson has a history of evaluating stroke and efficacy outcomes with alteplase. In 2018, he published data showed that patients with right hemispheric AIS are more likely to experience sICH after IV alteplase than those with left hemispheric AIS.2 To make their assessment, Anderson and colleagues took data from patients included in the original ENCHANTED study, which reported significantly fewer sICH’s associated with low-dose alteplase, and compared patients with right hemispheric and left hemispheric AIS.³

At the time of the previously published data in 2018, he told NeurologyLive, “The findings were of no difference in the severity of stroke, but of differences in the risk factors (ie hypertension and previous stroke) and patterns of the changes between the left and right hemisphere of patients. However, these differences did not translate into any differences in the patterns of recovery from using intravenous alteplase, although those with an acute ischemic stroke affecting the right hemisphere tended to be more likely to have the bleeding complication of symptomatic intracerebral hemorrhage.”

REFERENCES

1. Zhou Z, Delcourt C,Xia C, et al. Low- versus standard-dose alteplase in acute lacunar ischemic stroke: the ENCHANTED trial. Neurology. Published online February 3, 2021. doi: 10.1212/WNL.0000000000011598

2. S, Carcel C, Wang X, et al. Comparison between right and left acute ischemic stroke patients treated with intravenous alteplase in the ENCHANTED trial. Presented at: STROKE 2018; August 8, 2018; Sydney, Australia. Accessed February 17, 2021.

3. Anderson CS, Robinson TG, Lindley RI, et. al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med. 2016; 374:2313-2323. Doi: 10.1056/NEJMoa1515510.