Dabigatran Concentration: Variability and Potential Bleeding Prediction In “Real-Life” Patients With Atrial Fibrillation

Abstract

Routine laboratory monitoring is currently not recommended in patients receiving dabigatran despite its considerable variation in plasma concentration. However, in certain clinical situations, measurements of the dabigatran effect may be desirable. We aimed to assess the variability of dabigatran trough and peak concentration and explore the potential relationship between dabigatran concentration and adverse events. We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (D150) or 110 mg (D110) twice daily. They contributed 170 trough and peak blood samples that were collected 2-4 and 6-8 weeks after dabigatran initiation. Plasma dabigatran concentration was measured by LC-MS/MS and indirectly, by selected coagulation tests. D110 patients were older (74 AE 7 versus 68 AE 6 years), had lower creatinine clearance (68 AE 21 versus 92 AE 24 mL/min) and higher CHA 2 DS 2 -VASc score (3.1 AE 1.3 versus 2.3 AE 0.9) compared to D150 patients (all p < 0.05), but both had similar dabigatran concentrations in both trough and peak samples. Dabigatran concentrations varied less in trough than in peak samples (17.0 AE 13.6 versus 26.6 AE 19.2%, p = 0.02). During the 12-month follow-up, 4 patients on D150 and 6 on D110 suffered minor bleeding. There was no major bleeding or thromboembolic event. Patients with bleeding had significantly higher average trough dabigatran concentrations (93 AE 36 versus 72 AE 62 lg/L, p = 0.02) than patients without bleeding, while peak dabigatran values had no predictive value. Dabigatran dose selection according to the guidelines resulted in appropriate trough concentrations with acceptable repeatability. High trough concentrations may predispose patients to the risk of minor bleeding.Dabigatran etexilate is an oral prodrug that is transformed into its active compound, dabigatran, a direct thrombin inhibitor that affects both clot-bound and free thrombin. Dabigatran has been clinically developed for the prevention and treatment of patients with atrial fibrillation and venous thromboembolic disease. Current recommendations for dabigatran treatment include dosing at 110 or 150 mg twice daily regarding patient characteristics (renal function, body weight, age, concomitant use of P-glycoprotein inhibitors and bleeding risk) without the need for routine coagulation monitoring [1]. However, the plasma concentrations achieved with each dose varied widely across the patient population, depending on absorption, renal function, concomitant use of P-glycoprotein inducers or inhibitors and other patient characteristics [2,3]. For example, trough plasma concentrations of dabigatran in patients treated with dabigatran 150 mg twice daily was on average 91.0 ng/mL, with a 25th-75th percentile range of 61.0-143 ng/mL and a large variation above and below that range [4]. Therefore, in certain clinical situations, such as bleeding or a thromboembolic event, renal failure, potential overdose and major surgery, measurements of the dabigatran effect may be desirable and...

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Does One Dose Really Fit All? On the Monitoring of Direct Oral Anticoagulants: A Review of the Literature

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