Dabigatran, A Direct Thrombin Inhibitor, In Atrial Fibrillation: Is It Already Time For A Change In Oral Anticoagulation Therapy?

Atrial fibrillation (AF) is a common arrhythmia, and its prevalence increases with aging and the severity of heart disease. AF affects more than 2 million peo-ple in the US, and more than 4 million in Europe. It is expected that the age adjusted prevalence in US will excede 10 million people by the year 2050 [1-5]. In the last decade, we were able to see the light shed by several trials that dealt with AF mecha-nisms and the appropriate management of AF pa-tients. Clinical studies have focused mainly on the electrophysiological properties of the substrate in the atrial muscle during sinus rhythm and on the atrial electrical responses elicited by premature stimulation method [6-9]. However, many funda-mental aspects of this arrhythmia have been poorly understood until quite recently, and there are sev-eral features on the mechanisms of AF that makes it difficult to manage it properly. Increasing aware-ness of AF as a disease with possible fatal compli-cations rather than as an acceptable alternative to sinus rhythm has led to search for clear arguments to support a certain strategy as a golden standard. There is no atrial contraction during AF, a situation that renders the pooled blood inside the atrium susceptible to develop thrombus formation par-ticularly in the left atrium. AF increases the overall risk of stroke five-fold, and is associated with par-ticularly severe strokes [10-12]. About 76% of AF patients have a moderate to high risk of embolic complications, and they have also a significant risk factor for stroke recurrence [13-15]. It looks very clear that all the difficulties we have to face in find-ing proper answer to its therapeutic management. Vitamin K antagonist drugs, such as warfarin and acenocumarol, reduce the risk of AF-related stroke by about 70% [4, 16]. They are the only oral antico-agulants currently recommended for the preven-tion of stroke in patients with a moderate to high risk of stroke [15] These pharmacological agents produce their anticoagulant effect by preventing the g-carboxylation of the vitamin K-dependent coagulation factors prothrombin and Factors VII, IX, and X [17]. Despite the good clinical results obtained with these oral anticoagulants that are far from being ideal [Table 1], there are some in-convenient factors which make their conventional use difficult to implement and follow. There is a consistent suboptimal utilization of oral anticoag-ulation therapy. Warfarin is prescribed to only two thirds of appropriate candidates despite guide-lines recommendations [18]. The narrow therapeu-tic window in the anticoagulation process makes it neccessary to monitor closely the prothrombin time. Insufficient anticoagulation may result in embolic complications, while over-anticoagula-tion increases the risk of bleeding [19]. There are also other disadvantages related to the unpredict-able pharmacokinetics and pharmacodynamics of these oral anticoagulants, which are affected by genetic factors, drug to drug interactions, and con-sumption of foods containing vitamin K. There-fore, it is paramount that a regular coagulation monitoring and dose adjustment is necessary to ensure adequate anticoagulation. This fact leads to high rates of discontinuation of therapy, and many patients remaining on therapy have also in-adequate anticoagulation. Another important is-sue is the concern about real-world effectiveness which was found to be around 35% [18]. It is clear to see that there is a great need of new oral antico-agulants for stroke prevention in patients with AF.Connolly et al [20] reported recently in the New England Journal of Medicine, the clinical findings