Bleeding risk with warfarin therapy

TORONTO, CANADA. The initial clinical trials of warfarin for stroke prevention in atrial fibrillation (AF) patients concluded that the drug was effective in reducing the risk of ischemic stroke in patients having one or more risk factors (hypertension, diabetes, heart failure, age over 75 years, and prior stroke or TIA). The relative risk reduction was found to be about 65% when compared to placebo.

Later studies of “real world” populations found that the relative risk reduction may be substantially less – more like 40% for hypertension and 56% for prior stroke or TIA. The main reason that warfarin is less effective in a “real world” setting is that INR control is usually significantly poorer than in tightly controlled clinical trials. Too low an INR increases the risk of ischemic stroke, while an INR value above 4 materially increases the risk of a hemorrhagic stroke and major bleeding. Studies have shown that patients in “real world” settings achieve the recommended range of 2.0 to 3.0 only in about 50-60% of their INR tests.

While often ignored, warfarin therapy involves a significant risk of hemorrhagic stroke and major bleeding (bleeding requiring blood transfusions or hospital admission). This is particularly serious in older patients. A clinical trial carried out at the Boston University School of Medicine observed an overall incidence of major bleeding of 7.2% (including intracranial hemorrhage of 2.5%) in a group of patients with an average age of 77 years and one or more risk factors for stroke[1].

A team of researchers from Massachusetts General Hospital, University of California, and Kaiser Permanente of northern California carried out a 6-year study involving 13,559 patients with non-valvular AF and concluded that, when considering risk of hemorrhagic stroke, the net benefit of warfarin therapy is negative for patients with no risk factors for ischemic stroke and zero in those with one risk factor. As a matter of fact, the risk of ischemic stroke in patients with one risk factor (except in the case of prior stroke or TIA) was only 1.2%/year – far lower than the 3-4% quoted in the original studies done to prove the efficacy of warfarin[2].

A group of Canadian researchers now confirms that hemorrhage is a serious problem with warfarin therapy. Their study included 125,195 AF patients aged 66 years or older who began warfarin therapy between 1997 and 2008. The overall rate of hemorrhage (major bleeding) was 3.8%/year. However, during the first 30 days of treatment it was 11.8% (16.7% for patients with a CHADS2 score of 4 or greater). Over the 5-year follow-up, 10,840 patients visited a hospital for major bleeding and, of these, 1963 (18.1%) died in hospital or within 7 days of being discharged. The mortality was highest (42%) for patients admitted with intracranial hemorrhage (hemorrhagic stroke). The risk of major bleeding was significantly lower for patients with a CHADS2 score of 0 or 1 (1.8% and 2.5% respectively).
Gomes, T, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. Canadian Medical Association Journal, Vol. 185, No. 2, February 5, 2013, pp. E121-E127
Reference 1
Reference 2

Editor’s comment: This new Canadian study adds to the evidence that warfarin therapy carries a considerable risk of major bleeding. It also confirms that afib patients with no or only one risk factor for ischemic stroke (CHADS2 score of 0 or 1) do not benefit from and may actually be harmed by warfarin therapy.