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Wednesday, August 6, 2014

More Research is Needed to Effectively Treat Symptomatic Intracerebral Hemorrhage Associated with Thrombolytic Therapy

by Rebecca Hiscott

A new meta-analysis highlights a lack of conclusive data on how to best treat symptomatic intracerebral hemorrhage (sICH) associated with thrombolysis with intravenous recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke.

intracerebral hemorrhage

Coronal section through the skull reveals intracerebral hemorrhage; the central large dark area represents the hemorrhage. (LifeART image copyright © 2014 Lippincott Williams & Wilkins.)

The study, published in the July 28 online issue of JAMA Neurology, reviewed a variety of treatment options for sICH associated with thrombolytic therapy, and concluded that current guidelines for treatment of sICH may not reverse coagulopathy early enough to prevent hematoma expansion or improve patient outcomes.

Symptomatic ICH may occur in approximately 6 percent of acute ischemic stroke patients treated with thrombolytic therapy, according to the National Institute of Neurological Disorders and Stroke tPA Study, and has a mortality rate of nearly 50 percent. The authors of the meta-analysis note that more recent studies show a lower incidence of sICH, however. Older patients, patients with very severe strokes, and those who used aspirin before a stroke are at a higher risk of sICH.

Clinical guidelines from the American Heart Association (AHA)/American Stroke Association (ASA)  currently recommend treating sICH with replacement of coagulation factors and platelets. However, the study authors note that “the scientific evidence for this recommendation is based on empirical data and extrapolation from other organ systems,” adding that “the unanswered questions on efficacy may explain the wide variability observed in clinical practice.”

In their meta-analysis, study authors Shadi Yaghi, MD, fellow with the Division of Stroke and Cerebrovascular Diseases at Columbia University, Andrew Eisenberger, MD, physician and researcher with Columbia’s Division of Hematology and Oncology, and Joshua Z. Willey, MD, MS, assistant professor of neurology in Columbia’s Department of Neurology, reviewed evidence-based peer-reviewed articles on sICH published between January 1, 1990, and February 28, 2014. Most of the literature they reviewed involved sICH associated with the anticoagulant drug warfarin, which has a different mechanism of action than rtPA, because intravenous rtPA-related sICH has not been extensively studied.

The authors note that a lack of information on how best to treat sICH may lead to the underuse of rtPA, even though it is one of the more effective treatments of acute ischemic stroke when administered within 4.5 hours of symptom onset, improving clinical outcomes at three months. “An effective treatment for sICH may increase the usefulness of intravenous rtPA in treating acute ischemic stroke,” they wrote.

Furthermore, the definition of sICH tends to vary among studies in terms of clinical and imaging characteristics, and the timing of sICH onset has not been well characterized. “With the lack of consensus defining sICH, it may be challenging to determine whether medical treatment for sICH is effective,” the authors added.

They reviewed the efficacy of various treatment options to prevent hematoma expansion and neurologic worsening in sICH, including vitamin K, fresh frozen plasma, cryoprecipitate, prothrombin complex concentrates (PCCs), platelet transfusions, and epsilon-aminocaproic acid. “Because the coagulopathy related to rtPA may last up to 24 hours, early and sustained reversal is necessary before hematoma expansion and neurologic deterioration occurs,” they wrote. As such, common treatments such as vitamin K and fresh frozen plasma, which can take more than 24 hours to reverse coagulopathy, may be too slow to be effective.

            More promising therapies are those with a fast onset of action, such as epsilon-aminocaproic acid, recombinant factor VIIa, and PCCs, the authors wrote. However, clinical trials must still be conducted to weigh the risks versus benefits of these more aggressive treatments, they added.

Symptomatic ICH may also be associated with disruption with the blood-brain barrier, the authors noted, suggesting that treatment for thrombolysis-related sICH may benefit from testing in combination with neuroprotectant agents.

            In the absence of data showing a clear frontrunner for sICH treatment, the authors recommended that clinicians continue to follow the AHA/ASA treatment guidelines, despite questions of efficacy.

            For more coverage of thrombolysis-related symptomatic intracerebral hemorrhage, browse our archives here: