Two and Half Years with Dabigatran Etexilate in Neurological Units

Atrial fibrillation (AF) is the most frequently clinically significant cardiac arrhythmia, and is an important independent risk factor for thrombo embolic events. The prevalence of AF increases with age, with less than 1% among people under 60years, 5% at age 65 years, and more than 9% estimated in people over 80 years. AF is estimated to affect more than 6 million patients in Europe and approximately 2.3 million patients in the U.S., and with the aging population the number of patients with AF is increasing. AF is associated with a 4-5 fold risk of ischemic stroke and is up to 16% of all strokes and 30% of strokes in patients over 80 years of age. Furthermore, there is evidence that strokes associated with AF are more disabling than those not associated with FA [1-8]. Treatment with oral anticoagulation (ACO) is very effective in preventing stroke in patients with AF [9]. The vitamin K antagonists (VKA) have been the standard of care in recent decades. The new ACOs (NACOs) by their efficacy / safety profile and no-need of routine monitoring will replace in the near future warfarin / acenocumarol [10]. Meanwhile, dabigatran is a direct and selective potent inhibitor of thrombin, and unlike the AVK, can be administered without the need for routine monitoring of anticoagulation. The RE-LY trial demonstrated conclusively and categorically, that the dose of 150 mg twice daily of dabigatran was superior to warfarin in reducing stroke and systemic embolism, providing a risk reduction of 35% (RR 0.65, 95% CI, 0.52 to 0.81, P <0.001) further to the reduction obtained with warfarin [11,12]. One of the most interesting findings from the RE-LY was documenting a significant RRR in the rate of cerebral bleeding with both doses of dabigatran compared with warfarin (RRR 74%, p <0.001 and RRR 69%, p <0.001, dose 110 mg BID and 150mg respectively). In the three major clinical trials of new anticoagulants patients were introduced between 7-14 days post stroke. The waiting was explained to avoid earlier bleeding complications. In the case of dabigatran, the inclusion has been 14 days post stroke. Several clinical factors (other antithrombotic treatments) are associated with an increased risk of hemorrhagic transformation after ischemic stroke: stroke size, patient age, other concomitant medication (antihypertensive drugs, ant diabetic), previous stroke, small petechiae in the area appearing early post ischemic stroke and cardio embolic stroke. In most cases, symptomatic intracranial hemorrhage (SICH) appears between 7 and 10 days post stroke. However, in clinical practice, many patients initiate anticoagulant treatment between 4-7 days post stroke. In some centres, treatment is started with bridging both low weight heparins or heparin sodium and AVKs in the first 24-48 hours post stroke. It seems logical that patients with TIA or minor stroke might benefit from early treatment with new anticoagulants without increasing bleeding risk. New scales as CHADS2, CHA2DS2-VASc, HAS-BLED can help stratify risk of cerebral or systemic hemorrhage. Furthermore, neuroimaging study with gradient echo MRI can detect presence of petechiae zones associated with ischemia. It is likely that dabigatran may be justified to use a few days to two weeks post stroke based on risk of recurrent stroke and low risk of bleeding. However, clinical and biochemical data is missing in this population and would be of great interest and study. Generally, older patients have a higher risk of embolism by AF and most important independent predictor for having a stroke is to have had a previous stroke or TIA. In the RE-LY study only 19.9% of patients had a previous stroke and CHADS2 through the study was 2.1. The efficacy / safety did not change in patients with previous stroke or not. Typical neurological patient is a patient with a high CHADS2 and previous stroke. It would be of interest to confirm in this group of patients the benefit of early treatment with dabigatran.