Bleeding risk with dabigatran (Pradaxa)

HAMILTON, ONTARIO, CANADA. Although there is no evidence that otherwise healthy lone afibbers have an increased risk of ischemic stroke, it is clear that atrial fibrillation (AF) patients with heart failure, diabetes or hypertension have a significantly increased risk and this risk is further magnified if the patient has already suffered a heart attack or stroke. To date, oral anticoagulation with vitamin K antagonists such as warfarin (Coumadin) is still considered to be the best preventive therapy for patients at risk for stroke. Unfortunately, warfarin interacts with many foods and drugs and treatment requires constant, costly monitoring. Its use also substantially increases the risk of hemorrhagic stroke and major internal bleeding, particularly in older people, a group that, ironically, is also most at risk for an ischemic stroke.

Warfarin acts by inhibiting the activation of the vitamin K-dependent coagulation factors V, VII, and X in the extrinsic and common pathways of the coagulation cascade. Research aimed at replacing warfarin has focused on developing new pharmaceutical drugs which will inhibit specific coagulation factors. The most promising of these new drugs is the direct thrombin inhibitor dabigatran etexilate (Pradaxa).

Dabigatran was evaluated in a very large clinical trial (RE-LY) involving over 18,000 atrial fibrillation patients with one or more risk factors for stroke (average CHADS2 score was 2.1). NOTE: 79% of the participants had hypertension, 32% had heart failure, 20% had experienced a prior heart attack or stroke, and 23% had diabetes. The patients were randomly allocated to receive 110 or 150 mg of dabigatran twice daily, or standard warfarin therapy (INR range aim of 2.0 to 3.0). After two years of follow-up, the researchers conducting the RE-LY trial concluded that low-dose dabigatran (110 mg twice daily) is associated with an ischemic stroke rate similar to that obtained with warfarin, but results in a lower incidence of hemorrhagic stroke and major bleeding. High-dose dabigatran (150 mg twice daily) is superior to warfarin when it comes to preventing ischemic and hemorrhagic stroke, but has a similar rate of major hemorrhage.

Now the researchers (a group of scientists from 9 different countries) report on a follow-up study of the RE-LY data aimed at evaluating bleeding risk with dabigatran therapy. They specifically looked at the effect of age and kidney impairment on intracranial (intracerebral, hemorrhagic stroke) and extracranial (mainly gastrointestinal) bleeding. They conclude that low-dose dabigatran therapy (110 mg twice daily) compared with warfarin is associated with a 20% lower risk of major bleeding (2.87%/year vs. 3.57%/year), and a 70% reduced risk of intracranial bleeding (0.23%/year vs. 0.76%/year) with no significant difference in extracranial bleeding. There was no significant difference in the incidence of ischemic stroke between low-dose dabigatran and warfarin. The incidence of major bleeding in patients under the age of 75 years was significantly lower in the dabigatran group, but no difference was observed in the 75 years or older group. The incidence of intracranial bleeding was substantially lower in the dabigatran group irrespective of age, whereas the incidence of gastrointestinal bleeding was substantially higher among patients aged 75 years or older (2.19%/year for dabigatran vs. 1.59%/year for warfarin).

High-dose dabigatran therapy (150 mg twice daily) was associated with a major bleeding risk similar to that of warfarin (3.31%.year vs. 3.57%/year) and a 58% reduced risk of intracranial bleeding (0.32%/year vs. 0.76%/year) with no difference in extracranial bleeding. The incidence of ischemic stroke in the high-dose dabigatran group was significantly lower than in the warfarin group (1.69%/year vs. 1.10%/year) irrespective of age.

However, the incidence of gastrointestinal bleeding was substantially higher among patients aged 75 years or older (2.80%/year for dabigatran vs. 1.59%/year for warfarin). The researchers observed that the risk of major bleeding increased with the concomitant use of aspirin. They also found that renal impairment (kidney dysfunction) was a strong risk factor for bleeding with a creatinine clearance of less than 50 mL/min associated with a 2-fold higher risk of major bleeding than if creatinine clearance was more than 80 mL/min. The researchers speculate that renal impairment may be a major cause of the increased tendency for gastrointestinal bleeding observed with dabigatran therapy in elderly patients (dabigatran is renally excreted so a kidney dysfunction may result in higher blood concentrations of the drug).

The RE-LY investigators conclude that “both doses of dabigatran compared with warfarin provide substantial safety benefits in patients with AF and at least 1 additional risk factor for stroke. At ages <75 years, the higher dabigatran dose seems preferable because of the lower risk of stroke without any increase risk of bleeding, whereas at higher ages, the lower dabigatran dose might be considered a means to reduce the risk of bleeding in selected patients who are at high risk of bleeding.”

Eikelboom, JW, Yusuf, S, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation. Circulation, Vol. 123, May 31, 2011, pp. 2363-72

Editor’s comment: A recent report from France reveals the cases of two elderly, frail women who suffered massive bleeding (one fatal) on the 110 mg twice daily dabigatran dose. It is likely that renal impairment was a contributing factor in these incidents and that a dabigatran dose of 75 mg twice daily may be more appropriate for elderly patients with renal impairment. Nevertheless, dabigatran (Pradaxa) would appear to be a satisfactory replacement for warfarin in the treatment of AF patients with one or more risk factors for stroke. There is, however, no evidence whatsoever that lone afibbers with no stroke risk factors would achieve an overall benefit by taking this drug.