Does Long-Term Anticoagulation Improve Function After Stroke?

DAN BREWER, M.D., University of Tennessee Graduate School of Medicine, Knoxville, Tennessee

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation to help clinicians put evidence into practice. Dan Brewer, M.D., presents a clinical scenario and question based on the Cochrane Abstract, along with an evidence-based answer and a full critique of the abstract.

Clinical Scenario

A 70-year-old man with normal sinus rhythm had a thrombotic stroke that resulted in weakness in his non-dominant hand and leg.

Clinical Question

Should this patient receive long-term anticoagulation to improve function or reduce the possibility of recurrent vascular events and death?

Evidence-Based Answer

There is no evidence that anticoagulation with either heparin or warfarin improves these outcomes. There is clear evidence of increased hemorrhagic complications (both fatal and nonfatal) in patients who receive anticoagulation.

Cochrane Abstract Background. After a first ischemic stroke, further vascular events resulting from thromboembolism (especially myocardial infarction and recurrent stroke) are common and often fatal. Anticoagulants potentially could reduce the risk of such events, but any benefits could be offset by an increased risk of fatal or disabling hemorrhages. Objectives. The objective of this review1 was to assess the effect of prolonged anticoagulant therapy (compared with placebo or open control) following presumed non-cardioembolic ischemic stroke or transient ischemic attack. Search Strategy. The authors searched the Cochrane Stroke Group trials register. They contacted companies marketing anticoagulant agents. The most recent search for this review was carried out in August 2002. Selection Criteria. Randomized and quasi-randomized trials comparing at least one month of anticoagulant therapy with control in persons with previous presumed non-cardioembolic ischemic stroke or transient ischemic attack were included. Data Collection and Analysis. Two reviewers independently selected trials for inclusion, assessed trial quality, and extracted the data. Primary Results. Eleven trials involving 2,487 patients were included. The quality of the nine trials that predated routine computerized tomographic scanning and use of the International Normalized Ratio to monitor anticoagulation was poor. There was no evidence of an effect of anticoagulant therapy on the odds of death or dependency (two trials, odds ratio [OR], 0.83; 95 percent confidence interval [CI], 0.52 to 1.34) or of "nonfatal stroke, myocardial infarction, or vascular death" (four trials, OR, 0.96; 95 percent CI, 0.68 to 1.37). Death from any cause (OR, 0.95; 95 percent CI, 0.73 to 1.24) and death from vascular causes (OR, 0.86; 95 percent CI, 0.66 to 1.13) were not significantly different between treatment and control groups. The inclusion of two recently completed trials did not alter these conclusions. There was no evidence of an effect of anticoagulant therapy on the risk of recurrent ischemic stroke (OR, 0.85; 95 percent CI, 0.66 to 1.09). However, anticoagulants increased fatal intracranial hemorrhage (OR, 2.54; 95 percent CI, 1.19 to 5.45), and major extracranial hemorrhage (OR, 3.43; 95 percent CI, 1.94 to 6.08). This is equivalent to anticoagulant therapy causing about 11 additional fatal intracranial hemorrhages and 25 additional major extracranial hemorrhages per year for every 1,000 patients given anticoagulant therapy. Reviewers' Conclusions. Compared with control, there was no evidence of benefit from long-term anticoagulant therapy in persons with presumed non-cardioembolic ischemic stroke or transient ischemic attack, but there was a significant bleeding risk. These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Cochrane Critique

Did the author address a focused clinical question? Yes. Several other reviews in the Cochrane Stroke Group address specific issues such as acute anticoagulation, anticoagulant versus antiplatelet therapy, and anticoagulation in atrial fibrillation.

Were the criteria used to select articles for inclusion appropriate? Yes.

Is it likely that important relevant articles were missed? No. A search for unpublished articles, including those by relevant pharmaceutical manufacturers, was conducted.

Was the validity of the individual articles appraised? Yes.

Were the assessments of studies reproducible? Yes.

Were the results similar from study to study? Yes.

How precise were the results? The results on hemorrhage, recurrent stroke, and death are robust. Other end points, such as recurrent vascular events and function, are more difficult to base conclusions on because of the differing definitions and methods of the included trials.

Can the results be applied to patient care? Yes.

Do the conclusions make clinical and biologic sense? Yes.

Are the benefits worth the harms and costs? The review recommends against this intervention, so no extra cost is involved. There are significant cost savings.

Practice Pointers

There are about 4.6 million stroke survivors in the United States today, and 600,000 people have new strokes each year. These patients are at increased risk of recurrent stroke, other vascular events, dependency, and death.² Patients whose strokes had a cardioembolic source (e.g., atrial fibrillation) generally should receive anticoagulation for secondary prevention, but the appropriate treatment is more controversial in patients with thrombotic strokes. One survey³ noted that 53 percent of randomly selected U.S. physicians always or often prescribe an anticoagulant for patients with transient ischemic attack or recent minor stroke.

This review shows that there is no convincing evidence that prolonged anticoagulation is beneficial following presumed noncardioembolic stroke or transient ischemic attack. There is, however, convincing evidence that anticoagulation increases the rate of fatal intracranial hemorrhages and major extracranial hemorrhages. A separate Cochrane review⁴ and a recent joint American Heart Association/American Academy of Neurology committee⁵ found no evidence of benefit from anticoagulation within 48 hours from the onset of stroke. A third Cochrane review⁶ found no additional benefit from adding anticoagulant therapy to antiplatelet therapy.

Anticoagulant therapy has a narrow therapeutic window and is a difficult regimen to manage in a consistently safe manner. This is especially true in elderly patients, who have a higher rate of hemorrhagic complications and who often are on complex medical regimens with increased risk of drug-drug interactions. Although as physicians we want to be able to intervene to reduce the suffering of patients with stroke, the best course is to use antiplatelet therapy instead of anticoagulation.

Dan Brewer, M.D., is associate professor in the Department of Family Medicine at the University of Tennessee Graduate School of Medicine, Knoxville. He was previously in private practice in Maryville, Tenn. His interests include preventive medicine, especially in the area of cardiovascular diseases.

Address correspondence to Dan Brewer, M.D., University of Tennessee Graduate School of Medicine, Department of Family Medicine, 1924 Alcoa Hwy., Knoxville, TN 37920 (e-mail: dbrewer2@utk.edu). Reprints are not available from the author.

REFERENCES

1. Sandercock P, Mielke O, Liu M, Counsell C. Anticoagulants for preventing recurrence following presumed non-cardioembolic ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev 2003:CD000248.
2. American Heart Association. 2002 heart and stroke statistical update. Dallas, Tex.: The Association, 2001.
3. Goldstein LB, Farmer A, Matchar DB. Primary care physician-reported secondary and tertiary stroke prevention practices. A comparison between the United States and the United Kingdom. Stroke 1997;28:746-51.
4. Gubitz G, Counsell C, Sandercock P, Signorini D. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2003:CD000024.
5. Coull BM, Williams LS, Goldstein LB, Meschia JF, Heitzman D, Chaturvedi S, et al. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Stroke 2002;33:1934-42.
6. Berge E. Sandercock P. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database Syst Rev, 2003:CD003242.