Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy

Abstract

Objective: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy.

Methods: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity.

Results: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001).

Interpretation: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Conflict of interest statement

A.C. reports stock from FreeOx Biotech and has received speaker honoraria from Boehringer Ingelheim. All other authors declare that they have no conflicts of interest regarding this work.

© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

FIGURE 1

(A) Flowchart of the study. (B) Image analysis diagram. CBF = cerebral blood flow; CT = computed tomography; CTP = CT perfusion; DT = delay time; DWI = diffusion‐weighted imaging; eTICI = expanded Thrombolysis in Cerebral Infarction; MR = magnetic resonance; MRI = MR imaging; MT = mechanical thrombectomy; PWI = perfusion‐weighted imaging; rCBF = regional CBF; TMAX = time to maximum.

FIGURE 2

Flow diagram of the CHOICE imaging study. ASPECTS = Alberta Stroke Program Early CT Score; MRI = magnetic resonance imaging; MRSI = magnetic resonance spectroscopic imaging; mTICI = modified Thrombolysis in Cerebral Infarction; NIHSS = National Institutes of Health Stroke Scale.

FIGURE 3

Representative cases of perfusion patterns on follow‐up magnetic resonance imaging. DWI = diffusion‐weighted imaging; PWI = perfusion‐weighted imaging; TMAX = time to maximum.

FIGURE 4

Effect of adjunct intra‐arterial alteplase on brain imaging surrogate markers. Imaging surrogate markers in patients treated with alteplase (n = 17) or placebo (n = 19) are shown in box‐whisker plot of infarct expansion ratio according to study treatment (boxes indicate 25–75% interquartile range [IQR]; central horizontal bars indicate median; outer horizontal bars indicate 10–90% IQR).

FIGURE 5

N‐Acetylaspartate (NAA) peaks according to the perfusion pattern, functional outcome, and study treatment (boxes indicate 25–75% interquartile range [IQR]; central horizontal bars indicate median; outer horizontal bars indicate 10–90% IQR). mRS = modified Rankin Scale.