Intravenous Alteplase Is Safe, Improves Functional Outcomes in Lacunar Infarct

Pooja Khatri, MD, Professor of Neurology, Director of Acute Stroke, University of Cincinnati Health

Pooja Khatri, MD

The results of a recent post hoc analysis of the WAKE-UP trial indicate that functional outcome following intravenous alteplase does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.

A numerically higher rate of favorable outcome at 90 days was more likely in those subjects randomized to alteplase with lacunar infarcts compared to those with nonlacunar infarcts (59% vs. 46%, respectively). A numerical shift toward better outcomes across all categories of the modified Rankin Scale (mRS) was also reported.¹

“This new clarity regarding thrombolysis efficacy in lacunar infarction complicates the real-world landscape for selecting patients for thrombolysis more than 4.5 hours from last known well,” Pooja Khatri, MD, MSc, professor of neurology and director of acute stroke, at University of Cincinnati Gardner Neuroscience Institute, said in an accompanying editorial.² “We are now left with a logistically challenging new imaging landscape for selecting patients with acute ischemic stroke who are more than 4.5 hours from their last known well for thrombolysis. Emergency departments that have a policy of using CT imaging first will have to take many patients without occlusions visualized on CT angiography to the MRI scanner expeditiously, to avoid missing patients with lacunar infarcts. An MRI approach, which can consider mismatch strategies of perfusion-weighted imaging vs. diffusion-weighted imaging and diffusion-weighted imaging vs. fluid-attenuated inversion recovery sequences at the same time, may be the most inclusive and efficient approach for the largest proportion of patients.”

In a secondary post hoc analysis of the WAKE-UP trial, researchers sought to study the efficacy and safety of intravenous thrombolysis among those with lacunar infarcts diagnosed on prerandomization MRI.

This analysis included patients screened and enrolled between September 2012 and June 2017. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts; diagnosis was based on MRI and made by consensus of 2 independent investigators. Of th 503 patients, 108 patients, which included 74 men, had imaging-defined lacunar infarcts, whereas 395 patients, including 251 men, had nonlacunar infarcts. The researchers reported that patients with lacunar infarcts were younger than patients with nonlacunar infarcts (P =.003).

Of the 108 patients with imaging-defined lacunar infarcts, 50.9% (n=55) were assigned to treatment with alteplase and 49.1% (n=53) to the control. Infusion was not given or completed in 6 patients: 3 patients in the alteplase group and 3 patients in the placebo group.

The primary endpoint included favorable outcome defined as a score of 0 or 1 point on the mRS after stroke, adjusted for age and symptom severity. Secondary outcomes were ordinal analysis of the mRS, treatment response associating outcome on the mRS with stroke severity at baseline, functional health status and quality of life assessed by EuroQol-5 Dimensions at 90 days after stroke, and a global outcome score of patients who attained good outcome on 4 scales—mRS score, 0 to 1 point; National Institutes of Health Stroke Scale (NIHSS), 0 to 1 point; Barhel Index score, 95—100 points; and the Glasgow Outcome Scale, 5 points.

The safety outcome measures included mortality and death or dependence; the incidence of symptomatic intracranial hemorrhage (SICH) according to protocols of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), European Cooperative Acute Stroke Study II (ECASS II), ECASS III, and the National Institute of Neurological Disease and Stroke; and parenchymal hemorrhage type 2 on follow-up imaging 22 to 36 hours after treatment.

According to the results, treatment with alteplase was associated with higher odds of favorable outcome with no heterogeneity of treatment outcome for stroke subtypes and was observed in 31 of 53 patients (59%) with lacunar strokes compared with 24 of 52 patients (46%) in the placebo group (P =.20). The distribution of mRS scores at 90 days after stroke showed a nonsignificant difference in outcomes (P =.07). The analysis of treatment response demonstrated a significant benefit of treatment with alteplase observed in 36% (n=19) of patients in the alteplase group compared with 14% (n=7) of patients in the placebo group (P =.009).

“For patients with lacunar infarct, intravenous alteplase was associated with better scores on the mRS and a shift toward better outcomes across all categories of the mRS compared to placebo,” wrote Ewgenia Barow, MD, of University Medical Center Hamburg-Eppendorf Martinistra, and colleagues. “A similar trend favoring treatment with alteplase was observed for the other clinical end points assessed, such as the global outcome score or health- associated quality of life assessed by the EuroQol5 Dimensions.”

At 90 days, there was 1 death in the alteplase group, while there were no deaths reported in the placebo group. Death or dependence occurred in 4 (8%) patients in both the alteplase and placebo groups. One case of SICH was reported in the alteplase group, while none were observed in the placebo group.

“The WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients,” Barow and colleagues concluded. “However, these results suggest that intravenous alteplase is safe and improves functional outcome in patients with lacunar infarct with a similar outcome as in patients with other stroke subtypes.”

REFERENCE

1. Khatri P. Thrombolysis Works in Lacunar Infarct, Complicating Imaging Selection. Jama Neurol. 2019: e1­—e2.

doi

: 10.1001/jamaneurol.2019.0214.

2. Barow E, Boutitie F, Cheng B, et al. Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial. JAMA Neurol. 2019: e1­—e9.

doi

: 10.1001/jamaneurol.2019.0351.