IV Heparinoids and Outcome of Stroke
ABSTRACT & COMMENTARY
Source: The publications committee for the trial of ORG 10172 in acute stroke treatment (TOAST) investigators. Low molecular weight heparinoid ORG 10172 (Danaparoid), and outcome after acute ischemic stroke. JAMA 1998;279: 1265-1272.
Anticoagulation with intravenous (iv) unfractionated heparin is used to treat un- or under-anticoagulated patients with acute ischemic stroke, especially cases of progressing stroke or cardioembolic stroke. Nevertheless, the use of IV heparin remains controversial because it is not always effective and can cause serious bleeding. Low molecular weight heparins and heparinoids possess the antithrombotic characteristics of unfractionated heparin but have a lower propensity for bleeding and thrombocytopenia. The International Stroke Trial (IST) demonstrated a modest effect from subcutaneously administered heparin in preventing recurrent stroke within 14 days but no improvement in outcome.1
The present trial, TOAST, sought to test whether a low molecular weight heparinoid, ORG 10172, danaparoid, given IV would increase the likelihood of a favorable outcome at three months after acute ischemic stroke. TOAST was a randomized, double-blind, placebo-controlled, multicenter trial. Acute ischemic stroke patients were randomized to IV danaparoid or placebo given initially as a bolus within 24 hours of stroke, followed by a continuous infusion for seven days. (See Table 1.) Outcome was graded using a combination of the Glasgow Outcome Scale Score (GOSS) and a modified Barthel Index (BI). Patients with a GOSS of 1 or 2 and a BI of 12 or greater (maximum BI = 20) had a "favorable" outcome; those with a GOSS of 1 and a BI of 19 or 20 were rated as having a "very favorable" outcome.
Table 1
Characteristics of patients enrolled in TOAST
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|
|
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| Mean age, year + SD |
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| Men |
|
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| Cause of Stroke: | ||
| · Atherothrombotic |
|
|
| · Cardioembolic |
|
|
| · Small-artery occlusion |
|
|
| · Other |
|
|
| · Undetermined |
|
|
At seven days, 59% of treated and 54% of control patients had achieved a favorable outcome. The rates of very favorable outcomes were 34% and 28% among treated and control groups, respectively (P = 0.01; odds ratio 1.36, 95% confidence interval 1.06-1.73). By three months, approximately 48% of patients in each group had very favorable outcomes. For strokes due to large-artery atherosclerosis, the rates of favorable and very favorable outcomes were significantly higher among danaparoid-treated patients. (See Table 2.)
Table 2
Three-month outcomes vs. type of stroke
Outcome (%)|
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|
|
| Stroke Type |
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| Atherothrombotic
Cardioembolic Small vessel occlusion Other cause Undetermined |
|
|
* P = 0.04, OR 1.77, 95% CI 1.04-3.03
_ P = 0.02, OR 1.87, 95% CI 1.08-3.22
~ P = NS
Within 10 days of onset of treatment, serious intracranial bleeding occurred in 14 treated and four control patients (P = 0.05). Overall, 44 patients assigned to treatment with ORG 10172 and 38 patients given placebo died by three months. Two deaths in the treatment group occurred in patients who did not receive any study medication.
COMMENTARY
When all patients were grouped together irrespective of the subtype and cause of stroke, TOAST could demonstrate no treatment effect at three months, although higher rates of neurological improvement were apparent in treated patients at one week after stroke onset. A significant response to treatment was, however, evident at three months in 77 of 113 anticoagulated patients with atherothrombotic strokes. This positive response suggests that, in such patients with large intra- or extra-cranial artery atherosclerotic occlusions, IV anticoagulants may halt the progression of thrombosis or help to maintain the patency of the collateral circulation. This study does not prove the efficacy of IV heparinoid in acute ischemic stroke but does support its use in progressing strokes and perhaps also in acute partial infarcts to prevent progression. TOAST also supports those who maintain that effective treatment of patients with both fibrinolytic and antithrombotic drugs requires early, accurate determination of the subtype of stroke.2 Finally, TOAST reaffirms what was already well known, namely that the use of anticoagulants, whether heparinoids or unfractionated heparin, in acute stroke is associated with an increased risk of intracranial hemorrhage. -jjc
References
1. International Stroke Trial (IST) Collaborative Group. Lancet 1997;349:1569-1581; Neuro Alert 1997;16: 2-4.
2. Caplan LP, et al. N Engl J Med 1997;337:1309-312; Neuro Alert 1998;16:35.
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