After Acute Stroke: Hold the Heparin!
After Acute Stroke: Hold the Heparin!
Abstract & Commentary
Source: Saxena R, et al. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the international stroke trial. Stroke. 2001;32:2333-2337.
Cerebral embolism due to atrial fibrillation (AF) accounts for approximately 20% of acute ischemic strokes (Kittner SJ, et al. Neurology. 1990;40: 281-284). The reported risk of recurrent stroke among patients with AF varies between 10% and 20% during the first year (Cerebral Embolism Task Force. Arch Neurol. 1989;46:727-743). The risk of early recurrence is between 0.1% and 1.3% per day during the first 2 weeks after the initial stroke (Hart RG, et al. Stroke. 1983;14: 688-693). Acute ischemic stroke patients with AF also have a higher risk of early death and more morbidity compared to patients in sinus rhythm (International Stroke Trial Collaborative Group. Lancet. 1997;349: 1569-1581).
Saxena and colleagues used data from the International Stroke Trial (IST) to determine whether the higher case fatality in AF patients was related to clinical features such as a higher frequency of large cortical infarcts and concomitant ischemic heart disease, or to a higher frequency of early recurrent stroke. They also studied the effect of heparin therapy on the risk of recurrent ischemic stroke and intracranial hemorrhage (ICH) in patients with AF.
IST comprised more than 18,000 patients of whom more than 3000 (17%) had AF. Patients with AF were allocated to 3 treatment groups: 784 received high-dose unfractionated heparin (UFH) (12,500 IU SC twice daily); 773 received low-dose UFH (5000 IU SC twice daily); and 1612 received no heparin. Within each group, half of the patients were randomly assigned to treatment with aspirin (ASA) 300 mg daily. Treatment with UFH was started within 48 hours and continued until 14 days after stroke onset.
Compared to patients without AF, patients with AF were more likely to be female (55% vs 45%), to be older (mean age, 79 vs 71 years), and to have impaired consciousness (37% vs 20%). In AF patients, the initial stroke more often was a large infarct (36% vs 21%) and, therefore, they were more likely to die from the neurological effects of the stroke, from pneumonia, coronary artery disease, and pulmonary embolism, as well as from early recurrent stroke. The risk of recurrent ischemic stroke within 14 days was low and not altered by the presence or absence of AF: 123 (3.9%) in patients with AF, 500 (3.3%) in patients without AF.
The frequency of events among the 3 treatment groups is shown in the Table. Saxena et al found no evidence of an interaction effect between ASA and UFH and, therefore, did not exclude patients who received ASA from analysis. Although the high-dose UFH was associated with the fewest recurrent strokes, the benefit of heparin was offset by a significant and dose-dependent increase in the risk of ICH. There was no benefit from heparin on death and disability at 6 months.
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Commentary
Saxena et al found that in patients with AF and acute ischemic stroke, the risk of major recurrent stroke is lower than many clinicians have thought and feared. Heparinization, even with subcutaneously administered UFH rather than intravenous heparin, carries a significant, dose-dependent risk of symptomatic ICH. Therefore, in many acute stroke patients with AF, ASA offers a safe and effective treatment option for preventing early recurrent stroke before oral anticoagulation is instituted or achieves therapeutic levels.
Oral anticoagulant therapy remains the most effective, chronic means of primary and secondary prevention of embolic stroke. Nevertheless, the best time to begin anticoagulants after stroke remains uncertain and, therefore, depends upon preference and tradition in most cases. Many clinicians use heparin during the acute phase of stroke to prevent early recurrence and, some believe, to prevent stroke progression and improve outcome.
In the past, the inconvenience of intravenous heparin treatment and the danger of overanticoagulation led many clinicians to delay anticoagulation for days or omit heparin altogether in favor of slow-onset warfarin anticoagulation.
Today, the ease of using subcutaneously administered UFH has dramatically increased the incidence of acute anticoagulation of ischemic stroke patients who are not candidates for thrombolytic treatment. The editors hope that the information provided by Saxena et al on the lack of efficacy and the dangers of heparin therapy will dampen the current enthusiasm for its use. —John J. Caronna
Dr. Caronna, Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, is Associate Editor of Neurology Alert.
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