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New Data on Aspirin vs. Warfarin in TIA Patients, but Questions Persist
Henry I. Bussey, Pharm.D., FCCP, FAHA
March, 2005
Study: Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. New England Journal of Medicine 2005; 352:1305-1316.
Editorial: Koroshetz WJ. Warfarin, Aspirin, and Intracranial Vascular Disease. New England Journal of Medicine 2005; 352:1368-1370.
This week's issue of the New England Journal of Medicine contains the report of a very interesting study that compared aspirin (1300 mg daily or 4 "regular strength" tablets) to warfarin (brand name Coumadin) at a target INR of 2 to 3 in 569 patients who had experienced a transient ischemic attack (TIA or "mini-stroke") or non-disabling stroke within the past 90 days and who had a 50 to 99 percent stenosis of an intracranial artery. After an average follow-up of 1.8 years, the study was stopped early because of an increase in adverse effects in the warfarin group, but without a difference in the beneficial effects of either treatment. The primary end point of "ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke" was not different between the two treatments (22.1% with aspirin vs. 21.8% with warfarin. The authors conclude that aspirin should be used in preference to warfarin in such patients.
However, the accompanying editorial (and the article's authors in their discussion section) point out reasons why abandoning warfarin therapy may be unwarranted. Although the fact that patients' INRs were in range approximately 63% of the time would suggest good anticoagulation control, one should remember that how far out of range the INR is may also be important. Specifically, 25% of the major hemorrhages occurred with the INR at or above 4.5. Table 4 from the article (modified and recreated below) indicates that the vast majority of major hemorrhages, ischemic strokes, and major cardiac events occurred when the INRs were out of range.
Modified version of Table 4 from the article
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INR range
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Pat/yrs
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Maj. Hemorrhage
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Ischemic Strokes
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Maj. Cardiac Events
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Combined
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|
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No. Events
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Events/100 pat/yrs
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No. Events
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Events/100 pat/yrs
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No. Events
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Events/100 pat/yrs
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Events/100 pat/yrs
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< 2.0
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92.5
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1
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1.1
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23
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24.9
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10
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10.8
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36.8
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2-3
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256.9
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9
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3.5
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13
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5.1
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1
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0.4
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9.0
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3.1-4.4
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52.6
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8
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15.2
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3
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5.7
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3
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5.7
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26.6
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> 4.5
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4.9
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6
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123.3
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1
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20.6
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0
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0
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143.9
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The rapid increase in major bleeding with higher INRs is consistent with earlier studies that have evaluated anticoagulation in patients with cerebrovascular disease. Similarly, the ineffectiveness of warfarin at an INR of less than 2 in preventing cardiac events also is consistent with previous studies that have shown no benefit of warfarin in post-MI patients at an INR of less than 2; but substantial benefit at an INR of 2 to 3 when combined with aspirin or an INR of 3 to 4 without aspirin.
Further, the fact that these event rates were reduced by 70% or more when the INRs were within the target range suggests that tightly controlled warfarin (as might be achieved with more frequent testing or home monitoring and expert management) could be more effective than aspirin, and perhaps as safe in reducing the terrible primary endpoint rate of 22% that was found in this trial.
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