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Therapies for stroke are advancing rapidly, and we as emergency physicians are in the forefront of care. We have seen emergent stroke therapy rapidly progress from essentially supportive care to thrombolytics, to in some centers, emergent intra-arterial thrombolysis. As most stroke patients are seen in the emergency department, it is important for us to keep up with new and emerging therapies as they soon may play a role in our treatment and indeed become the standard of care. We can divide up the areas of major stroke research into those therapies dealing with ischemic stroke and those that are related to hemorrhagic infarction. The following is an overview of Stroke’s annual review of research (Quinn, TJ, Lees, KR. Advances in Stroke 2007. Stroke. 2008; 39:255-257.)
 
The SITS-MOST (Safe Implementation of Thrombolysis in Stroke) trial taking place in European centers is in the midst of confirming the safety and efficacy of the routine use of intravenous thrombolytics for selected patients in a three-hour window much as the NINDS trial did in the United States.

The DIAS (Desmoteplase In Acute Ischemic Stroke) study attempted to evaluate the safety and efficacy of intravenous desmoteplase, a thrombolytic agent that is very fibrin-specific and not neurotoxic. Desmoteplase was administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI, and this first trial showed a higher rate of reperfusion and better clinical outcome compared with placebo. The intracerebral hemorrhage rate was low using doses up to 125 µg/kg. The DIAS II trial attempted to build on those results. However, mortality actually increased with the 125 µg/kg dose versus both the placebo and 90 µg/kg doses. Of the 14 deaths in the 125-µg/kg group, 10 were considered to be unrelated to the treatment, 9 were “nonneurologic”, and 9 occurred more than 10 days after administration of the study drug. There was no significant systemic bleeding with treatment, however, and although there was intracerebral hemorrhage in the 2 treatment groups, the rate was apparently not high enough to explain the difference in mortality.

In contrast to the failure of DIAS II, the DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) study used MRI profiles to determine how reversible an ischemic lesion was; i.e. was there an ischemic penumbra that could be viable and thus saved after acute therapy. It attempted to predict what patient subgroups were likely to benefit from thrombolytic therapy in the 3 to 6 hour window. It based this prediction on blood flow parameters and an assessment of the degree of early ischemic brain injury for which the specialized MRI techniques of perfusion-weighted-imaging and diffusion-weighted-imaging are suited for.
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The intra-arterial administration of thrombolytic has been studied in the past and shown efficacy and a potential for a reduction in systemic effects, but a follow-up study has not been performed. In Japan the MELT trial (MCA Embolism Local fibrinolytic intervention Trial) attempted to answer whether intra-arterial thrombolysis was a feasible alternative. The secondary end points of significant middle cerebral artery recanalization, a low frequency of hemorrhage, and no difference in mortality was achieved. However, the study showed no difference in primary end point, namely, a significant proportion of patients with insignificant or no neurologic disability at 90 days.

Animal models had shown that neuroprotectants, including free-radical trapping agents, minimize injury after ischemia. One of the more promising agents - NXY-059 - had been tested in animal models of ischemic stroke and had been shown to improve functional recovery and reduce the size of cerebral infarction in those models. The SAINT-I (Stroke Acute Ischemic NXY-059) trial used NXY-059 within six hours of ischemic stroke and showed significant improvement in the primary outcome of reduced disability at 90 days. However, it failed to show any significant effect on other outcomes, including NIHSS scores. SAINT-II was initiated to confirm those results with a larger study population. The results were disappointing, as SAINT-II had equal mortality between the study and placebo groups and had no difference in adverse events. It was hoped that neuroprotective agents would be the next step in the evolution of the treatment of ischemic stroke but it seems more research is needed in this area.

Non-randomized studies had suggested that decompressive surgery reduced the 80% mortality of malignant MCA infarctions without increasing the number of severely disabled survivors. Results from three European randomized controlled trials were pooled and showed that decompressive surgery performed within 48 hours of stroke onset reduced mortality in those with malignant MCA infarction and increased the number of patients with a favorable functional outcome. Of course, the decision to perform surgery must be made individually.

Hemorrhagic stroke research too had seen its share of successes and failures. The INTERACT pilot study showed that rapid reduction of blood pressure to the goal of 140/90 mm Hg is well tolerated and is practical. The pilot FAST (Factor Seven for Acute Hemorrhagic Stroke) study had demonstrated promise in the treatment of hemorrhagic stroke, but the phase 3 results were disappointing, demonstrating cessation of bleeding yet unfortunately no change in outcome defined as proportion of patients who died or had severe disability graded as 5 or 6 on the modified Rankin Scale at 90 days.
Finally, the GIST (Glucose Insulin in Stroke Trial) showed that there was no significant reduction in mortality at 90 days in those patients who had tight control of their glucose.

These studies prove that stroke research is progressing rapidly and it is only a matter of time before some of these promising therapies wind up as part of our emergency department stroke protocol.
 
continue next for a simple, inexpensive alternative for acute CVA  
{mospagebreak title=Minocycline}
 
 
Minocycline: A simple, inexpensive alternative for acute CVA 
 
We all know minocycline works for acne, intestinal amebiasis and Rocky Mountain Spotted Fever. Now it looks like it may also work for acute stroke.

In a recent placebo-controlled, open-label, 152 patient clinical trial published in Neurology [Neurol 2007; 69:1404-1410], researchers administered 200mg of Minocycline orally to subjects with stroke for 5 days. Minocycline was given to subjects 6 to 24 hours after the onset of the stroke. Subjects were excluded from the study if they had a hemorrhagic stroke, evidence of other disease of the CNS, pre-existing neurologic disability, known allergy to tetracyclines, renal failure, an infectious disease requiring antibiotics, swallowing difficulties or if they had received systemic or intra-arterial thrombolytic therapy. The subjects were scored on days 7, 30, and 90.

The results were impressive. The minocycline-treated group saw their admission NIHSS fall from 7.5 to 1.6 at day 90 (control group fell from 7.6 on admission to 6.5 at day 90). The decreases in NIHSS at day 7, 30 and 90 were all statistically significant. However, the number of deaths due to recurrent stroke, myocardial infarction or hemorrhagic transformation between the two groups was not significant.

There are several proposed mechanisms by which minocycline may be beneficial for acute ischemic stroke, including an anti-inflammatory effect, reduction of microglial activation, and inhibition of apoptotic cell death. Further, as shown by this study and others [Stroke 2005;36:1495-1500], it is likely that the positive effect exhibited by minocycline is not shared by other antibiotics.

There are a number of limitations of this study, including the most obvious: this was an open-label, evaluator-blinded study. As the authors note, a double-blinded, placebo-controlled study is needed. Further, optimal dosages, routes and treatment times were not established in this study.

The bottom line is that with all the millions of dollars being spent on stroke research, this may be a promising, simple and inexpensive treatment for acute CVA. Further, unlike thrombolytics and other invasive therapies for stroke, minocycline appears to be low risk. Based on this one small study, it may be too early to treat ED patients with CVA with minocycline. However, it is one experimental therapy to keep your eye on.
 

-Michael Breyer, MD

 
 

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