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. It is therefore not surprising that a vast amount of medical research is being directed at finding a replacement for warfarin.

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 essentially focuses on developing new pharmaceutical drugs which will inhibit specific coagulation factors. A new direct thrombin inhibitor dabigatran etexilate (Pradax) has successfully undergone 3 large-scale phase III trials for the treatment of deep vein thrombosis (DVT). A recent trial involving 502 AF patients with at least one additional risk factor for stroke found that 150 mg of dabigatran twice a day is as effective and safe as standard warfarin therapy.

Now a very large group of researchers from 41 countries reports on a trial involving over 18,000 atrial fibrillation patients who had 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 study participants 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). The patients were re-examined 2 weeks and 1 and 2 months after randomization, every 3 months thereafter in the first year, and then every 4 months until the end of the 2-year follow-up period. The INR of warfarin users was checked monthly, but no monitoring of blood levels of dabigatran was required.

A comparison of the incidence of ischemic stroke and systemic embolism, hemorrhagic stroke, major bleeding, heart attack, and overall mortality is shown below:

It is clear that dabigatran, either at 110 mg or 150 mg twice daily, gives better protection against strokes (ischemic and hemorrhagic) and bleeding than does warfarin, although a slightly increased risk of heart attack (myocardial infarction) was noted at both levels of dabigatran. There was a significantly higher rate of major gastrointestinal bleeding with dabigatran at the 150 mg dose than with warfarin (1.51%/year versus 1.02%/year).

Adverse events were similar in the 3 groups except in the case of indigestion (dyspepsia) which was experienced by about 11.5% of dabigatran users versus only 5.8% among warfarin users. Several other direct thrombin inhibitors, most prominent among them, ximelagatran, proved to cause liver toxicity and, for this reason, has not been approved by the FDA for treatment of atrial fibrillation. In this 2-year long trial there was no indication that dabigatran caused a greater elevation of liver enzymes (alanine aminotransferase and aspartate aminotransferase) than did warfarin.

The researchers conclude 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. NOTE: The description of the financial ties between the authors of this report and the pharmaceutical industry takes up half a page of fine print!

Connolly, SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, Vol. 361, September 17, 2009, pp. 1139-51

Editor's comment: Dabigatran (Pradax) looks promising indeed as a replacement for warfarin in the treatment of afib patients with multiple risk factors for ischemic stroke. However, there is no evidence whatsoever that lone afibbers with no stroke risk factors would achieve an overall benefit by taking this drug.