On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation

Skeppholm, Mika; Hjemdahl, Paul; Antović, Jovan P.; Muhrbeck, Josephine; Eintrei, Jaak; Rönquist-Nii, Yuko; Pohanka, Anton; Beck, Olof; Malmström, Rickard E.

doi:10.1016/j.thromres.2014.06.016

Cited by 47 publications

(57 citation statements)

References 22 publications

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“…Of 44 patients, 41 individuals provided four blood samples and three provided two samples, for a total of 170 samples. The correlations between dabigatran concentration determined directly by LC-MS/MS and standard coagulation test for both trough and peak values were similar to those observed in previous studies [6,15]. It seems that the inhoused TT and ECA-T express the best correlation ( fig.…”

Section: Resultssupporting

confidence: 87%

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

Šinigoj

Malmström

Vene

et al. 2015

Basic Clin Pharmacol Toxicol

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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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Section: Resultssupporting

confidence: 87%

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

Šinigoj

Malmström

Vene

et al. 2015

Basic Clin Pharmacol Toxicol

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“…A dose reduction from 5 mg BID to 2.5 mg BID is currently recommended in patients with at least two of the following characteristics; age ≥ 80 years, body weight ≤ 60 kg or serum creatinine ≥ 133 μmol/l [8], but selective monitoring of apixaban therapy to optimize its efficacy and safety in certain groups of patients could eventually prove useful. Although the variability in concentration maybe less pronounced for apixaban than for dabigatran, it is reasonable to suppose that there is a relationship between apixaban exposure and efficacy/safety that is overall in line with what has been suggested and much debated for dabigatran [9,10].…”

Section: Introductionmentioning

confidence: 52%

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

Skeppholm

Al-Aieshy

Berndtsson

et al. 2015

Thrombosis Research

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“…However, a week correlation was reported also for plasma levels of dabigatran with creatinine clearance [10]. Limitations include methodological factors that influence the variability of the data: control samples were not used, repeated freezing and thawing experiments were not performed, and not the same lot of reagents were used over the period of analysis of the samples.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the claim that dabigatran treatment does not to require laboratory-guided dose adjustment, due to the low bioavailability ( < 6.5%), predominant renal elimination ( > 80%) [7], and genetic variants' influence on the responses to dabigatran [9], assessing the intensity of anticoagulation may be useful in patients at risk of overdose and in highrisk (both for thromboembolism and for bleeding) patients in general [10]. The standard for measuring NOAC concentrations in biological fluids is high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).…”

Section: Introductionmentioning

confidence: 99%

Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods

Du¹,

Weiß²,

Christina³

et al. 2015

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: Assessing the anticoagulant effect of dabigatran may be useful in certain clinical settings. When plasma sampling is not available, serum or urine samples may provide another option for dabigatran determinations. Methods: Dabigatran was assessed in patients on treatment under real-life conditions in plasma samples by four clotting time-based assays and in plasma, serum, and urine samples by two chromogenic substrate methods. Results: The concentrations of dabigatran in patients' plasma samples were not different for the Hemoclot test (106.8 ± 89.4 ng/mL) and the ecarin clotting time (ECT, 109.5 ± 74.5 ng/mL, p = 0.58). Activated partial thromboplastin time and prothrombinase-induced clotting time showed low correlations with the other assays. Chromogenic assays measured similar concentrations as Hemoclot and ECT. For both chromogenic assays, the concentrations of dabigatran were about 70% lower in serum than in plasma samples (p < 0.0001). The intra-class coefficient (ICC, Bland-Altman analysis) was strong comparing ECT, Hemoclot thrombin inhibitor (HTI) assay, and the two chromogenic assays (r = 0.889-0.737). The ICC was low for comparisons of the chromogenic assays of serum vs. plasma values (ICC, 0.15 and 0.66). The ICC for the determination of

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On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation

Cited by 47 publications

References 22 publications

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

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

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods

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