Dabigatran Etexilate

The most common complication is bleeding, including severe and potentially fatal bleeding. Risk factors for bleeding include concurrent use of drugs that increase the risk of bleeding (eg, antiplatelet agents, heparin), renal impairment, and elderly patients (especially if low body weight). Discontinue in patients with active pathological bleeding. Important: Idarucizumab is commercially available and is the most effective agent for dabigatran reversal. Protamine and vitamin K do not reverse or impact anticoagulant effects of dabigatran. Dabigatran is dialyzable (~57% removed over 4 hours); however, supporting data are limited for utilizing this method. Depending on the bleeding severity, activated oral charcoal should be considered if ingestion occurred within 1 to 2 hours of presentation. The following alternative options may also be considered depending on specific clinical scenario: 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) or 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA). Some studies and case reports have shown moderate success in correcting coagulation tests with some of these agents; however, correction of coagulation tests does not imply reversal of the anticoagulation effect of the medication (AHA/ASA [Hemphill 2015; EHRA [Heidbuchel 2015]; NCS/SCCM [Frontera 2016]). Platelet concentrates should be considered when thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Upon premature discontinuation, the risk of thrombotic events is increased. If dabigatran must be discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider the use of another anticoagulant during the time of interruption. In patients with non-valvular atrial fibrillation who had an acute ischemic stroke while receiving a DOAC (eg, dabigatran), guidelines generally support withholding oral anticoagulation until 1 to 2 weeks after the ischemic stroke (time frame may vary with shorter times for transient ischemic attack or small, non-disabling stroke and longer times for moderate-to-severe stroke) (AHA [Raval 2017]; AHA/ASA [Kernan 2014]; EHRA [Heidbuchel 2015]). Disease-related concerns:

Use in patients with moderate hepatic impairment (Child-Pugh class B) demonstrated large inter-subject variability; however, no consistent change in exposure or pharmacodynamics was seen. Patients with active liver disease were excluded from the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial (Connolly 2009).

Evaluate renal function prior to and during therapy, particularly if used in patients with any degree of preexisting renal impairment or in any condition that may result in a decline in renal function (eg, hypovolemia, dehydration, concomitant use of medications with a potential to affect renal function); dabigatran concentrations may increase in any degree of renal impairment and increase the risk of bleeding. In moderate impairment, serum concentrations may increase 3 times higher than normal compared to concentrations in patients with normal renal function. However, in patients with nonvalvular AF, US labeling only requires dosage reduction in patients with severe renal impairment (CrCl 15 to 30 mL/minute) and dosing recommendations cannot be provided in patients with CrCl • Valvular heart disease: Use is not recommended in patients with valvular heart disease, including the presence of a bioprosthetic heart valve (has not been evaluated); use is contraindicated in patients with mechanical prosthetic heart valves. In addition to several case reports (Chu 2012; Price 2012; Stewart 2012), one clinical trial reported significantly more thromboembolic events (valve thrombosis, stroke, TIA, and MI) and an excess of major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) in patients with mechanical prosthetic heart valves receiving dabigatran compared to those receiving adjusted-dose warfarin. Concurrent drug therapy i

Due to an increased risk of bleeding, avoid use, if possible, with other direct thrombin inhibitors (eg, bivalirudin), unfractionated heparin or heparin derivatives, low molecular weight heparins (eg, enoxaparin), fondaparinux, thienopyridines (eg, clopidogrel), GPIIb/IIIa antagonists (eg, eptifibatide), aspirin, coumarin derivatives, sulfinpyrazone, and ticagrelor. NSAIDs should be used cautiously. Appropriate doses of unfractionated heparin may be used to maintain catheter patency.

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult Drug Interactions database for more detailed information. Special populations:

Use with extreme caution or consider other treatment options. No dosage adjustment is recommended in the manufacturer's labeling based on age alone (unless renal impairment coexists); however, risk of bleeding increases with age. Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]). In particular, an increased risk of GI bleeding has been observed in patients ≥75 years of age despite similar efficacy observed with dabigatran in the elderly as compared to warfarin-treated patients (Graham 2015; Sharma 2015). Dabigatran is associated with more than a 5-fold variation in plasma concentrations in patients receiving the same dose, indicating a wide therapeutic range. Significant factors affecting increased dabigatran plasma concentrations have been found to be increasing age, decreased CrCl, lower body weight and female gender. Renal function was the predominant patient characteristic determining plasma concentrations, with age as the most important covariate (Reilly 2014). Depending on individual patient characteristics, particularly advanced age and potential for renal impairment, consider other treatment options, particularly in the US where lack of other available dosing options exist (ie, 110 mg dose) (Kalbalik 2015). Other warnings/precautions:

Spinal or epidural hematomas may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients who are anticoagulated; may result in long-term or permanent paralysis. The risk of spinal/epidural hematoma is increased with the use of indwelling epidural catheters, concomitant administration of other drugs that affect hemostasis (eg, NSAIDs, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, or a history of spinal deformity or spinal surgery. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the optimal timing between the administration of dabigatran and neuraxial procedures is not known. Monitor frequently for signs and symptoms of neurologic impairment (eg, midline back pain, numbness/weakness of legs, bowel/bladder dysfunction); prompt diagnosis and treatment are necessary. In patients who are anticoagulated or pharmacologic thromboprophylaxis is anticipated, assess risks versus benefits prior to neuraxial interventions. Also see ‘Invasive or surgical procedures’.