Low-Molecular-Weight Heparin vs. ASA in Patients with AF and Acute Stroke
abstract & Commentary
Source: Berge E, et al. Low molecular-weight heparin versus aspirin in patients with acute ischemic stroke and atrial fibrillation: A double-blind randomized study. Lancet 2000; 355:1205-1210.
Primary prevention trials in patients with atrial fibrillation (AF) have shown that oral anticoagulant therapy reduces the risk of stroke by up to 70%.1 After a stroke, the best time to start anticoagulant therapy is not known. Previous observational studies showed that the risk of recurrent embolic stroke was approximately 1% per day during the first two weeks after stroke onset.2
In the International Stroke Trial, subgroup analysis of patients with AF given unfractioned heparin subcutaneously (sq) showed that the reduction in recurrent stroke was offset by an increase in cerebral hemorrhage.3
The Heparin in Acute Embolic Stroke Trial (HAEST) was a multicenter, randomized, double-blind trial on the effect of low-molecular-weight heparin (LMWH) 100 IU/kg sq twice daily or aspirin 160 mg daily for the treatment of 449 patients with acute ischemic stroke and AF. The study investigated whether LMWH, started within 30 hours of stroke onset, is superior to aspirin for the prevention of recurrent stroke during the first 14 days.
Patients were allocated to treatment with LMWH (dalteparin) and placebo tablets every day, or aspirin tablets every day and placebo ampules injected sq twice daily. In addition to frequent neurological evaluations, patients had brain CT scans before randomization, after seven days, and on clinical deterioration. At 14 days or earlier discharge, outcome was assessed by the Bartel Index4 and modified Rankin Scale.5 At three months, patients were assessed again by the International Stroke Trial Scale.6
The frequency of recurrent ischemic stroke during the first 14 days was 8.5% (19/224) in LMWH-treated patients vs. 7.5% (17/225) in aspirin-treated patients. The odds ratio of 1.13 (95% confidence interval 0.57-2.24) indicates no significant benefit from LMWH.
There was no significant difference between the frequency of symptomatic cerebral hemorrhage during the first 14 days in patients on LMWH 2.7% (6/224) vs. 1.8% (4/225) in patients on aspirin. The frequency of symptomatic and asymptomatic cerebral hemorrhages detected on CT scan was similar (11.6% on LMWH vs 14.2% on aspirin); however, hemorrhages in the LMWH group were more severe. LMWH was associated insignificantly with a higher frequency of progression of stroke symptoms within the first 48 hours (10.7% vs 7.6%). There were no significant differences in functional outcome or death at 14 days or three months.
The results of HAEST do not indicate that LMWH is superior to aspirin for the treatment of acute ischemic stroke in patients with AF.
Commentary
The results of the study by Berge and associates are consistent with those of other studies that showed no net benefit of unfractionated heparin,3 LMWH,7 or heparinoid8 in patients with any type of acute ischemic stroke.
The 8% incidence of early recurrent stroke in the present study is lower than in earlier observational studies1 but higher than in the recent IST3 and TOAST8 acute stroke treatment trials. Despite this relatively high incidence of stroke recurrence, Berge et al could not detect an effect of LMWH on prevention. They also found that progression of stroke symptoms until 48 hours after onset was more frequent on LMWH than on aspirin. Therefore, the results of the present study do not support the routine use of LMWH either to prevent stroke-in-evolution or early recurrence of cerebral embolism. The decision whether to use heparin in these situations remains one of personal preference. —jjc
Editor’s Note—Aside from aspirin reducing clotting mechanisms, heparinoid occasionally may inhibit platelet production to a dangerous level. Whether the early use of these factors enhances post-stroke hemorrhage is uncertain. On another note, FaxWatch Inc. on April 24, 2000, announced a prereleased danger about clopidogrel in the New England Journal of Medicine for June 15, 2000. Bennett reported that 11 patients taking the drug developed thrombolytic pupura (TTP) during or soon after treatment. The authors warned, "Physicians should be aware of the possibility of this syndrome." —jjc
References
1. Cerebral Embolism Task Force. Arch Neurol 1989;46: 727-743.
2. Adams HP Jr, et al. Stroke 1994;25:1901-1914.
3. International Stroke Trial Collaborative Group. Lancet 1997;349:1569-1581.
4. Mahoney FI, Barthel DW. N Engl J Med 1965;14:61-65.
5. Van Swieten JC, et al. Stroke 1988;19:604-607.
6. Dennis M, et al. Cerebrovasc Dis 1997;7:22-27.
7. Kay R, et al. N Engl J Med 1995;333:1588-1595.
8. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA 1998;279;1265-1272.
The use of unfractioned heparin, LMWH, or heparinoid has been shown to have a new benefit in preventing:
a. stroke in evolution.
b. cerebral hemorrhage.
c. acute recurrence of cerebral embolism.
d. early death after stroke.
e. None of the above
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