COCHRANE FOR CLINICIANS: PUTTING EVIDENCE INTO PRACTICE

Are Anticoagulants Better than Antiplatelet Agents
for Treatment of Acute Ischemic Stroke?

GLENN GRIFFIN, M.D., United Arab Emirates University Faculty of Medicine and Health Sciences, Al-Ain, United Arab Emirates

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

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available at www.update-software.com/abstracts/ab003242.htm.

Clinical Scenario

Your mother-in-law just had a stroke, and the computed tomographic scan shows no evidence of hemorrhage. The neurologist in the emergency department is debating whether to use heparin or aspirin for treatment.

Clinical Question

Should aspirin, warfarin, or heparin be used to treat acute ischemic stroke?

Evidence-Based Answer

Aspirin has a small benefit for long-term outcome and survival. Anticoagulants increase the risk for bleeding and do not have long-term benefit.

Cochrane Abstract Background. Antiplatelet agents produce a small but worthwhile benefit in long-term functional outcome and survival, and they have become standard treatment for acute ischemic stroke. Anticoagulants often are used as an alternative treatment, despite evidence that they are ineffective in producing long-term benefits. The authors1 wanted to review trials that have directly compared anticoagulants and antiplatelet agents to assess whether an anticoagulant regimen offers net advantages over use of antiplatelet agents, overall or in a particular category of patients (e.g., patients with atrial fibrillation). Objectives. To assess the effectiveness of anticoagulants compared with antiplatelet agents in acute ischemic stroke and to assess whether the addition of anticoagulants to antiplatelet agents offers a net advantage over antiplatelet agents alone. Search Strategy. The authors searched the Cochrane Stroke Group Trials Register, the Cochrane Controlled Trials Register (Central/CCTR), the trials register held by the Antithrombotic Therapy Trialists' Collaboration, MEDLINE (1966-2000), and EMBASE (1980-2000). All searches were performed during April and May 2001. Selection Criteria. Truly unconfounded, randomized controlled trials comparing anticoagulants with antiplatelet agents, or a combination of anticoagulants and antiplatelet agents with antiplatelet agents alone, given within 14 days of onset of presumed or confirmed ischemic stroke. Data Collection and Analysis. Both reviewers independently selected trials for inclusion in the review, assessed trial quality, and extracted data. Primary Results. A total of 16,558 patients from four trials contributed to the analyses. The methodologic quality was high in all trials. The anticoagulants tested were unfractionated heparin (UFH) and low-molecular-weight heparin. Aspirin was used as a control in all trials. Overall, there was no evidence that anticoagulants were superior to aspirin in reducing death or dependency at long-term follow-up (odds ratio [OR], 1.07; 95 percent confidence interval [CI], 0.98 to 1.15). Compared with aspirin, anticoagulants were associated with a small but significant increase in the number of deaths at the end of follow-up (OR, 1.10; 95 percent CI, 1.01 to 1.29), equivalent to 20 more deaths (95 percent CI, zero to 30) per 1,000 patients treated; a significant increased risk of symptomatic intracranial hemorrhage (OR, 2.35; 95 percent CI, 1.49 to 3.46); and a nonsignificant increased risk of any recurrent stroke during treatment (OR, 1.20; 95 percent CI, 0.99 to 1.46). The neutral or adverse effects outweighed a small but significant effect on symptomatic deep venous thrombosis (DVT; OR, 1.20; 95 percent CI, 0.07 to 0.58), equivalent to 10 fewer (95 percent CI, zero to 30) DVTs by 14 days per 1,000 patients treated with anticoagulants instead of aspirin. Subgroup analysis could not identify any type, dosage, or route of administration of anticoagulants associated with net benefit or any benefit in patients with atrial fibrillation. Overall, the combination of UFH and aspirin was not associated with a net benefit over aspirin alone. A subgroup analysis showed that, compared with aspirin, the combination of low-dosage UFH and aspirin was associated with a nonsignificant trend toward reduced risk of any recurrent stroke (OR, 0.75; 95 percent CI, 0.56 to 1.03), reduced risk of death at 14 days (OR, 0.84; 95 percent CI, 0.69 to 1.01), and no effect on death at the end of follow-up (OR, 0.98; 95 percent CI, 0.85 to 1.12). Reviewers' Conclusions. Anticoagulants offered no net advantage over antiplatelet agents in acute ischemic stroke. The combination of low-dosage UFH and aspirin appeared in a subgroup analysis to be associated with net benefits compared with aspirin alone, and this finding merits further research. 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 authors address a focused clinical question? Yes.

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

Is it likely that important relevant articles were missed? No.

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? Very precise.

Can the results be applied to patient care? Yes.

Do the conclusions make biologic and clinical sense? The conclusions make sense from a biologic and clinical point of view, and the benefits, harms, and costs favor the use of antiplatelet agents for all of the important outcomes.

Practice Pointers

The participants in this review were patients who had suffered an ischemic stroke within 48 hours of being randomized for entry into the trial. The interventions included unfractionated or low-molecular-weight heparin, aspirin plus heparin, and aspirin alone.

Reading the Numbers Publication bias results from the fact that we all prefer good news over bad. This preference leads to the publication of a higher proportion of studies with positive outcomes than studies with negative outcomes. Publication bias exists,3 and much has been written about it. However, its impact on the outcome of systematic reviews is less clear.4 When evaluating the quality of a systematic review, it is sufficient to note that publication bias has been assessed.

The authors studied many outcomes, including death or dependency at the end of follow-up, death from any cause during follow-up, death from any cause during treatment, silent or symptomatic DVT, symptomatic pulmonary embolus during treatment, progression of symptoms during treatment, recurrent stroke during treatment, symptomatic intracranial hemorrhage during treatment, recurrent stroke, and major extracranial hemorrhage during treatment.

Among these outcomes, the most important to patients and their physicians is death or dependency at the end of follow-up. For this outcome, the trials of anticoagulants versus antiplatelet agents showed a trend (that was very nearly statistically significant) in favor of the antiplatelet agent. The trials of anticoagulant plus antiplatelet agent versus antiplatelet agent alone showed no difference between interventions for the primary outcome.

All other outcomes except one showed no difference between interventions or a trend favoring antiplatelet agents. The only outcome that favored anticoagulants was the presence of symptomatic DVT during treatment. This outcome is not insignificant, but it pales in comparison with the primary outcome of death or dependency at the end of follow-up. Surprisingly, there was no significant decrease in symptomatic pulmonary embolus in the anticoagulant group.

The authors did not find any trials that compared oral anticoagulants with antiplatelet agents. A recently published trial, the Warfarin-Aspirin Recurrent Stroke Study,² found no difference in rates of death or recurrent stroke when aspirin was compared with warfarin.

Aspirin is as effective as anticoagulants in reducing death or dependency, and it is at least as safe to use. Because it does not require monitoring, aspirin is easier to use and is much less expensive than anticoagulants.

To reduce morbidity and mortality from ischemic stroke, physicians should prescribe 75 to 150 mg of aspirin per day beginning immediately after diagnosis.

REFERENCES

1. Berge E, Sandercock P. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database Syst Rev, 2003:CD003242.
2. Hankey GJ. Warfarin-Aspirin Recurrent Stroke Study (WARSS) trial: is warfarin really a reasonable therapeutic alternative to aspirin for preventing recurrent noncardioembolic ischemic stroke? Stroke 2002;33:1723-6.
3. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991;337:867-72.
4. MacLean CH, Morton SC, Ofman JJ, Roth EA, Shekelle PG; Southern California Evidence-Based Practice Center. How useful are unpublished data from the Food and Drug Administration in meta-analysis? J Clin Epidemiol 2003;56:44-51.

Glenn Griffin, M.D., is associate professor of family medicine at United Arab Emirates University Faculty of Medicine and Health Sciences, Al-Ain.

Address correspondence to Glenn Griffin, M.D., Department of Family Medicine, United Arab Emirates University Faculty of Medicine and Health Sciences, P.O. Box 17666, Al-Ain, United Arab Emirates (e-mail: griffing@uaeu.ac.ae). Reprints are not available from the author.