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Widely Used Therapy May Not Be Effective in Treatment of Acute Stroke

For release: Tuesday, April 21, 1998

General use of anticlotting drugs, like low-molecular-weight (LMW) heparinoids, immediately after a stroke has little effect in producing a good outcome or in preventing a second stroke in most patients, according to the results of a large clinical trial published in the April 22, 1998, issue of The Journal of the American Medical Association.*

These results may bring about a change in the way the medical community treats stroke. For many years it has been common practice to administer anticoagulants to patients immediately after a stroke in an effort to limit brain injury and to prevent recurrent strokes. However, the results of this study show that, for most patients, this therapy may not work.

"If early treatment of acute ischemic stroke with an anticoagulant like heparin does not help," says Harold P. Adams, Jr., M.D., principal investigator of the study and a professor of neurology at the University of Iowa College of Medicine in Iowa City, "then we should be treating patients with other therapies."

The study, called the Trial of Org 10172 in Acute Stroke Treatment (TOAST), was a 7-year, randomized, double-blind, placebo-controlled, multi-center study of 1,281 acute stroke patients in 36 centers across the United States. TOAST, sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), is the largest trial of an intravenously administered anticoagulant drug for treatment of acute ischemic stroke.**

The purpose of the trial was to discover the effectiveness of LMW heparinoid (danaparoid/Org 10172) combined with conventional care in improving outcomes of stroke patients at 7 days and at 3 months after stroke in comparison to conventional therapy alone. Conventional or usual management includes individualized treatment recommended by a patient's doctor, such as other medications, surgery, and/or rehabilitation including speech therapy or physical therapy.

The researchers found that at 7 days, patients receiving LMW heparinoid had a trend toward better recovery than did patients receiving only conventional therapy. However, by 3 months after stroke, the conventional therapy group had caught up with the anticoagulant group and both groups were doing equally well. About 75 percent of patients in each group experienced a positive outcome at 3 months, a higher rate than that reported in other similar stroke trials. Patients reached a good outcome if they received a good score on two scales: a score of I or II on the Glasgow Outcome Scale and a score of 12 to 20 (out of 20) on the modified Barthel Index. The investigators noted worsening in the condition within the first week in about 10 percent of patients in both groups. Less than two percent of patients in both groups had a recurrent stroke within the first week after the initial stroke. Thus, the urgency for treatment with anticoagulants to prevent recurrent stroke may not be as great as previously thought.

"Physicians need to reconsider when they should use heparin," says John Marler, M.D., a neurologist in the Division of Stroke, Trauma, and Neurodegenerative Disorders at the NINDS, "especially considering the availability of other acute stroke treatments."

The use of the LMW heparinoid may have a positive effect in a certain group of stroke patients, those with large artery atherosclerosis, a disease in which fatty materials (plaque) build up on the inside of the walls of large arteries, such as the large carotid arteries in the neck that carry the majority of blood to the brain. As part of the trial, the investigators established a guideline to classify different subtypes of ischemic stroke, such as strokes secondary to clots arising in the heart. This set of guidelines, called the TOAST Stroke Subtype Classification, is now widely used in other clinical stroke trials.

Stroke often results when blood clots form on the surface of the plaques in the arteries. The blood clot may close off the artery entirely or a piece of the clot may break off and travel to the brain (embolism). For many years, medications such as antiplatelets (for example, aspirin) and anticoagulants (for example, warfarin) have been used to prevent stroke in high-risk persons. However, the value of giving these medications to patients once a stroke had occurred was uncertain. Anticoagulants, such as heparin or danaparoid/Org 10172, prevent formation of clots and, because they act immediately, they might be helpful in an emergency situation such as stroke.

Unfortunately, heparin has potentially dangerous side effects, such as an increased risk of bleeding. The LMW heparins and heparinoids are newer anticoagulants which are effective in preventing deep vein thrombosis (large vein blood clots) in stroke patients and they appear safer than unfractionated heparin, an older form of heparin. Still, these newer agents also carry risks, primarily bleeding, especially in the area of the brain where the stroke occurred. In the TOAST trial, patients receiving the LMW heparinoid had a higher rate of bleeding than did patients who received conventional treatment alone.

The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.

*Adams, H.P., Jr.; Woolson, R.F.; Helgason, C.; Karanjia, P.N.; Gordon, D.L. "Low Molecular Weight Heparinoid, Org 10172, and Outcome After Acute Ischemic Stroke. A Randomized Controlled Trial." JAMA, Vol. 279, No. 16, April 22/29, 1998, pp. 1265-1272.

**Adams, H.P., Jr., Bendixen, B.H., Kappelle, L.J., Biller, J., Love, B.B., Gordon, D.L., Marsh, E.E., and the TOAST Investigators: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Stroke 24: 35-41, 1993.

Originally prepared by Marcia Vital, NINDS Office of Communications and Public Liaison.

Last Modified August 7, 2009