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Aspirin vs. Heparin Therapy in Prevention of Stroke



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Am Fam Physician. 2000 Oct 15;62(8):1889-1892.

Patients with atrial fibrillation are at increased risk of stroke; these are often significant cerebrovascular events with a poor prognosis. Results from early observational trials reveal that following an initial stroke episode, patients with atrial fibrillation have an approximately 20 percent risk of recurrent stroke within two weeks. In primary prevention trials that included patients with atrial fibrillation, oral anticoagulation therapy was estimated to reduce the risk of stroke by 60 to 70 percent; however, the optimal time to initiate prophylactic anticoagulation therapy to reduce recurrence following the initial stroke is unknown. Results from the International Stroke Trial revealed that the increased risk of cerebral hemorrhage offset the benefits of anticoagulation therapy. Currently, anticoagulant therapy with heparins is widely advocated for use in patients with atrial fibrillation who survive an initial stroke, but limited research evidence is available to support the efficacy and safety of this strategy. Berge and colleagues compared subcutaneous low-molecular-weight heparin (LMWH) to oral aspirin in the prevention of early recurrent stroke in patients with atrial fibrillation.

A multicenter, randomized, double-blind trial was conducted at 45 health centers in Norway between 1996 and 1998. Adult patients more than 18 years of age were eligible if they had acute ischemic stroke and atrial fibrillation. Confirmation of atrial fibrillation had to be obtained by electrocardiography on admission or within the 24 months before the stroke onset. Randomization had to take place within 30 hours of stroke onset, with a computed tomographic (CT) scan conducted to exclude cerebral hemorrhage. Exclusions from the study included patients with serious medical conditions that might interfere with assessment, serious persistent hypertension, pregnancy and any contraindication to anticoagulation. Randomization of 449 patients occurred: 224 patients were assigned to receive 100 IU per kg of subcutaneous dalteparin, and 225 patients were assigned to receive 160 mg of aspirin twice daily for two weeks. Placebo tablets and injections were given to ensure that all patients received the same treatment formats and schedules.

Neurologic status was checked daily during the first week and every other day during the second week using the Scandinavian Stroke Scale (SSS). This assessment plus a CT scan were repeated if any clinical deterioration occurred. Testing at 14 days included several standardized scales measuring facets of functional outcome. Patients were reassessed after three months.

More women were randomized to aspirin therapy than to dalteparin therapy (61 compared with 50 percent). The aspirin- and dalteparin-treatment groups were comparable at initiation of treatment, and the mean SSS score in each group was 39. The mean duration of treatment was 13 days. The breakdown of the 90 patients (20 percent) who discontinued therapy included: 36 deaths, seven cerebral hemorrhages, five recurrent strokes or progression of symptoms, five extracerebral hemorrhages, one hip fracture, five venous thromboembolisms, nine unspecified and 22 patients with early discharge from the hospital. The groups were balanced in use of non-study treatments, and about one half of the patients in each group began oral anticoagulation before the end of the study period. Events after 14 days are provided in the accompanying table.

Events After 14 Days of Post-stroke Therapy

Event Dalteparin (%) Aspirin (%)

Recurrent ischemic stroke

19 (8.5)

17 (7.5)

Symptomatic cerebral hemorrhage

6 (2.7)

4 (1.8)

Asymptomatic and symptomatic cerebral hemorrhages

26 (11.6)

32 (14.2)

Progression of symptoms

24 (10.7)

17 (7.6)

Death, any cause

21 (9.4)

16 (7.1)

Recurrence, progression or death

51 (22.8)

36 (16.0)

Recurrence, progression, death or symptomatic cerebral hemorrhage

55 (24.6)

38 (16.9)

Extracerebral hemorrhage

13 (5.8)

4 (1.8)

Venous thromboembolism

1 (0.4)

5 (2.2)

Acute myocardial infarction

1 (0.4)

3 (1.3)

Pneumonia

15 (6.7)

16 (7.1)

Urinary tract infection

8 (3.6)

5 (2.2)


Adapted with permission from Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000;355:1207.

Events After 14 Days of Post-stroke Therapy

View Table

Events After 14 Days of Post-stroke Therapy

Event Dalteparin (%) Aspirin (%)

Recurrent ischemic stroke

19 (8.5)

17 (7.5)

Symptomatic cerebral hemorrhage

6 (2.7)

4 (1.8)

Asymptomatic and symptomatic cerebral hemorrhages

26 (11.6)

32 (14.2)

Progression of symptoms

24 (10.7)

17 (7.6)

Death, any cause

21 (9.4)

16 (7.1)

Recurrence, progression or death

51 (22.8)

36 (16.0)

Recurrence, progression, death or symptomatic cerebral hemorrhage

55 (24.6)

38 (16.9)

Extracerebral hemorrhage

13 (5.8)

4 (1.8)

Venous thromboembolism

1 (0.4)

5 (2.2)

Acute myocardial infarction

1 (0.4)

3 (1.3)

Pneumonia

15 (6.7)

16 (7.1)

Urinary tract infection

8 (3.6)

5 (2.2)


Adapted with permission from Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000;355:1207.

The authors conclude that the results of this trial do not provide evidence that high-dose LMWH is superior to aspirin in the immediate treatment of patients with acute ischemic stroke and atrial fibrillation. They suggest a strategy of treating patients with aspirin during the acute phase of the stroke and initiating short-term prophylactic treatment with low-dose LMWH for prevention of venous thromboembolism, as assessed on an individual basis. Most of these patients require long-term oral anticoagulation therapy, but the optimal time to begin this therapy following a stroke is unknown.

Berge E, et al. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet. April 8, 2000;355:1205–10.


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