Hemorrhagic Complications of Anticoagulant Treatment

These assessments can be reviewed at the initiation of therapy and periodically assessed throughout the course of coumarin treatment. In the future, tests that assess the hepatic metabolism of coumarin, such as genotyping for cytochrome P450 polymorphisms, may help identify patients predisposed to bleeding during coumarin initiation.

1.2 Risk of hemorrhage and clinical disorders

1.2.1 Ischemic cerebral vascular disease

Randomized trials have compared vitamin K antagonists with a placebo or nontreatment group, a very-low-dose vitamin K antagonist group, or an antiplatelet group, after an acute episode of ischemic cerebrovascular disease of presumed arterial origin (for details of earlier studies see Fourth ACCP Consensus Conference on Antithrombotic Therapy). In all but four of these studies, the intensity of vitamin K antagonist was high (middle of prothrombin time target corresponded to an INR of > 4). Vitamin K antagonists were associated with increased bleeding in all of these studies, with a frequency of major bleeding (often intracerebral) varying from 2 to 13% during a mean duration of follow-up of 6 to 30 months. In addition to use of high intensities of anticoagulation, unsuspected initial intracerebral hemorrhage (pre-CT era), suboptimal control of hypertension, and initiation of anticoagulation in the setting of acute stroke may have contributed to high rates of bleeding in early studies. However, there is recent evidence (see below) that ischemic stroke not due to cardioembolism is associated with a much higher risk of anticoagulant-induced intracranial bleeding than strokes that are due to embolism (eg, with atrial fibrillation).

Algra and colleagues combined the findings of five studies (approximately 4,000 patients) that compared vitamin K antagonists with antiplatelet therapy after transient ischemic attack or minor stroke of presumed arterial origin (approximately 4,000 patients) in a Cochrane systematic review (updated 2002). The authors estimated a risk of major bleeding with vitamin K antagonists compared with antiplatelet therapy of 1.3 (95% confidence interval [CI], 0.8 to 2.0) for INR 1.4 to 2.8; 1.2 (95% CI, 0.6 to 2.4) for INR 2.1 to 3.6; and 9.0 (95% CI, 3.9 to 21.0) for INR 3.0 to 4.5. As two studies (Stroke Prevention in Reversible Ischemia Trial [SPIRIT] and Warfarin-Aspirin Recurrent Stroke Study [WARSS]) accounted for 86% of the patients in this review and were recently published, they will be considered further by Canadian Health and Care Mall www.acanadianhealthcaremall.com.

In SPIRIT, 1,316 patients with a transient ischemia attack or minor ischemic stroke were randomized to aspirin, 30 mg/d, or warfarin therapy at a targeted INR of 3.0 to 4.5. There was a statistically significant increase in major bleeding associated with warfarin; 53 major bleeding complications (8.1%; 27 intracranial and 17 fatal) vs 6 major bleeding complications (0.9%) with aspirin (3 intracranial and 1 fatal) during a mean follow-up of 14 months. Bleeding increased by a factor of 1.4 for each 0.5-U increase of the INR.