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Decreased Size of Acute Ischemic Stroke: An Additional Benefit from Chronic Warfarin Therapy?
Abstract & Commentary
By Dana Leifer, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Leifer reports no financial relationships relevant to this field of study.
Synopsis: Chronic treatment with warfarin, prior to presentation with an ischemic stroke, is associated with a significant decrease in infarct size.
Source: Ay H, Arsava EM, Gungor L, et al. Admission international normalized ratio and acute infarct volume in ischemic stroke. Ann Neurol 2008;64:499-506.
Warfarin is well known to decrease the incidence of ischemic stroke in patients with atrial fibrillation, and guidelines published by the American Heart Association (Stroke 2006;37:577-617) and other groups strongly recommend its use. Nevertheless, studies have repeatedly shown that many appropriate candidates for warfarin are not treated because of fears about its hemorrhagic complications and the need for monitoring of the international normalized ratio (INR).
Ay and colleagues have now found an additional reason for treating appropriate patients with warfarin. Not only does warfarin reduce the risk of stroke, but, according to their study, it also appears to reduce the size of infarcts, and therefore, the disability associated with the stroke. Ay and colleagues retrospectively examined a series of 93 patients who were taking warfarin at the time of admission for an acute ischemic stroke.
The primary finding of the study was that for patients taking warfarin, there is an inverse correlation between the admission INR and the admission infarct volume as measured by diffusion-weighted imaging (r = -0.38; p < 0.001). This association remained significant after controlling for other predictors of lesion volume, including a history of atrial fibrillation, prior transient ischemic attack or stroke, stroke etiology, warfarin use for cardiac source of embolism, and intravenous thrombolytic treatment for the acute stroke (p = 0.014 for the multivariate analysis).
Additional analysis showed that the median lesion volume was significantly smaller in patients with an admission INR ≥ 2, compared to those with an INR < 2 (3.4 mL compared to 13.1 mL, p < 0.001). Significant effects were found both for strokes considered to be the result of cardiogenic embolism and for strokes thought to have other mechanisms.
The authors also compared patients on warfarin at stroke onset to a group of control patients matched for etiology of stroke who were not taking warfarin. Infarct volume tended to be smaller in the group on warfarin (p = 0.72), and was significantly smaller in the group on warfarin with INR ≥ 2 compared to patients not taking warfarin (p = 0.001). Multivariate analysis confirmed that the difference remained significant after controlling for other predictors of lesion volume (p = 0.048).
The authors confirmed the results with several additional analyses that suggest that the effect is a robust one. Admission INR had significant inverse correlations with the volume of hypoperfused areas on perfusion MRI on admission, with final infarct size on follow-up imaging, with initial clinical severity, as measured by the National Institutes of Health Stroke Scale, and by clinical disability at discharge, measured by the modified Rankin Scale.
As the authors point out, there are several possible explanations for the results. Therapeutic anticoagulation may reduce the size of emboli or make them more fragile so that they are more likely to break up spontaneously. In addition, inhibition of the thrombotic system may decrease thrombus propagation and tend to allow the fibrinolytic system to prevail, or prevent microvascular thrombosis in regions of slow flow.
In any case, the finding that treatment with warfarin at therapeutic levels can reduce the size of ischemic strokes and thereby reduce the disability that they cause, provides an additional compelling reason to treat appropriate patients with warfarin and to adjust warfarin doses carefully to maximize the percentage of time during which patients have a therapeutic INR.