Dabigatran-Associated Intracranial Hemorrhage

Abstract

Dabigatran etexilate is an oral direct thrombin inhibitor approved for prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. Although dabigatran has a favorable safety profile, predictable pharmacokinetics, fewer drug interactions than warfarin, and does not require monitoring, clinical data regarding dabigatran reversal are limited. In addition, currently available laboratory assays allow measurement of the presence, but not extent, of dabigatran-associated anticoagulation. Patient age, renal function, weight, concurrent drug therapy, adherence, and concomitant disease states can affect dabigatran's efficacy and safety. Management of dabigatran-related intracranial hemorrhage must be approached on a case-by-case basis and include assessment of degree of anticoagulation, severity of hemorrhage, renal function, timing of last dabigatran dose, and risk of thromboembolic events. Initial management includes dabigatran discontinuation and general supportive measures. Oral activated charcoal should be administered in those who ingested dabigatran within 2 hours. Four-factor prothrombin complex concentrates (4PCCs), activated PCC, or recombinant activated factor VII use may be reasonable but is not evidence based. Reserve fresh frozen plasma for patients with dilutional coagulopathy. If readily available, hemodialysis should be considered, particularly in patients with advanced kidney injury or excessive risk of thromboembolic events. More clinical studies are needed to determine a standardized approach to treating dabigatran-associated intracranial hemorrhage. Institutional protocol development will facilitate safe, efficacious, and timely use of the limited management options.

Stroke Prevention in Atrial Fibrillation

“…This trial also supports uninterrupted intraprocedural anticoagulation as an alternative to bridging heparin therapy [67]. WOEST (What is the Optimal anti-platElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) uncovered reduction of bleeding risks and overall mortality with the same thrombotic rate in DAPT with warfarin and clopidogrel, compared to triple anti-thrombotic therapy [67,72].…”

“…Apixaban also proved to be unprofitable in trials APPRAISE (Apixaban for Prevention of Acute Ischemic Events) and APPRAISE-2 and it has also been demonstrated that the concomitant use of anti-platelet drugs with these agents increases risk without benefit. ATLAS ACS 2-TIMI 46 and 52 investigated reduced doses of rivaroxaban and revealed its association with lower ischemic and bleeding risks, as well as a decrease in both stent thrombosis and mortality rates; therefore suggesting rivaroxaban to be a potential choice for anticoagulation in triple therapy in the future [68,[70][71][72].…”

“…Ongoing trials like ISAR-TRIPLE (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluing Stent Implantation), MUSICA-2 and LASER are sources of further information for the optimalization of current management in PCI in patients with AF [68,72].…”

Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

“…P-gp inhibitors increase dabigatran bioavailability by ~10% to 20% [ 71 ]. There are also case reports of major bleeding in elderly patients taking concomitant dabigatran with P-gp inhibitors that might have been due in part to the inhibition of P-gp, in addition to other factors such as age and decreased renal function [ 72 , 73 ] (Table 1 ). More recently, in a retrospective cohort study of AF patients on dabigatran, concomitant use of digoxin, which is a substrate of P-gp, was associated with 33% increased risk of gastrointestinal bleeding (Table 1 ) [ 74 ].…”