The pharmacokinetics of dabigatran in a rat model of hyperlipidaemia induced by poloxamer 407.

Various pharmacokinetic changes have been reported in experimental hyperlipidemic (HL) animal models. To evaluate whether P-glycoprotein (P-gp) activity was affected in HL rats, we assessed the pharmacokinetics of dabigatran after oral administration of dabigatran etexilate (DABE); this is a dabigatran prodrug and a well-known P-gp substrate.HL and control rats exhibited similar area under the plasma concentration-time curve (AUC), total body clearance (CL), and steady state volume of distribution (Vss) values following intravenous administration of dabigatran (1 mg/kg). This suggested that the distribution and elimination of dabigatran were similar in control and HL rats.The hepatic and intestinal P-gp protein levels did not differ significantly between control and HL rats. The dabigatran AUC and extent of absolute oral bioavailability (F) values were similar in control and HL rats following oral administration of DABE (10 mg/kg as dabigatran). Therefore, there was no apparent change in intestinal P-gp activity in HL rats compared to control rats.This study revealed no significant change in P-gp expression or activity in the intestine or liver of HL rats, and similar pharmacokinetics of dabigatran. Hyperlipidaemia may not directly affect the oral absorption of P-gp substrate drugs.

Unified Methodology for the Primary Preclinical In Vivo Screening of New Anticoagulant Pharmaceutical Agents from Hematophagous Organisms.

The development of novel anticoagulants requires a comprehensive investigational approach that is capable of characterizing different aspects of antithrombotic activity. The necessary experiments include both in vitro assays and studies on animal models. The required in vivo approaches include the assessment of pharmacokinetic and pharmacodynamic profiles and studies of hemorrhagic and antithrombotic effects. Comparison of anticoagulants with different mechanisms of action and administration types requires unification of the experiment scheme and its adaptation to existing laboratory conditions. The rodent thrombosis models in combination with the assessment of hemostasis parameters and hematological analysis are the classic methods for conducting preclinical studies. We report an approach for the comparative study of the activity of different anticoagulants in vivo, including the investigation of pharmacodynamics and the assessment of hemorrhagic effects (tail-cut bleeding model) and pathological thrombus formation (inferior vena cava stenosis model of venous thrombosis). The reproducibility and uniformity of our set of experiments were illustrated on unfractionated heparin and dabigatran etexilate (the most common pharmaceuticals in antithrombic therapy) as comparator drugs and an experimental drug variegin from the tick Amblyomma variegatum. Variegin is notorious since it is a potential analogue of bivalirudin (Angiomax, Novartis AG, Basel, Switzerland), which is now being actively introduced into antithrombotic therapy.

Safety and effectiveness of dabigatran in routine clinical practice: the RE-COVERY DVT/PE study.

RE-COVERY DVT/PE is a two-phase, international, observational study of anticoagulant therapy in patients with deep vein thrombosis and/or pulmonary embolism (DVT/PE). The objective of the second phase was to compare the safety and effectiveness of dabigatran versus a vitamin K antagonist (VKA) over 1 year of follow-up. Primary safety and effectiveness outcomes were major or clinically relevant nonmajor bleeding events (MBE/CRNMBEs) and symptomatic recurrent venous thromboembolism (VTE) (including deaths related to recurrent VTE). To minimize bias due to unbalanced patient characteristics, only patients in an overlapping range of estimated propensity scores were included (analytic set), and propensity score weighting was applied to compare outcomes. Outcome analysis used an as-treated approach, censoring patients after they stopped or switched their initial anticoagulant. Overall, 3009 patients enrolled from 2016 to 2018 were eligible: 60% were diagnosed with DVT alone, 21% with PE alone, and 19% with DVT plus PE. The analytic set consisted of 2969 patients. The incidence rate in %/year (95% confidence interval [CI]) of MBE/CRNMBEs was 2.63 (1.79-3.74) with dabigatran versus 4.48 (3.23-6.06) with warfarin; hazard ratio 0.63 (95% CI 0.32-1.25). For symptomatic recurrent nonfatal or fatal VTE the incidence rate was 1.53 (0.91-2.42) with dabigatran versus 2.01 (1.21-3.14) with VKAs; hazard ratio 0.78 (95% CI 0.30-2.02). In conclusion, we found lower annualized rates of MBE/CRNMBEs with dabigatran than VKA, although the difference was not statistically significant. Annualized rates of symptomatic VTE or related mortality were similar with dabigatran and VKA. These observational results with 1 year of follow-up reflect those of the randomized clinical trials. Trial registration: ClinicalTrials.gov identifier NCT02596230, first registered November 4, 2015.

Dabigatran plasma concentration indicated the risk of patients with non-valvular atrial fibrillation.

This study aimed to evaluate the variability of dabigatran plasma concentration and the association with clinical events in Chinese patients treated with dabigatran etexilate (DE) for non-valvular atrial fibrillation (NVAF). The steady-state concentration of dabigatran (the active metabolite of DE) was determined at trough and peak. The effect of dabigatran concentration variability and related factors on clinical outcomes were explored. Data from 86 patients receiving a fixed dose of 110 mg showed that dabigatran trough concentration varied remarkably. Age, BMI and history of heart failure were identified as important covariates for dabigatran trough concentration. Dabigatran trough concentration (P = 0.002) and history of hypertension (P = 0.012) scores were identified as key factors for predicting the risk of bleeding events. Dabigatran trough concentration, affected by Age, BMI and history of heart failure, may serve as an independent risk factor for bleeding events in Chinese patients treated with DE for NVAF.

Rhabdomyolysis happened after the start of dabigatran etexilate treatment: A case report.

There are few reports of rhabdomyolysis caused by anticoagulants, and it is extremely rare for it to be caused by dabigatran etexilate. An 86-year-old female experienced sudden muscle weakness and pain, a significant increase in Creatine kinase, and renal impairment after oral administration of dabigatran etexilate for 3 weeks. The enhanced thigh MRI showed abnormal signal in multiple thigh muscle groups, indicating that the lesions should be considered inflammatory diseases. In conclusion, the possibility of rhabdomyolysis should be ruled out when muscle weakness and myalgia occur at the beginning of dabigatran etexilate treatment.

Biopharmaceutics considerations for direct oral anticoagulants.

Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) have been clinically used in the treatment of coagulation disorders. There are four DOACs approved since 2010 (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban), and they were designed to overcome the practical limitations of VKA. This review summarized biopharmaceutics considerations about DOACs, which are critically discussed, applying risk analyses to subside the further classification of these drugs according to the Biopharmaceutics Classification System (BCS). These discussions included data compiled about physicochemical properties, equilibrium solubility, permeability, and drug dissolution of DOACs. From the biopharmaceutics characteristics is possible to identify critical variables related to the absorption process, which can help in the design of new formulations. The data were compared with the criteria recommended by regulatory agencies for the biopharmaceutics classification according to the BCS. From that, these data may be used to discuss the approval of generic medicines by the BCS-based biowaiver, and the clinical risks arising from novel formulations with DOACs. However, although there are indications of biopharmaceutics classifications for DOACs, conclusive information to classify these compounds according to the BCS is lacking, requiring more experimental studies to achieve this aim. Conclusive information is essential for a safe decision about the biowaiver, as well as to guide the development of new formulations containing the DOACs.

Acute limb ischemia in a patient with pre-fibrotic myelofibrosis complicated by heparin-induced thrombocytopenia and thrombosis - case report and systematic review of dabigatran use.

A 49-year-old man was diagnosed with pre-fibrotic myelofibrosis after acute left lower-limb ischemia requiring amputation and portal vein thrombosis. After surgery he developed heparin-induced thrombocytopenia (HIT) with venous thromboembolism, successfully treated with argatroban followed by dabigatran. Our systematic review of the literature supports the use of dabigatran for suspected HIT.

Renal Excretion of Dabigatran: The Potential Role of Multidrug and Toxin Extrusion (MATE) Proteins.

Following oral administration, dabigatran etexilate (DABE) is rapidly hydrolyzed to its active form, dabigatran. DABE, but not dabigatran, presents as a P-glycoprotein (P-gp) substrate and has increasingly been used as a probe drug. Therefore, although dosed as DABE, a P-gp drug-drug interaction (DDI) is reported as a dabigatran plasma concentration ratio (perpetrator versus placebo). Because the majority of a DABE dose (80 to 85%) is recovered in urine as unchanged dabigatran (renal active secretion is ∼25% of total clearance), dabigatran was evaluated in vitro as a substrate of various human renal transporters. Active (pyrimethamine-sensitive) dabigatran uptake was observed with human embryonic kidney (HEK) 293 cells expressing multidrug and toxin extrusion protein 1 (MATE1) and 2K (MATE2K), with Michaelis-Menten constant (Km) values of 4.0 and 8.0 µM, respectively. By comparison, no uptake of 2 µM dabigatran (versus mock-transfected HEK293 cells) was evident with HEK293 cells transfected with organic cation transporters (OCT1 and OCT2) and organic anion transporters (OAT1, 2, 3, and 4). The efflux ratios of dabigatran across P-gp- and BCRP (breast cancer resistance protein)-MDCK (Madin-Darby canine kidney) cell monolayers were 1.5 and 2.0 (versus mock-MDCK cell monolayers), suggesting dabigatran is a relatively poor P-gp and BCRP substrate. Three of five drugs (verapamil, ketoconazole, and quinidine) known to interact clinically with dabigatran, as P-gp inhibitors, presented as MATE inhibitors in vitro (IC50 = 1.0 to 25.2 µM). Taken together, although no basolateral transporter was identified for dabigatran, the results suggest that apical MATE1 and MATE2K could play an important role in its renal clearance. MATE-mediated renal secretion of dabigatran needs to be considered when interpreting the results of P-gp DDI studies following DABE administration.

Irinotecan-induced gastrointestinal damage impairs the absorption of dabigatran etexilate.

Irinotecan causes serious gastrointestinal damage. Dabigatran etexilate (DABE), an oral anticoagulant and substrate of P-glycoprotein (P-gp), is poorly absorbed and exhibits low bioavailability in humans. The aim of this study was to evaluate the effects of irinotecan-induced gastrointestinal damage on the pharmacokinetics/pharmacodynamics (PK/PD) of DABE. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. To investigate the PK profile of dabigatran (DAB), an active moiety of DABE, DABE was administered orally on day 5, and then DAB was administered intravenously on day 6. To evaluate the PD profile of DAB, the activated partial thromboplastin time (APTT) was measured. The protein expression level of intestinal P-gp was evaluated. In the irinotecan-treated rats, the area under the concentration-time curve of DAB after the oral administration of DABE and the bioavailability of DABE were decreased significantly. The APTT ratio also decreased, suggesting that the impaired efficacy of DABE was attributable to a reduction in its bioavailability. The expression of intestinal P-gp was higher in the irinotecan-treated rats. Taking into consideration the histological damage caused to the intestinal epithelium, both the increased P-gp expression and the reduced passive diffusion were considered to be responsible for the reduction in the bioavailability of DABE.

[Perioperative management of trauma surgery patients treated with direct oral anticoagulants]. / Perioperatives Management unfallchirurgischer Patienten unter Therapie mit direkten oralen Antikoagulanzien.

As the population gets older the prevalence of atrial fibrillation and venous thromboembolism also increases. Therefore, more patients require anticoagulation and currently direct oral anticoagulants (DOAC), such as dabigatran etexilate, apixaban, rivaroxaban and edoxaban are preferred to vitamin K antagonists (VKA), mainly because of the more favorable risk-benefit profile with respect to bleeding. Older patients in particular frequently present at the accident and emergency department due to falls and an increased risk of fractures. The perioperative management of these patients who are treated with DOACs is a challenge in the clinical routine and needs special consideration. This article discusses these issues in an interdisciplinary approach and develops strategies for the perioperative management of patients treated with DOACs and undergoing trauma or orthopedic surgery.

Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs).

The use of warfarin, the most commonly prescribed oral anticoagulant, is being questioned by clinicians worldwide due to warfarin several limitations (a limited therapeutic window and significant variability in dose-response among individuals, in addition to a potential for drug-drug interactions). Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of antithrombotic effects and a predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile led to the approval of five new drugs: the direct factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence of the need for drug monitoring for changes in anti-coagulation and fewer clinically significant PK and PD drug-drug interactions. NOACs exposure will likely be increased by the administration of strong P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-gp inducers could significantly decrease the NOACs plasma concentration with an associated reduction in their anticoagulant effects. This manuscript gives an overview of NOACs PK profiles and their drug-drug interactions potential. This is meant to be of help to physicians in choosing the best therapeutic approach for their patients.

Successful treatment with idarucizumab for diffuse alveolar hemorrhage induced by dabigatran etexilate: a case report.

We report the case of an 81-year-old man taking dabigatran etexilate (dabigatran) for chronic atrial fibrillation, who presented with acute-onset hemoptysis and hypoxia. Chest high-resolution computed tomography showed bilateral ground grass opacities. After admission, his respiratory failure progressed rapidly and bronchoalveolar lavage was performed immediately, which showed copious amounts of bloody fluid and hemosiderin-laden macrophages with Prussian blue staining. He was diagnosed as having diffuse alveolar hemorrhage (DAH). We therefore stopped dabigatran and initiated multimodality therapy including idarucizumab, which is a reversal agent for dabigatran. Clinical and radiological improvement was observed and he was discharged without any impairment. There has been no relapse of DAH since then. No abnormalities were detected on further investigation; finally, we concluded that his DAH was caused by dabigatran. This is the first known case of idarucizumab use for severe DAH caused by dabigatran. Our case suggested that dabigatran can cause life-threatening DAH; in such cases, administering idarucizumab could be an effective treatment option.

Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™.

The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Post-hoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0-3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant non-major bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68-0.95 and RE-MEDY, HR 0.73; 95% CI 0.59-0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control.

Dabigatran etexilate in a vitamin-K antagonist non responder patient during Heartware HVAD support.

We report a case of a patient supported with a HeartWare left ventricular assist device for idiopathic cardiomyopathy who was resistance to vitamin-K antagonists three months after implantation. The patient initially started low-molecular-weight heparin therapy and then, after the onset of an ischemic stroke, switched to dabigatran etexilate (DE). The patient had progressive recovery of cardiac function for which the device was explanted. No thrombotic or bleeding events occurred during DE therapy.

Improved oral bioavailability and therapeutic efficacy of dabigatran etexilate via Soluplus-TPGS binary mixed micelles system.

The clinical use of dabigatran etexilate (DABE) is limited by its poor absorption and relatively low bioavailability. Our study aimed to explore the potential of a mixed micelle system composed of Soluplus® and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral absorption and bioavailability of DBAE. DBAE was first encapsulated into Soluplus/TPGS mixed micelles by a simple thin film hydration method. The DBAE loaded micelles displayed an average size distribution of around 83.13 nm. The cellular uptake of DBAE loaded micelles in Caco-2 cell monolayer was significantly enhanced by 2-2.6 fold over time as compared with DBAE suspension. Both lipid raft/caveolae and macropinocytosis-mediated the cell uptake of DBAE loaded micelles through P-glycoprotein (P-gp)-independent pathway. Compared with the DBAE suspension, the intestinal absorption of DBAE from DBAE mixed micelles in rats was significantly improved by 8 and 5-fold in ileum at 2 h and 4 h, respectively. Moreover, DBAE mixed micelles were absorbed into systemic circulation via both portal vein and lymphatic pathway. The oral bioavailability of DBAE mixed micelles in rats was 3.37 fold higher than that of DBAE suspension. DBAE mixed micelles exhibited a comparable anti-thrombolytic activity with a thrombosis inhibition rate of 63.18% compared with DBAE suspension in vivo. Thus, our study provides a promising drug delivery system to enhance the oral bioavailability and therapeutic efficacy of DBAE.

A comparison of apixaban and dabigatran etexilate for thromboprophylaxis following hip and knee replacement surgery.

INTRODUCTION: Patients who have undergone hip or knee replacement surgery are exposed to a high risk of developing a post-operative venous thromboembolus and so have a need for an effective, medication-based, thrombosis prophylaxis. New orally active anticoagulants have been available for a few years now. These specific substances directly block either thrombin (e.g., dabigatran etexilate) or Factor Xa (e.g., apixaban). It is not clear whether there are any efficacy differences between these two substances because there have never been any head-to-head studies carried out. MATERIALS AND METHODS: We have carried out a study comparing two new orally active anticoagulants dabigatran etexilate (Pradaxa®) and apixaban (Eliquis®) that were each given to two groups of 200 patients respectively, who had undergone elective hip or knee arthroplasty (100 each). Each patient was assessed for pre- and post-operative hemoglobin concentrations, post-operative blood loss, the number of transfused erythrocyte concentrates, the duration of wound secretion, clinical thromboembolic complications (deep vein thrombosis, pulmonary embolism, myocardial infarct), as well as gastrointestinal, intracranial or wound-related bleeding complications. RESULTS: Dabigatran etexilate treatment led to a significant increase in the duration of wound secretion in both arthroplasty groups when compared to apixaban: wound secretion lasted 1.2 days longer on average in the dabigatran etexilate group than in the apixaban group (4.1 ± 2.1 vs. 2.9 ± 1.8 days). There were no significant differences observed between the two anticoagulant groups when comparing pre- and post-operative Hb values, post-operative blood loss and the other clinical parameters. CONCLUSIONS: Thus, it appears that the direct thrombin inhibitor, dabigatran etexilate, is associated with a longer period of wound secretion following the implantation of hip and knee endoprostheses than that associated with the Factor Xa inhibitor, apixaban.

Assessment of Direct Oral Anticoagulant Prescribing and Monitoring Pre- and Post-Implementation of a Pharmacy Protocol at a Community Teaching Hospital.

Background: Direct oral anticoagulants (DOACs) have become popular alternatives to vitamin K antagonists for the treatment and prevention of thromboembolic diseases; however, there are limited data regarding the appropriate use of DOACs in clinical practice. To ensure safety and efficacy of these medications, it is important that decisions regarding their use in patients rely on the available evidence. Objective: The purpose of this study was to evaluate the appropriateness of DOAC prescribing in adult patients before and after the implementation of a pharmacist-driven DOAC protocol. Methods: Data were collected on adult patients admitted to a community teaching hospital who received DOAC therapy for at least 2 days between January and March 2015 (pre-intervention group) and between January and March 2016 (post-intervention group). These data were analyzed to measure inappropriately prescribed DOACs, defined based on DOAC indication, renal function, drug interactions, and other pertinent patient-specific factors. Prior to the start of data collection for the post-intervention group, a pharmacist-driven protocol was developed and implemented. DOAC education was provided to pharmacists, including an evidence-based prescribing table to guide appropriate DOAC therapy. Comparisons were made between the pre-intervention and post-intervention groups to determine the impact of the pharmacist-driven service on appropriate DOAC prescribing. Results: Fifty patients were analyzed in the pre-intervention group compared with 85 patients in the post-intervention group, with a total of 333 and 816 doses administered, respectively. Of the total doses administered, 32.4% were considered inappropriate in the pre-intervention group compared with 13.8% in the post-intervention group (adjusted odds ratio [OR], 0.42, 95% CI, 0.19-0.96; p = 0.039). Conclusions: Implementing a pharmacist-driven DOAC service significantly improved appropriate prescribing of these agents. Provider education regarding DOAC use is essential to further increase appropriate prescribing of DOACs, optimize patients' therapy, and prevent adverse drug events.

Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation.

AIMS: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. METHODS AND RESULTS: The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). CONCLUSION: Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.

Dabigatran etexilate for thromboprophylaxis in over 5000 hip or knee replacement patients in a real-world clinical setting.

BACKGROUND: Thromboprophylaxis is recommended for patients undergoing total hip or total knee replacement (THR, TKR). An international, open-label, prospective, observational, single-arm study in a routine clinical setting was performed to assess the safety and efficacy of dabigatran etexilate 220 mg once daily in patients undergoing THR or TKR, and in subgroups of patients with potentially increased risk of bleeding or venous thromboembolism (VTE). MATERIALS AND METHODS: Patients were ≥18 years and required to be eligible to receive dabigatran 220 mg once daily (first dose 110 mg 1-4 h after THR/TKR surgery) according to the European Summary of Product Characteristics. The primary safety and efficacy outcomes were incidence of major bleeding events (MBEs), and the composite incidence of symptomatic VTE events and all-cause mortality, respectively. RESULTS: In total, 5292 patients (median age 64 years) were enrolled and received dabigatran (2734 THR and 2558 TKR). Median drug exposure was 31 days (THR 34 days; TKR 27 days). Overall incidence of MBEs was 0.72 % (95 % confidence interval [CI] 0.51, 0.98), and this rate was comparable between types of surgery and was not significantly affected by protocol-defined risk factors. The overall incidence of symptomatic VTE and all-cause mortality was 1.04 % (95 % CI 0.78, 1.35); the only significant risk factor was history of VTE events (odds ratio 5.59; 95 % CI 2.53, 11.08). A post-hoc analysis showed that the incidence of MBEs in this observational study was similar to or lower than those reported in previous phase 3 trials. CONCLUSIONS: Results from this observational study of dabigatran etexilate administered to patients undergoing THR or TKR surgery are reassuring and supportive of those obtained in dabigatran phase 3 trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00846807.

Carbon-13 and carbon-14 labeled dabigatran etexilate and tritium labeled dabigatran.

Dabigatran etexilate or pradaxa, a novel oral anticoagulant, is a reversible, competitive, direct thrombin inhibitor. It is used to prevent strokes in patients with atrial fibrillation and the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or a knee. Pradaxa is the only novel oral anticoagulant available with both proven superiority to warfarin and a specific reversal agent for use in rare emergency situations. The detailed description of the synthesis of carbon-13 and carbon-14 labeled dabigatran etexilate, and tritium labeled dabigatran is described. The synthesis of carbon-13 dabigatran etexilate was accomplished in eight steps and in 6% overall yield starting from aniline-13 C6 . Ethyl bromoacetate-1-14 C was the reagent of choice in the synthesis of carbon-14 labeled dabigatran etexilate in six steps and 17% overall yield. Tritium labeled dabigatran was prepared using either direct tritium incorporation under Crabtree's catalytic conditions or tritium-dehalogenation of a diiodo-precursor of dabigatran.