Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions

Abstract

The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

Type 2 Diabetes, Atrial Fibrillation, and Direct Oral Anticoagulation

“…Dabigatran etexilate [26] is the first DOAC introduced for the prevention of stroke and systemic embolism in AF patients by the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study [27]. Acting as direct thrombin (factor IIa) inhibitor (inhibiting both free and platelet bond thrombin), dabigatran rapidly inhibits coagulation (Figure 1) and might also affect (reduce) thrombin-induced platelet aggregation [28, 29].…”

“…It has a plasma half-life of 14–17 hours (in individuals with normal kidney functions) and is eliminated mostly by the kidneys, mostly through glomerular filtration. Considering these data, the change of P-gp transport capacity, reduced glomerular filtration, and change in gastric pH (for example, during concomitant coadministration of proton pump inhibitors) might change dabigatran half-life, its plasma levels, and its activity [26, 30]. In addition, previously published studies showed that diabetes itself could affect the P-gp transport capacity [31]; therefore, there is a theoretic possibility that the efficacy of dabigatran therapy could be changed in T2D patients.…”

Practical issues in measuring the anticoagulant effect of direct oral anticoagulants

“…Therefore, acute renal or liver impairment may also substantially impair the blood levels of all DOACs and expose the patients to a significant risk of overcoagulation or undercoagulation. (2,27). The most commonly used laboratory profile includes general laboratory tests for screening renal and hepatic function and assessing bleeding risk.…”

“…The direct oral anticoagulants (DOACs) including dabigatran (inhibits thrombin), rivaroxaban, apixaban, and edoxaban, (inhibits factor Xa) are increasingly replacing classic anticoagulant drugs vitamin K antagonists and heparin preparations for the following indications: for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, for the primary prevention of venous thromboembolic events in patients undergoing elective surgery, for the treatment of deep vein thrombosis and pulmonary embolism, as well as for the prevention of these conditions reoccurring in adults (1,2). DOACs were introduced to overcome the limitations of Vitamin K antagonists (the narrow therapeutic range, inter-and intra-individual variability of anticoagulant response as a result of environmental and genetic factors, laboratory monitoring for dose adjustment, drug-drug interactions).…”

Left Atrial Appendage Thrombus Formation in a Patient on Dabigatran Therapy Associated With ABCB1 and CES-1 Genetic Defect

“…As the renal clearance of dabigatran is 80%, renal function should be monitored regularly in patients taking dabigatran (Mega and Simon, 2015 ). Accordingly, changes in the process of absorption or elimination could have a great effect on dabigatran plasma concentrations (Antonijevic et al, 2017 ; Favaloro et al, 2017 ). We reported a dabigatran-treated patient who presented with severe left atrial appendage thrombus formation, of whom ABCB1 and CES1 genetic polymorphism and drug-drug interaction may have been the contributing factors.…”