December 17, 2020

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.

September 3, 2020

Background: The risk of a subsequent ischemic stroke in the first few months after an acute ischemic stroke or transient ischemic attack is approximately 5 to 10%. In these patients Aspirin has been used to prevent secondary ischemia, and trials have shown a reduced risk thereof when the P2Y12 receptor blocking antiplatelet agent Clopidogrel is added. Clopidogrel, however, requires hepatic conversion to its active form through a pathway that is inefficient in 25% of white and 60% of Asian patients and efficacy is uncertain in these patients. Not dependent on metabolic activation is the direct-acting ticagrelor with similar P2Y12 receptor blocking effect. While a trial of ticagrelor alone did not show benefit over aspirin; in their sub-group analysis of patients who had received aspirin within 7 days before randomization, treatment with ticagrelor may have reduced the risk of major vascular events. This finding suggested that the effect of aspirin received before entry into the trial might have persisted for several days after treatment and that the combination of ticagrelor and aspirin may prevent subsequent strokes.

July 27, 2020

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.

June 18, 2020

Background: Here we go again with another “Time is Brain,” acute ischemic stroke study.  The authors start out by saying that earlier administration of intravenous tPA in acute ischemic stroke is associated with reduced mortality by the time of hospital discharge and better functional outcomes at 3 months.  These statements are based on flawed studies [3][4] (Check out Ken Milne discussing these issues HERE). Additionally, tPA has not been demonstrated to decrease mortality in any randomized clinical trial though it does increase early mortality. If you can’t tell, I am very skeptical about the spin of this trial.

February 6, 2020

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.