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Essentials Factor Xa inhibitors cause more abnormal menstrual bleeding (AUB) than vitamin-K antagonists (VKA). We analyzed data of AUB in women, evaluating dabigatran versus VKA. We observed a 41% lower risk of AUB in women on dabigatran compared to those on VKA. Our findings of lower AUB risk on dabigatran should be corroborated in future studies., Summary: Introduction Although direct oral anticoagulants (DOACs) are associated with a better safety profile than warfarin in patients with acute venous thromboembolism (VTE), direct factor Xa inhibitors involve a higher risk of abnormal uterine bleeding (AUB). We aimed to determine the risk of AUB during anticoagulation with dabigatran compared with warfarin. Methods Post-hoc analysis of the pooled RE-COVER studies and the RE-MEDY trial. Incidences of AUB, based on a defined preferred terms search for adverse events, in female patients aged 18-50 years treated with dabigatran, were compared with those in women treated with warfarin. Results Of the 2964 women included in the above-mentioned trials, 1280 women were in the relevant age category (18-50 years) and included in the current analysis. A total of 643 patients were randomized to treatment with dabigatran and 637 to treatment with warfarin. The overall rate of AUB was 8.1%, 5.9% for the women treated with dabigatran and 9.6% in those treated with warfarin, for an odds ratio for dabigatran-treated patients of 0.59 (95% confidence interval [CI], 0.39-0.90; P = 0.015). In the dabigatran-treated patients, three (0.5%) suffered major bleeding (MB) vs. five (0.8%) in the warfarin-treated patients (HR, 0.65; 95% CI, 0.15-2.72). MB or non-major relevant bleeding occurred in 30 (4.7%) patients randomized to receive dabigatran and 57 (8.9%) randomized to receive warfarin (HR, 0.53; 95% CI, 0.34-0.83). None of the bleeding events was fatal. Conclusion Dabigatran treatment was associated with a significantly (41%) lower risk of AUB than warfarin. Future studies in daily practice are needed to corroborate these findings., (© 2018 International Society on Thrombosis and Haemostasis.)

Management of acute venous thromboembolism (VTE) with anticoagulants in elderly patients and those with chronic kidney disease poses special challenges. The RE-COVER and RE-COVER II trials showed that dabigatran 150 mg twice daily was as effective as warfarin over 6 months in preventing recurrent VTE, with a lower bleeding risk. We now assess the effects of old age and renal impairment (RI) on pooled trial outcomes in 5,107 patients: 4,504 aged <75 years and 603 aged ≥75 years. The primary efficacy outcome was symptomatic VTE/VTE-related death. Safety outcomes were centrally adjudicated major bleeding events (MBEs), MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeds. Baseline renal function was categorized as normal, mild RI or moderate RI. A total of 3,698 had normal renal function and 1,100 and 237 had mild and moderate RI, respectively (23 patients with severe RI and 49 with missing creatinine clearance data were not included). For dabigatran, VTE/VTE-related death decreased from 3.1% (normal renal function) to 1.9% for mild RI and to 0.0% for moderate RI. For warfarin, the event rates were 2.6, 1.6 and 4.1%, respectively. Overall, major bleeding increased with increasing RI ( p  = 0.0037) and with age ( p  = 0.4350), with no apparent difference between the dabigatran and warfarin patients. Dabigatran shows better efficacy than warfarin in RI and in the elderly patients, probably because of an increase in the concentration of dabigatran. However, bleeding risk increases with both dabigatran and warfarin in the presence of RI., Competing Interests: Conflicts of Interest: Samuel Z. Goldhaber receives honoraria for consulting activities from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, Portola and Zafgen. Dr. Goldhaber receives research support from BiO2 Medical, Boehringer Ingelheim, BMS, BTG EKOS, Daiichi, the National Heart, Lung, and Blood Institute of the National Institutes of Health, Janssen and the Thrombosis Research Institute.Henry Eriksson receives honoraria for lecturing and consulting activities from Boehringer Ingelheim, Bayer, Pfizer and LeoPharma.Ajay Kakkar receives honoraria for consulting activities from Boehringer Ingelheim, Bayer, Janssen, Daiichi Sankyo, and Sanofi. He receives research support from Bayer.Sebastian Schellong receives honoraria for lecturing and for consulting activities from Boehringer Ingelheim, Bayer, Bayer HealthCare, BMS, Daiichi Sankyo and Pfizer.Sam Schulman receives honoraria for consulting activities from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Bristol-Myers-Squibb, and research grants from Boehringer Ingelheim, Baxalta and Octapharma.Martin Feuring is an employee of Boehringer Ingelheim.Mandy Fraessdorf is an employee of Boehringer Ingelheim.Jörg Kreuzer is an employee of Boehringer Ingelheim.Elke Schueler is an employee of HMS Analytic Software Gmbh., (Schattauer GmbH Stuttgart.)

It is unclear whether thrombophilia causes resistance to anticoagulant therapy. Post hoc analyses of data from RE-COVER ® , RE-COVER ™ II, and RE-MEDY ™ were performed to compare dabigatran etexilate with warfarin for the treatment and prevention of venous thromboembolism (VTE) in patients with thrombophilia or antiphospholipid antibody syndrome (APS). There were no significant differences in symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. All bleeding event categories were less frequent with dabigatran etexilate than with warfarin, regardless of whether patients had thrombophilia, no thrombophilia, or were not tested. However, these differences did not reach significance in every group. In patients with APS, there was no significant difference in VTE/VTE-related deaths between the two treatment arms. Rates of bleeding events tended to be lower with dabigatran etexilate than with warfarin, reaching statistical significance for any bleeding event. In conclusion, the efficacy and safety of dabigatran etexilate were not significantly affected by the presence of thrombophilia or APS. ClinicalTrials.gov RECOVER IDENTIFIER NCT00291330; RECOVER II IDENTIFIER NCT00680186; RE-MEDY IDENTIFIER NCT00329238., (© The Author(s) 2016.)

Dabigatran was non-inferior to warfarin for prevention of recurrent venous thromboembolism (VTE), and dabigatran had a lower rate of bleeding compared with warfarin in two large-scale randomised trials, RE-COVER and RE-COVER II. In this study, we investigate the efficacy and safety of dabigatran versus warfarin according to the index event that qualified the patient for enrollment, either symptomatic pulmonary embolism (PE) with or without deep-vein thrombosis (DVT), or DVT alone. We then analyse the anticoagulant effect of dabigatran vs warfarin on patients enrolled with PE. The pooled dataset for the efficacy analysis consisted of 2553 and 2554 patients who were randomised to dabigatran and warfarin, respectively. Recurrent VTE/VTE-related death during the study period and additional 30-day follow-up occurred in 2.7 % of all patients on dabigatran and in 2.4 % on warfarin (hazard ratio [HR] 1.09 [95 % confidence interval 0.77, 1.54]). In patients with PE as their index event, recurrent VTE/VTE-related death occurred in 2.9 % vs 3.1 % of patients (HR 0.93 [0.53, 1.64]). There were significantly fewer major bleeding events in patients treated with dabigatran than with warfarin (HR 0.60 [0.36, 0.99]). The pattern was similar both in patients with PE and in those with DVT alone as the index event. These analyses of the pooled dataset from the RE-COVER and RE-COVER II trials indicate that dabigatran is as effective as warfarin in preventing recurrent VTE, regardless of whether patients present with symptomatic PE (with or without DVT) or with symptomatic DVT alone. Dabigatran was also associated with a lower risk of bleeding than warfarin, regardless of the index event.

Introduction: Venous thromboembolism (VTE) can be life-threatening and requires anticoagulant treatment; for many years, vitamin K antagonists, e.g. warfarin, were the only oral anticoagulants available for long-term treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug-drug and drug-food interactions, and a narrow therapeutic range. These limitations spurred the search for non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran etexilate., Areas Covered: The authors illustrate the progression of preclinical and clinical studies leading to the development of dabigatran, the only approved NOAC to act by direct thrombin inhibition. They focus on molecule discovery, animal models of thrombosis, clinical trials and post-launch activities in VTE treatment., Expert Opinion: Dabigatran demonstrated comparable efficacy to the highly effective warfarin, and a more favourable safety profile in trials of VTE treatment. A favourable anticoagulant safety profile in addition to efficacy is essential for VTE treatment. Availability of the dabigatran-specific reversal agent, idarucizumab, provides a means of rapidly reversing the anticoagulant effect if required. Future investigations into the optimal duration of VTE treatment and an evaluation of the impact of idarucizumab, in real-world studies, could provide valuable information to help optimise treatment for selected patients.

Background: Strategies used for the management of dabigatran-related major bleeding events (MBEs), and their effectiveness have not been systematically evaluated., Methods: Reports on 1034 individuals experiencing 1121 MBEs (696 on dabigatran, and 425 on warfarin) in 5 phase III randomized controlled trials were assessed independently by two investigators., Results: MBEs were managed either by drug discontinuation only (37%), or drug discontinuation with either transfusion of only red cell concentrates (38%), or plasma (23%). Few MBEs (2%) were treated with coagulation factor concentrates. The effectiveness of the management was assessed as good in significantly larger proportion of MBEs on dabigatran (91%) than on warfarin (84%, odds ratio [OR] 1.68; 95% confidence interval [CI], 1.14-2.49), which was consistent with the lower 30-day mortality (OR (OR 0.66; 95% CI, 0.44-1.00)). The effectiveness of bleeding management in non-traumatic bleeding was better in patients with dabigatran than with warfarin (OR 1.82; 95% CI, 1.18-2.79) but was similar in traumatic bleeding (OR 0.75; 95% CI, 0.25-2.30). The relative effectiveness of management of bleeding and 30-day mortality rates across other key subgroups of patients or sites of bleeding, the use of platelet inhibitors, age-, sex- and renal function subgroups, were comparable in MBEs on dabigatran or warfarin., Conclusion: Despite the unavailability of a specific antidote at the time of these studies, bleeding in patients receiving dabigatran was managed in the overwhelming majority of patients without coagulation factor concentrates, with comparable or superior effectiveness and lower 30-day mortality rates versus those who bleed while receiving warfarin., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The efficacy and safety of dabigatran for treatment of venous thromboembolism (VTE) were demonstrated in two trials. It is unclear if the results pertain to patients with cancer and VTE. Data from two randomised trials comparing dabigatran and warfarin for acute VTE were pooled. Primary efficacy outcome was symptomatic recurrent VTE and related death from randomisation to the end of the treatment period. Safety outcomes were major, major and clinically relevant non-major, and any bleeding during the oral-only treatment period. Patients with active cancer (=within 5 years) at baseline or diagnosed during the study were analysed. Compared with 4,772 patients without cancer, recurrent VTE occurred more frequently in 335 patients with cancer at any time (hazard ratio [HR] 3.3; 95 % confidence interval [CI], 2.1-5.3) and more often in 114 with cancer diagnosed during the study compared to 221 with cancer at baseline (HR 2.6; 95 % CI, 1.1-6.2). There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95 % CI, 0.20-2.8) or diagnosed during the study (HR 0.63; 95 % CI, 0.20-2.0). Major bleeding (HR 4.1; 95 % CI, 2.2-7.5) and any bleeding (HR 1.5; 95 % CI, 1.2-2.0) were more frequent in patients with cancer than without, but with similar incidence in cancer with dabigatran or warfarin. In conclusion, in cancer patients, dabigatran provided similar clinical benefit as warfarin. VTE recurrence or bleeding were similar in patients on dabigatran or warfarin. The efficacy of dabigatran has not been assessed in comparison with low-molecular-weight heparin.

Purpose: Dabigatran etexilate is an oral, reversible, direct thrombin inhibitor licensed for the prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. The aim of this study was to investigate whether, and to what extent, a switch from enoxparin to dabigatran etexilate affects the pharmacokinetic (PK) and pharmacodynamic (PD) parameters and safety profile of dabigatran., Methods: Enoxaparin 40 mg was administered subcutaneously once daily for 3 days followed by a single dose of dabigatran etexilate 220 mg (test treatment) on day 4 in an open-label, two-way cross-over trial in healthy volunteers. Dabigatran plasma levels were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. Anticoagulant activity was measured using a number of clotting tests, including prothrombinase-induced clotting time (PiCT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT)., Results: PK, PD, and safety data were available for 23 subjects for each treatment. The adjusted geometric mean test/reference ratio of area under the concentration-time curve for total dabigatran was 84% (90% confidence interval 67.2-105.0%) and 86% (67.0-110.0%) for maximum plasma concentration. The PiCT test/reference ratio, which represents the activity of enoxaparin and dabigatran, was elevated by approximately 15% for peak maximum effect ratio to baseline and total area under the effect curve (AUEC₀₋₄₈) activity, suggesting that some anticoagulant activity of enoxaparin was still present. Enoxaparin pre-treatment increased the AUEC₀₋₄₈ of activated partial thromboplastin time by approximately 14%. All other dabigatran-related PD markers were unaffected. Tolerability was good, with only mild and reversible adverse events during the treatment., Conclusion: Prior administration of enoxaparin did not meaningfully affect the PK or PD properties of dabigatran, and the switch from enoxaparin to dabigatran etexilate was well tolerated among the study subjects. These data support the safety of switching patients from enoxaparin to dabigatran etexilate.

1. The low molecular weight heparin (LMWH) dalteparin is used, for example, to prevent primary venous thromboembolism in patients undergoing surgery or in medically ill patients. The anticoagulant activity of dalteparin can be monitored by measuring anti-factor Xa levels and activated partial thromboplastin time (aPTT); however, aPTT is an unreliable parameter in this case. The aim of the present in vitro study was to evaluate the thrombelastograph ROTEM(®) (Tem International, Munich, Germany) with respect to determining the anticoagulant activity of dalteparin at therapeutic and supratherapeutic plasma concentrations. 2. The ROTEM(®) parameters, namely coagulation time (CT), clot formation time (CFT) and maximum clot firmness (MCF), were measured using the reagents EXTEM and INTEM (Pentapharm, Munich, Germany) at increasing concentrations of dalteparin (0.01-10 μg/mL, which corresponded to anti-factor Xa levels of 1-1000 U/mL, respectively). 3. The mean CT measured using EXTEM was found to increase from 65.4 ± 27.9 s at baseline to 173.3 ± 112.2 s and 332.2 ± 200.7 s at drug concentrations of 1 and 10 μg/mL, respectively (P < 0.0001 for both). Moreover, the mean CFT value (EXTEM) increased from 97.7 ± 21.5 s at baseline to 187.6 ± 115.2 s (P = 0.0001) at a drug concentration of 10 μg/mL, which is greater than the therapeutic anti-factor Xa concentrations for LMWH. The results obtained when INTEM was used as the reagent were similar to those obtained using EXTEM. 4. In conclusion, the results indicate that the thrombelastograph ROTEM(®) can detect the anticoagulant effects of dalteparin only at supratherapeutic levels of anti-factor Xa., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)

Background: The aim of this in-vitro pilot study was to assess the usefulness of the thrombelastograph ROTEM® for determining the anticoagulant activity of lepirudin., Methods: The ROTEM® parameters, clotting-time, clot formation time and maximum clot firmness were measured in the presence of increasing concentrations of lepirudin (10-4 μg/ml - 10 μg/ml). Citrated blood was obtained from 16 healthy male subjects., Results: Clotting-time increased from 79.1 ± 53.4 s at baseline to 194.1 ± 151.9 s at a drug concentration of 1μg/ml as measured with EXTEM (p < 0.0001). Borderline significance was found for the difference between maximum clot firmness at baseline (60.2 ± 4.3 mm) and after drug application (55.5 ± 6.5 mm)., Conclusions: This pilot investigation shows that the ROTEM® device may be suitable for monitoring lepirudin at low concentrations but the results should be confirmed in a larger study and the ROTEM® device validated against standard methods.

Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.

The objective of the study was to demonstrate the bioequivalence of subcutaneously (s.c.) and intravenously (i.v.) administered fixed, high-dose low-molecular-weight heparin (LMWH) on anti-activated factor X activity (anti-FXa). Secondary objectives were the analysis of the pharmacodynamic effects on Heptest, thrombin inhibition, tissue factor pathway inhibitor (TFPI), and the urinary excretion of LMWH in the randomized cross-over study following i.v. and s.c. application of 8000 anti-FXa units LMWH Certoparin in 18 healthy subjects. The bioequivalence following s.c. administration was demonstrated from the antilog of the point estimator for the application differences (s.c. minus i.v.) by an area under the activity-time curve (0-24 h) of 101% (range, 93-110%). LMWH was bioequivalent also on Heptest and TFPI, and was 50% on thrombin inhibition. The urinary excretion of biologically active material was 4.1 and 3.6% following i.v. and s.c. administration, respectively. Differences in the pharmacodynamic parameters of the assays indicate specific biological actions of high and low molecular sacharide chains of the LMWH.

[14C]-Serotonin release assay (14C-SRA) from platelets is considered to be the most sensitive test for laboratory confirmation of heparin-induced thrombocytopenia (HIT). This study compared 14C-SRA with an enzyme immunoassay (EIA) to determine the release of serotonin from platelets in the presence of heparin and serum from HIT patients. The normal range (median, 2.5 and 97.5 percentiles) of serotonin release from platelets in healthy subjects (n = 149) is 38 ng/ml (19 and 62) measured by EIA-SRA. Serum from HIT patients (n = 42) released 2548 ng/ml (244 and 7987) serotonin in the presence of 0.1 IU/ml heparin and 29 ng/ml (13 and 76) in the presence of 100 IU/ml heparin. One hundred per cent and 15% of HIT samples exhibited an elevated serotonin release from platelets in the presence of 0.1 IU/ml low molecular weight (LMW) heparin, 2100 ng/ml (869 and 5968), or danaparoid, 272 ng/ml (143 and 403), respectively. The sensitivity and specificity of the EIA-SRA was 100% and 97.4% and of the 14C-SRA 100% and 92.9% in HIT patients. No false-positive results were found in patients receiving heparin (n = 28), in patients with elevated levels of bilirubin (n = 5), in patients with antiphospholipid antibody syndrome (n = 10) or in non-HIT patients (n = 78) with both assays. The EIA technique to quantify serotonin release from platelets provides a reliable non-radioactive method to diagnose heparin-induced thrombocytopenia and to assess in vitro crossreactivity of low molecular weight heparins and heparinoid.