DEFUSE 3: Late-Stroke Thrombectomy Benefits All Subgroups

January 31, 2019

Endovascular therapy should not be withheld because of old age, mild symptoms, or late presentation in patients with large-vessel strokes and salvageable tissue on perfusion imaging, subgroup analysis of the DEFUSE 3 trial suggests. 

The DEFUSE 3 randomized trial, presented last year at the International Stroke Conference (ISC) 2018, and published in the New England Journal of Medicineat that time, demonstrated benefit of endovascular thrombectomy for acute ischemic stroke in the 6- to 16-hour time window for patients shown to have salvageable brain tissue on imaging.  

Subgroup results from the trial were published online January 28 in JAMA Neurology.

"Endovascular thrombectomy, initiated up to 16 hours after last known well time in patients with salvageable tissue on perfusion imaging, benefits patients with a broad range of clinical features," the authors conclude. 

The researchers, led by Maarten G. Lansberg, MD, PhD, of Stanford University Medical Center and Stanford Stroke Center, Palo Alto, California, say it is important to know if the treatment benefit of latethrombectomy is universal.

"As these findings are translated into clinical practice, a fundamental question is whether the benefits of thrombectomy apply to diverse patient subgroups, including very elderly persons, patients with mild symptoms, and patients who present toward the end of the 16-hour time window," they write. 

"Furthermore, there is uncertainty regarding whether magnetic resonance imaging (MRI) or computed tomography (CT) perfusion is the optimal imaging modality for evaluation of late window patients, and whether both patients with middle cerebral artery (MCA) and internal carotid artery (ICA) occlusion have similar treatment benefits. The goal of this study is to examine if the benefit of thrombectomy is uniform among diverse patient subgroups," the authors add. 

This study included 182 patients (median age 70; median National Institutes of Health Stroke Scale [NIHSS] score 16; 51% women). In the overall cohort, independent predictors of better functional outcome were younger age, lower baseline NIHSS score, and lower serum glucose level. 

The odds ratio (OR) for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1 (95% confidence interval [CI] 1.8 - 5.4).

Results of the current subgroup analysis showed that the treatment effect was not significantly modified by age, symptom severity (NIHSS score), time to randomization, arterial occlusive lesion location (internal carotid artery or middle cerebral artery), or imaging modality (CT or MRI). 

Specifically, there was no significant interaction between the treatment effect and age (P= .93), NIHSS score (P= .87), time to randomization (P= .56), imaging modality (P= .49), or location of the arterial occlusion (P= .54).

The probability of being functionally independent (modified Rankin Scale [mRS] score of 2 or less at day 90), the secondary study endpoint, declined with older age and higher NIHSS score in both the endovascular and medical treatment arms. 

"This study demonstrates worse functional outcomes in patients who are older, have more severe symptoms on presentation (higher NIHSS score), and have higher serum glucose, but does not show modification of the treatment effect according to these or other baseline variables," the authors state.  

"The proportional benefit of endovascular thrombectomy is uniform across patients with a wide range in age, symptom severity, and time from stroke onset-to-randomization, and also does not differ according to the location of the arterial occlusive lesion and the imaging modality used for patient selection," they add. However, differences do exist in the absolute treatment benefit (the increase in the probability of achieving a desired functional outcome) across patients. 

The researchers say their results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy provided that the patient is fully independent prior to stroke onset. 

"In DEFUSE 3, only about 20% of very elderly persons achieved functional independence following thrombectomy; however, the rate in the medical control group was nearly 0," they note.  

In terms of stroke severity, while the proportional benefits were similar, patients with low NIHSS scores experienced a substantial absolute benefit in their chance of achieving functional independence, but had no reduction in mortality, whereas patients with high NIHSS scores experienced a very limited benefit in functional independence but did have a reduction in mortality and severe disability.  

In another analysis, both patients with ICA and MCA occlusions who had endovascular therapy were more likely to achieve functional independence (mRS score 0-2) than those treated medically (OR,10.6 for ICA; 6.0 for MCA).  

Analysis stratified by imaging modality showed an adjusted OR for functional independence of 11.9 for patients selected with MRI and 6.1 for patients selected with CT.

"These results indicate that both CT and MRI perfusion can be used for patient selection and that patients with ICA and MCA occlusions are suitable candidates for late window endovascular therapy," the researchers say. 

Time Since Stroke Onset 

Results also show that among patients with known time of stroke onset, there was no attenuation of the treatment effect with increasing time between stroke onset and randomization.  

The authors suggest this is likely explained by the requirement for all enrolled patients to have substantial volume of salvageable tissue, known as the penumbra, and a small ischemic core on perfusion imaging.

But they stress that these findings should not be used as a justification to treat late-presenting patients with less urgency than those patients presenting early.

"Since the ischemic core grows with time and the penumbra thus shrinks with time,a patient's chance of having a substantial volume of salvageable tissue that fulfills criteria for late-window endovascular therapy decreases if imaging is delayed," they write.   

They also caution that while no differences in treatment effects between patient subgroups were found in this analysis, it is possible that small differences went undetected owing to the small sample size of this study. These results therefore warrant validation in other trials of late-window endovascular therapy.

The study was funded by grants from the National Institute for Neurological Disorders and Stroke. Lansberg has disclosed no relevant financial relationships.  

JAMA Neurology. Published online January 28, 2019.  Abstract.   

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