Burton J. Tabaac, MD
The following discussion is documented via “LIVE Blogging,” a Journal Club held at Johns Hopkins Hospital in Baltimore, Maryland, on May 14, 2019. The journal article presented is “Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke,” published in The New England Journal of Medicine on May 9, 2019. The Journal Club presentation and discussion was led by Dr. Rebecca Gottesman, a neurology professor, cerebrovascular specialist, and International Stroke Conference 2019 award recipient.
Current American Heart Association/American Stroke Association guidelines for ischemic stroke limit the time to initiate intravenous thrombolytic therapy to within 4.5 hours after the onset of stroke. Representatives from the EXTEND trial and collaborators from the University of Melbourne, Royal Melbourne Hospital, in Australia published an article that challenges this limit. By carefully selecting the appropriate patient population using advanced imaging, patients who have salvageable brain tissue beyond 4.5 hours may benefit from treatment via IV thrombolysis! The authors tested the hypothesis that “intravenous thrombolysis with alteplase initiated between 4.5 and 9.0 hours after stroke onset or on awakening with stroke symptoms (for which the time of onset was not known) would provide a benefit in patients who had a small core volume of cerebral infarction that was disproportionate to a larger area of hypoperfusion.”
This paradigm change to carefully select the appropriate patients who may benefit from therapy outside current guidelines parallels a similar historical trajectory to that of endovascular intervention in treating large vessel occlusion. For an epoch, the standard of care in approaching embolectomies relied on the patient presenting to clinical attention within 6 hours of onset and a favorable ASPECTS score on “dry” CT brain imaging. This limit was breached via conclusions drawn from the DAWN and DEFUSE 3 trials. By carefully selecting the appropriate patient population in concordance with advanced imaging (e.g., CTP, hyperacute MRI), offerable treatment was readily introduced to a much larger eligible patient population.
Dr. Gottesman underscored that the NEJM article was stopped early when the WAKE-UP stroke trial was published (May 2018). By focusing on the hypoperfused, but salvageable brain tissue, patients were selected if they had a small infarct core. This is a randomized trial between alteplase and placebo, and patients were not eligible if the investigator was considering the use of endovascular thrombectomy at the time of enrollment [involvement of the internal carotid artery (ICA), first division of the middle cerebral artery (M1), and proximal portion of the second division of the middle cerebral artery (M2)]. Patients were also excluded if their MRS (Modified Rankin scale) was greater than 2 prior to having the deficits. Patients with an NIHSS between 4-26 were included. A mismatch ratio of greater than 1.2 between the volume of hypoperfusion and the volume of the ischemic core were included, with an ischemic core volume of less than 70mL. Notably, the characteristics of the patients at baseline (Table 1) in this paper show that the median volume of irreversibly injured ischemic core tissue at initial imaging (IQR) was 4.6mL (with a range from 0-23.2mL) in the tPA group! Also in Table 1, it is shown that this study had a relatively small sample size. The primary outcome in this study is the proportion of patients with an MRS of 0 or 1 at 90 days “indicating an excellent functional outcome with a return to all usual activities.” It is important to point out that there are a number of secondary and tertiary outcomes that were not met. Patients were stratified by geographic region (Australia, New Zealand, and Asia), and by time of presentation.
In looking at the results, Dr. Gottesman brought attention to Table 2: Efficacy and Safety Outcomes. The researchers found that 35.4% of patients met the primary outcome (with 29.5% of placebo patients meeting this outcome), but this effect is more significant after adjusting for age and NIHSS. An interesting tertiary outcome, recanalization at 24hr, 67.3% of the placebo group met this outcome vs 39.4% of patients in the placebo group. Death rates were not significantly higher in the alteplase group compared to placebo with symptomatic intracranial hemorrhage within 36 hours after intervention, 6.2% vs. 0.9% in the tPA vs. placebo group, respectively. (It is important to point out that this ICH rate is similar to tPA given to patients within the 4.5 hour time window). The subgroup analysis (page 10 of the article appendix supplement) shows a much greater benefit in the patients recruited from Asia.
Dr. Victor Urrutia, the Director of the Comprehensive Stroke Center at Johns Hopkins Hospital, commented that the result obtained from this study is a step forward but remains unclear. “Although the pre-specified adjusted risk ratio for mRS 0-1 was statistically significant, the unadjusted risk ratio was not,” noted Urrutia. “A confirmatory trial is needed. Given the relatively small sample size and heterogeneity of the multitude of centers, this is not a definitive positive trial. Rather, this is a trial that emerges with good evidence that supports the necessity for further study and investigation.”