Background: Intravenous alteplase is the current standard care for treatment of acute ischemic stroke (AIS) despite active debate on the research supporting its use. The window for its use has been restricted to <3h of symptom onset based on the results of the NINDS trial and extended to a time window of <4.5h based on the results of the ECASS-3 trial. Both studies excluded patients with unknown time of onset and these patients are excluded from consideration for thrombolytics in real life as well. These trials are the only randomized studies showing benefit of intravenous alteplase vs placebo in acute ischemic stroke to date. Of note, both of these trials have undergone reanalysis calling the validity of their results into question. Despite which side of the debate you fall on, stroke care has moved on with advanced perfusion imaging and thrombectomy in large vessel occlusion strokes. Increased use of perfusion imaging has challenged the idea that time is a critical determinant of which patients should be considered for thrombolytics....Read More
Background: The scientific process in medicine is complicated. Obtaining high-quality data to guide management requires hypothesis formulation, data to support the hypothesis and study replication. Time and again beneficial findings in therapeutic studies fail to be replicated in subsequent studies. A single positive trial may cause some to feel it unethical to assign patients to a standard therapy that could potentially deprive them of benefit. Alternatively, pharmaceutical companies have little impetus to attempt or support collecting additional data that may jeopardize their product. In research, repetition is the pillar on which clinical trials results should be founded on. As this may not be feasible, complete transparency of all aspects of a trial are essential.
One of the most hotly debated topics in emergency medicine is the use of systemic thrombolysis in acute ischemic stroke. There are only two randomized clinical trials that demonstrate benefit in neurologic outcomes: NINDS-II and ECASS-III (see table below). Methodological experts, however, have raised concerns that both studies had baseline imbalances in stroke severity that may have biased the trials final results. Both studies have undergone re-analysis taking these baseline differences into account....Read More
Background Information: The administration of alteplase (tPA) in acute ischemic stroke (AIS) continues to remain a highly debated topic. As hospital systems continue to undergo major changes to facilitate this controversial drug’s administration, more studies are coming out focusing on neuroimaging and how it plays a role in the time window of AIS. The WAKE-UP trial was one of the first studies to identify MRI patterns suggestive of a stroke in patient whose onset time was unknown.1,2 Over the past 10+ years, other studies have also attempted to identify the role of advanced neuroimaging guiding tPA administration for improved functional outcomes. The authors conducted a meta-analysis to test the hypothesis that tPA improves functional outcomes compared with placebo 4.5 - 9 hours after onset in AIS patients who received advanced neuroimaging. Before getting into the study, we need to better understand the terminology and different types of neuroimaging modalities available and how they play a role in strokes.
Background: Currently, alteplase is the mainstay of treatment of acute ischemic stroke. Advocates of alteplase suggest that the benefit of alteplase is greatest when given early and declines with increasing time from stroke symptom onset (i.e. time is brain). Therefore, the AHA/ASA guidelines recommend intravenous alteplase within 4.5 hours after stroke onset, which is based on very weak evidence (i.e. NINDS & ECASS III).
Due to weak evidence in support of it’s use and significant patient risks associated with alteplase, it’s use in acute ischemic stroke remains controversial. One of the big issues is that by decreasing the time for evaluation and treatment, there is an increased risk of administrating alteplase to patients presenting with noncerebrovascular conditions that can resemble an acute ischemic stroke (i.e. stroke mimics). This puts patients with no chance of improvement with alteplase at risk for increased mortality and symptomatic ICH. There is some limited data on the safety of alteplase in stroke mimics and this study adds to that knowledge....Read More
Background: No matter which side of the debate you sit on in regard to systemic thrombolysis in acute ischemic stroke (AIS), there is one truth: systems have undergone major changes to ensure tPA is offered to patients in the ≤4.5-hour window. The debate surrounding tPA in AIS lies in the equipoise surrounding benefits while there are very real harms. Advocates of tPA in AIS hang on to two trials that have never been replicated (i.e. NINDS and ECASS-III), and both have major methodological issues. Skeptics of tPA in AIS appropriately argue that there are 11 other randomized clinical trials which have shown almost no benefit, but come at the cost of early increased early mortality and symptomatic intracranial hemorrhage (sICH) (Nice breakdown of individual trials of thrombolysis in stroke can be found at First10EM). Now there is a push to extend the window of tPA out to 9 hours in AIS with newer imaging modalities such as MRI diffusion-weighted studies in patients with unknown onset of symptoms. The push for this stems from the fact that patients with a visible ischemic lesion on diffusion-weighted imaging, combined with the absence of a clearly visible hyperintense signal in the same region on fluid-attenuated inversion recovery (FLAIR) is predictive of symptom onset within 4.5 hours before imaging....Read More