On the monitoring of dabigatran treatment in "real life" patients with atrial fibrillation.

INTRODUCTION: The oral direct thrombin inhibitor dabigatran is increasingly used to prevent thromboembolic stroke in patients with atrial fibrillation (AF). Routine laboratory monitoring is currently not recommended, but measurements of dabigatran and/or its effect are desirable in certain situations. We studied dabigatran exposure and compared different tests for monitoring of dabigatran in a real-life cohort of AF patients. MATERIAL AND METHODS: Ninety AF patients (68 ± 9 years, 67% men, mean CHADS2 score 1.5) were treated with dabigatran 150 (n=73) or 110 mg BID (n=17). Trough plasma concentrations of total and free dabigatran by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to indirect measurements by Hemoclot thrombin inhibitors (HTI) and Ecarin clotting assay (ECA), as well as PT-INR and aPTT. RESULTS: Total plasma dabigatran varied 20-fold (12-237 ng/mL with 150 mg BID) and correlated well with free dabigatran (r(2)=0.93). There were strong correlations between LC-MS/MS and HTI or ECA (p<0.001) but these assays were less accurate with dabigatran below 50 ng/mL. The aPTT assay was not dependable and PT-INR not useful at all. There were weak correlations between creatinine clearance (Cockcroft-Gault) and LC-MS/MS, HTI and ECA (p<0.001 for all). A high body weight with normal kidney function was associated with low dabigatran levels. CONCLUSIONS: HTI and ECA reflect the intensity of dabigatran anticoagulation, but LC-MS/MS is required to quantify low levels or infer absence of dabigatran. Most real life patients with a normal creatinine clearance had low dabigatran levels suggesting a low risk of bleeding but possibly limited protection against stroke.

Evaluation of coagulation assays versus LC-MS/MS for determinations of dabigatran concentrations in plasma.

BACKGROUND: Dabigatran is an oral direct thrombin inhibitor for which routine laboratory monitoring is currently not recommended. However, there are situations in which measurements of the drug and its effect are desirable. We therefore compared and validated different coagulation methods for assessments of dabigatran in clinical samples in relation to measurements of plasma dabigatran, without the purpose of establishing effective and safe concentrations of dabigatran in plasma. METHODS: Samples were obtained from 70 atrial fibrillation patients treated with dabigatran etexilate. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and were compared with coagulation methods Hemoclot thrombin inhibitors (HTI) and Ecarin clotting assay (ECA), as well as with prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT). RESULTS: A wide range of dabigatran concentrations was determined by LC-MS/MS (<0.5-586 ng/mL). Correlations between LC-MS/MS results and estimated concentrations were excellent for both HTI and ECA overall (r(2) = 0.97 and 0.96 respectively, p < 0.0001), but the precision and variability of these assays were not fully satisfactory in the low range of dabigatran plasma concentrations, in which ECA performed better than HTI. aPTT performed poorly, and was normal (<40 s) even with dabigatran levels of 60 ng/mL. PT-INR was normal even at supratherapeutic dabigatran concentrations. CONCLUSION: LC-MS/MS is the gold standard for measurements of dabigatran in plasma. Alternatively, either HTI or ECA assays may be used, but neither of these assays is dependable when monitoring low levels or to infer total absence of dabigatran. The aPTT assay is relatively insensitive to dabigatran, and normal aPTT results may be observed even with therapeutic dabigatran concentrations.

Pneumatic tube transport affects platelet function measured by multiplate electrode aggregometry.

Multiple electrode aggregometry (MEA) is used to measure platelet function. Pneumatic tube transport systems (PTS) for delivery of patient samples to a central laboratory are often used to reduce turnaround time for vital analyses. We evaluated the effects of PTS transport on platelet function as measured by MEA. Duplicate samples were collected from 58 individuals. One sample was sent using PTS and the other was carried by personnel to the lab. Platelet function was measured by means of a Multiplate® analyzer using the ADP test, ASPI test, COL test, RISTO test and TRAP test. Samples transported using PTS showed a reduction of AUC-values of up to a 100% of the average as compared to samples carried by personnel and a majority showed reductions of AUC-values greater than 20% of the average. Bias±95% limits of agreement for the ADP test were 26±56% of the average. Bias±95% limits of agreement for the ASPI test were 16±58% of the average. Bias±95% limits of agreement for the COL test were 20±54% of the average. Bias±95% limits of agreement for the RISTO were 14±79% of the average. Bias±95% limits of agreement for the TRAP test were 19±45% of the average. We conclude that PTS transport affect platelet activity as measured by MEA. We advise against clinical decisions regarding platelet function on the basis of samples sent by PTS in our hospital settings.