Anticoagulation With Dabigatran: When to Worry

Devada Singh-Franco, PharmD

Disclosures

September 03, 2015

Question

What patient factors affect bleeding risk with dabigatran?

Response from Devada Singh-Franco, PharmD
Associate Professor, Nova Southeastern University College of Pharmacy; Clinical Pharmacist, Broward Health Medical Center, Fort Lauderdale, Florida

Dabigatran etexilate is the prodrug of dabigatran, a direct thrombin inhibitor that is used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and to prevent and treat venous thromboembolism (VTE).[1,2]

Unlike warfarin but similar to the other newer oral anticoagulants (NOACs) apixaban, edoxaban, and rivaroxaban, laboratory tests to assess anticoagulation are not available for dabigatran. Patient-specific variables such as renal function, age, body weight, and concurrent medications should guide treatment based on the pharmacologic profile of dabigatran.

Patient-Specific Variables

Renal Impairment

Dabigatran is eliminated predominantly as an unchanged drug (80%-85%) via glomerular filtration, and about 20% is excreted as glucuronides, which are pharmacologically active.[1,2,3]

In healthy volunteers, the terminal half-life of dabigatran was 13.4 hours; the half-life increased to 18.4 hours with moderate renal impairment (creatinine clearance [CrCL], 30-59 mL/min) and to 27.2 hours with severe renal impairment (CrCL, 15-29 mL/min).[2] Renal impairment is associated with higher rates of bleeding,[4] and dabigatran trough concentrations are 2.29-fold higher with CrCL 30-50 mL/min than with CrCL ≥ 80 mL/min.[5]

Periodic monitoring to identify renal function deterioration with appropriate dosage adjustment of dabigatran may help limit adverse outcomes.

The recommended dosage is 150 mg twice daily for patients with CrCL >30 mL/min and 75 mg twice daily for those with CrCL 15-30 mL/min. Dabigatran should not be used in patients with CrCL <15 mL/min or who are on dialysis.[1,2]

Advanced Age

Renal function declines with age[6]; however, clearance of dabigatran decreases with increasing age independent of renal function.[2,7]

In a subgroup analysis of the pivotal RE-LY trial[8] comparing patients with NVAF who were younger than 75 years vs patients 75 years of age or older, the risk of major bleeding increased with increasing age (dabigatran 150 mg twice daily vs warfarin: relative risk [RR], 1.18; 95% confidence interval [CI], 0.98-1.42; P < .001). Extracranial bleeding occurred most frequently in patients aged 75 years or older (RR, 1.39; 95% CI, 1.13-1.70; P < .001).

In a pooled analysis of the pivotal studies of dabigatran for VTE (RE-COVER[9] and RECOVER II[10]), the overall risk of bleeding was not increased in patients older than 75 years with CrCL 30-49 mL/min. The risk of major or clinically relevant nonmajor bleeding was lower for dabigatran in younger patients but higher than for warfarin in patients around 85 years of age.[9]

The risk of gastrointestinal bleeding was associated with increasing age in a large retrospective cohort study of 21,033 patients treated with dabigatran. Compared with patients younger than 55 years, the risk of gastrointestinal bleeding was highest in patients aged 75 years or older (adjusted hazard ratio [aHR], 4.52; 95%CI, 2.68-7.64; P < .001). Increased gastrointestinal bleeding risk also was associated with patients aged 64-75 years (aHR, 2.72; 95% CI, 1.59-4.65; P < .001).[11]

Dabigatran may be similar to warfarin in terms of gastrointestinal bleeding risk in older adults. In a retrospective cohort study comparing dabigatran with warfarin, the risk of gastrointestinal bleeding in patients older than 65 years was not significantly different between dabigatran and warfarin (1.07; 95% CI, 0.75-1.53).[12]

Lower dabigatran doses should be considered in patients with advanced age and/or renal impairment.

Weight

Dabigatran dosing is not based on weight, and experience with patients with a low body weight is limited.

In the RE-LY trial,[8] the mean body weight for patients randomly assigned to dabigatran 150 mg twice daily was 82.5 (±19.4) kg. In the RE-COVER trial,[9] the mean weight was 85.5 (±19.2) kg. In an evaluation of the effect of body mass index (BMI) on the outcomes of patients in the RE-LY trial, both the 1-year major bleeding rate and the rate of stroke/systemic embolization were higher in patients with a BMI of 22.5 kg/m2 or less, compared with higher BMI values (P < .001), for both dabigatran and warfarin.[13]

Drug Interactions

Dabigatran etexilate is a substrate of the drug efflux transporter P-glycoprotein (P-gp).[1,2] Drugs that inhibit P-gp may increase the anticoagulant effect of dabigatran and increase the risk of bleeding.

In patients with NVAF and CrCL 30-50 mL/min, the dabigatran dose should be reduced to 75 mg twice daily with concomitant dronedarone or systemic ketoconazole.[1,2] Dose adjustments are not necessary with concomitant administration of the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor.[1,2,7]

The impact of P-gp interaction theoretically may be reduced by administering dabigatran at least 2 hours before P-gp inhibitors.[1,2] In patients with NVAF and CrCL < 30 mL/min or VTE and CrCl < 50 mL/min, avoid dabigatran coadministration with P-gp inhibitors.[1,2]

Drugs that induce P-gp may reduce the anticoagulant effect of dabigatran and increase the risk for stroke; avoid use with inducers such as rifampin.[1,2]

Concomitant use of dabigatran with other anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatory agents can increase the risk of bleeding.[1,2]

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