Idarucizumab reverses the anticoagulant effect of dabigatran even in patients with impaired renal function – clinical practice commentary

Direct oral anticoagulants and their antidotes

Dabigatran, approved in the European Union in 2008, was the very first direct oral anticoagulant (NOAC) on the market. It exerts its anticoagulant effect through direct binding to thrombin and inhibiting its action. The advent of NOACs revolutionized the approach to anticoagulant therapy in patients with non-valvular atrial fibrillation because these agents do not carry some of the problems associated with warfarin use, such as numerous drug interactions, the need for frequent monitoring, dietary restrictions, and a narrow therapeutic window.

Dabigatran was also the first in this class of drugs to have an agent available for the immediate reversal of its anticoagulant effect in the event of urgent surgical procedures or life-threatening bleeding – idarucizumab. It is a monoclonal antibody that binds specifically and with high affinity to dabigatran and blocks its effect. Idarucizumab was approved in 2015 based on interim results from the RE-VERSE AD study.

Reversal of NOAC effects in patients with impaired renal function

However, the administration of NOACs is associated with certain concerns – for example, regarding their dosing and safety in patients with chronic kidney disease (CKD), or even its end-stage (ESRD). This issue was addressed in a subanalysis of the RE-VERSE AD study, which evaluated the reversal of dabigatran’s effect using idarucizumab in patients with impaired renal function. Having a reliable anticoagulant, including a rapid reversal agent, is crucial in the CKD population because these patients have a higher risk of atrial fibrillation compared to the general population. In the dialysis population, atrial fibrillation occurrence reaches almost 15%.

Commentary on the results of the RE-VERSE AD subanalysis

According to the results of this subanalysis, idarucizumab is an effective antidote for dabigatran even in patients with CKD. Although both dabigatran and idarucizumab are renally excreted, the study demonstrated that the reversal of dabigatran’s effect by idarucizumab does not depend on renal function at study entry. In some patients with severe renal impairment, dabigatran levels in the blood rose again 12–24 hours after antidote administration. This suggests that, in cases of recurrent bleeding or the need for additional surgical procedures, it may be appropriate to re-determine plasma dabigatran levels and possibly administer a second dose of idarucizumab.

Conclusion

This is the first study to evaluate the reversal of dabigatran's effect with idarucizumab in patients with CKD. It remains to be seen whether its results will influence the prescribing of this NOAC with the knowledge of the possibility of safe reversal of its effect regardless of the patient's renal impairment status. 

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Source: Khedraki R., Muse E. D., Steinhubl S. R. Expanding the toolbox for reversal of anticoagulation in chronic kidney disease. J Am Coll Cardiol 2019; 74: 1769–1771, doi: 10.1016/j.jacc.2019.07.073.