A 2010 meta-analysis looked specifically at outcomes in stroke based on time to treat with alteplase using pooled data from the NINDS, ATLANTIS, ECASS (1, 2, and 3), and EPITHET trials.9 It showed that the number needed to treat for a favorable outcome at three months increased steadily when time to treatment was delayed. It also showed that the risk of death after alteplase administration increased significantly after 4.5 hours. Thus, after 4.5 hours, it suggests that harm might exceed the benefits of treatment.
Anticoagulant use in ischemic stroke. Clinical trials have not been effective in demonstrating the use of heparin and low-molecular-weight heparins (LMWHs). A 2008 systematic review of 24 trials (approximately 24,000 patients) demonstrated:
- Anticoagulant therapy did not reduce odds of death;
- Therapy was associated with nine fewer recurrent ischemic strokes per 1,000 patients, but also showed a similar increase in symptomatic intracranial hemorrhages; and
- Overall, researchers could not specify a particular anticoagulant mode or regimen that had an overall net patient benefit.
The use of heparin in atrial fibrillation and stroke has generated controversy in recent years. Review of the data, however, indicates that early treatment with heparin might cause more harm than benefit. A 2007 meta-analysis did not support the use of early anticoagulant therapy. Seven trials (4,200 patients) compared heparin or LMWH started within 48 hours to other treatments (aspirin, placebo). The study authors found:
- Nonsignificant reduction in recurrent ischemic stroke within seven to 14 days;
- Statistically significant increase in symptomatic intracranial hemorrhages; and
- Similar rates of death/disability at final follow-up of studies.
For those patients who continue to demonstrate neurological deterioration, heparin and LMWH use did not appear to improve outcomes. Therefore, based on a consensus of national guidelines, the use of full-dose anticoagulation with heparin or LMWH is not recommended.
The data suggest that in patients with stroke secondary to:
- Dissection of cervical or intracranial arteries;
- Intracardiac thrombus and valvular disease; and
- Mechanical heart valves, full-dose anticoagulation can be initiated. However, the benefit is unproven.
Back to the Case
Our patient with acute ischemic stroke with right-sided weakness on exam presented outside of the window within which alteplase could be administered safely. She was started on aspirin 325 mg daily. There was no indication for full anticoagulation with intravenous heparin or warfarin. Her weakness showed slight improvement on exam during the hospitalization. As an insulin-dependent diabetic, she was thought to be at high risk for recurrent stroke. As such, she was transitioned to a combination of aspirin and clopidogrel prior to her discharge to an acute inpatient rehabilitation hospital.
Early aspirin therapy (within 48 hours) is recommended (initial dose 325 mg, then 150 mg-325 mg daily) for patients with ischemic stroke who are not candidates for alteplase, IV heparin, or oral anticoagulants.10 Aspirin is the only antiplatelet agent that has been shown to be effective for the early treatment of acute ischemic stroke. In patients without contraindications, aspirin, the combination of aspirin-dipyradimole, or clopidogrel is appropriate for secondary prevention.
The subset of patients at high risk of recurrent stroke should be transitioned to clopidogrel or aspirin/clopidogrel, unless otherwise contraindicated. TH
Dr. Chaturvedi is an instructor in the Division of Hospital Medicine at Northwestern University’s Feinberg School of Medicine in Chicago, and medical director of HM at Northwestern Lake Forest Hospital. Dr. Abraham is an instructor in the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine.