The use of dabigatran in clinical practice


By Giuseppe Di Pasquale

Oral anticoagulant therapy for stroke prevention in patients with atrial fibrillation is underused in clinical practice. The difficulties of the management of vitamin K antagonists (VKAs) account for this underuse (for example, the problems of ensuring patients are well controlled).

Three novel oral anticoagulants, dabigatran etexilate, rivaroxaban, and apixaban have been recently approved for stroke prevention in patients with non-valvular atrial fibrillation and they will probably replace the use of VKAs in the near future.

Among the new oral anticoagulants, dabigatran (Pradaxa) was the first one to be approved in the USA and Canada (at the end of 2010) and the first one to be approved in Europe (in April 2011, via the European Medicines Agency). The FDA, in a recent safety review of the post-market use of dabigatran in the USA, confirmed the safety of the drug in the clinical arena. The results of this assessment indicate that bleeding rates associated with use of dabigatran do not appear to be higher than bleeding rates associated with the new use of warfarin, which is consistent with the results of the RE-LY trial (the main trial for dabigatran; Connolly et al. N Engl J Med 2009; 361:1139–51).

However, the introduction of dabigatran in the clinical practice raises a number of practical issues that are mainly related to the clinical follow-up of patients taking the drug-including the treatment of major or life-threatening bleedings and the management of patients undergoing surgery.

Before starting a patient on dabigatran, it is important to exclude contraindications such as severe renal impairment (creatinine clearance [CrCL] <30mL/min) and co-medications. The 150m bid dose is indicated for most patients, and the 110mg bid dose is indicated for older patients aged ≥80 years and in patients taking verapamil. In patients aged 75–80 years at high risk of bleeding and in those with moderate renal impairment (CrCL 30–60mL/min), the decision to use 110mg bid is at the discretion of physician.

However, in the USA, the FDA did not approve the 110mg dose and, therefore, a twice daily 75mg dose (which was approved) is recommended for patients with a CrCL of 15–30ml/min. It is not recommended for patients with a CrCL of <15ml/min or patients on dialysis.

A follow-up visit at three months and then at six months, and then every six months, after the initiation of treatment is appropriate to check compliance, thromboembolic or bleeding events, and potentially interfering medications. Renal function should be checked yearly and should be checked more frequently in older patients (>75 years) and in those with moderate renal dysfunction.

Coagulation monitoring is not required with dabigatran etexilate; however, its effects on various coagulation assays have been studied. In certain clinical situations, such as serious bleeding or emergency surgery, an assessment of the anticoagulant status of a patient receiving dabigatran is warranted. If available, diluted thrombin time (dTT), and ecarin clotting time (ECT) are sensitive tests to evaluate the anticoagulant effect of dabigatran. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment.

In the case of serious bleeding complication, an antidote is not yet available. General measures include symptomatic treatment, fluid replacement, blood product transfusion, oral charcoal application and haemodialysis. The administration of prothrombin complex concentrates (non-activated or activated) and recombinant factor VII (NovoSeven, NovoNordisk) can be considered.

If a patient is undergoing elective surgery, dabigatran should be withheld for 24–96 hours before intervention, depending on renal function and the bleeding risk of the surgery.

Giuseppe Di Pasquale is the director of the Department of Medicine and Division of Cardiology, Maggiore Hospital, Bologna, Italy.