Dabigatran Research Articles

Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: A population-based nested case-control study.

AimsTo assess the association between concurrent use of potential pharmacokinetic or pharmacodynamic interacting drugs and major bleeding among direct oral anticoagulant (DOAC) users.MethodsWe performed a case–control study nested in a cohort of new users of DOACs (dabigatran etexilate, apixaban or rivaroxaban). Data were obtained from the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics (2008–2015). Cases were patients hospitalized having a primary diagnosis of major bleeding. Up to 4 controls were matched on age, sex, index date and region. Odds ratios (ORs) for the risk of major bleeding were assessed by conditional logistic regression analysis and adjusted for well‐known covariates for the risk of bleeding.ResultsWe identified 393 patients with a major bleeding from a total of 23 492 new users of DOACs and 1494 matched controls. Most subjects were users of rivaroxaban (58.8%) on the index date. The concurrent use of pharmacodynamic interacting drugs was associated with an increased risk of major bleeding (21.6% of cases vs 13.5% of controls, adjusted odds ratio [aOR] 1.92; 95% confidence interval [CI], 1.40–2.66). For the antiplatelet drugs the aOR was 2.01 (95% CI, 1.29–3.11) and for the selective serotonin reuptake inhibitors the aOR was 1.68 (95% CI, 1.10–2.59). We found no increased risk of major bleeding for concurrent use of pharmacokinetic interacting drugs vs DOACs alone (45.0 vs 51.2%; aOR: 0.77; 95% CI: 0.53–1.10).ConclusionAmong patients taking DOACs the concurrent use of antiplatelet drugs or selective serotonin reuptake inhibitors was associated with increased risk of major bleeding, while pharmacokinetic interacting drugs do not increase this risk.

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children

AbstractThis open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

A CLINICAL CASE OF LYSIS OF THROMBUS IN THE LEFT ATRIAL APPENDAGE IN A PATIENT WITH ATRIAL FIBRILLATION PREVIOUSLY TREATED WITH WARFARIN

The article describes the clinical observation of LAA thrombosis in a 46-year-old patient with atrial fibrillation that first occurred during taking warfarin; discusses further management of the patient. Due to inefficacy of medical cardioversion (CV) and the need to restore sinus rhythm, electric CV was planned. Before the planned restoration of the rhythm, transesophageal echocardiography was performed and a thrombus in the LAA was detected. Given that the patient had been on adequate warfarin therapy for a long time, it was decided to prescribe a drug from the direct oral anticoagulants group dabigatran etexilate at a dose of 150 mg BID for 8 weeks. The control transesophageal echocardiographic examination showed evidence of complete lysis of thrombus.

Monitoring the use of dabigatran etexilate for stroke prevention: compliance with renal function guidelines.

INTRODUCTION Dabigatran etexilate has become widely used in New Zealand, but information relating to when renal function monitoring is being undertaken is lacking. AIM To investigate if clinically appropriate renal function monitoring is being undertaken in New Zealand primary care for stroke prevention in non-valvular atrial fibrillation patients prescribed dabigatran etexilate. METHODS New Zealand non-valvular atrial fibrillation patients' prescription and primary care health data were extracted from national administrative databases for the period 1 July 2011 to 31 December 2015. The proportion of patients who had serum creatinine measurements at close proximity to treatment initiation and 12-months post initiation were assessed with 95% confidence intervals (CIs) and compared with Fisher's exact test. Log-rank tests for univariate analysis (gender, age, ethnicity and deprivation) effects on serum creatinine testing at dabigatran etexilate treatment initiation and 12-months post initiation were performed. RESULTS Overall, 1,948 patients who had been dispensed dabigatran etexilate with available primary care health data were identified. A total of 1,752 (89.9% [CI: 88.5-91.2]) patients had a renal function test at dabigatran etexilate initiation. There were 929 (72.8% [CI: 70.2-75.2]) patients who received ≥1 year supply of dabigatran etexilate and of these 207 (22.3% [CI: 19.6.6-25.1]) had a serum creatinine test 1 year after initiation. Demographic univariate analysis yielded insignificant log-rank tests for association with having serum creatinine measurements, except for Pacific Peoples. DISCUSSION There appears to be sub-optimal adherence to renal function monitoring for non-valvular atrial fibrillation patients who receive more than 12-months' treatment with dabigatran etexilate in New Zealand primary care.

Is dual therapy the correct strategy in frail elderly patients with atrial fibrillation and acute coronary syndrome?

Atrial fibrillation (AF) is a very common arrhythmia in clinical practice. Its incidence and prevalence are age-related and are growing in the last years. Age is a risk factor also for coronary artery disease (CAD), and with the evolution of preventive care, the first event (acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI)) takes place at a later age. If elderly patients with AF and CAD undergo ACS or PCI, they have indication to assume triple therapy. Triple therapy (oral anticoagulation (OAC) plus dual antiplatelet therapy (DAPT)) exposes patients to high bleeding risk. In the last 10 years, several clinical trials have tested dual therapy (OAC plus single antiplatelet therapy) in AF patients who undergo ACS or elective PCI. WOEST trial has tested warfarin + clopidogrel against triple therapy. PIONEER AF-PCI trial has tested low-dose rivaroxaban + P2Y12 inhibitor or very low-dose rivaroxaban + DAPT against standard triple therapy with warfarin. RE-DUAL PCI trial has tested two doses of dabigatran + P2Y12 inhibitor against standard triple therapy with Warfarin. AUGUSTUS trial has tested apixaban against warfarin both in dual therapy with P2Y12 inhibitor and in triple therapy with a P2Y12 inhibitor and aspirin. ENTRUST-AF PCI, last published study, has tested edoxaban + P2Y12 inhibitor against triple therapy. All these trials show dual therapy reduces significantly bleeding risk than triple therapy. In this paper, we analyze these clinical trials to understand if dual therapy results can be applied to elderly patients and what is probably the better approach in elderly AF patients undergo to ACS or PCI.

Effects of Long-term Thrombin Inhibition (Dabigatran Etexilate) on Spontaneous Thrombolytic Activity during the Progression of Atherosclerosis in ApoE-/--LDLR-/- Double-Knockout Mice.

Background and ObjectivesAtherosclerosis is characterized by a hypercoagulable state, during which coagulation and fibrinolytic factors are activated simultaneously. However, details regarding the thrombolytic pathway in this context remain unknown. Here we investigated how direct long-term inhibition of thrombin influenced spontaneous thrombolytic activity during atherosclerotic progression in apolipoprotein E (ApoE)–/––low density lipoprotein receptor (LDLR)–/– double-knockout mice.MethodsAll mice received either standard chow (placebo group) or dabigatran-containing chow for 22 weeks, after which we evaluated them. The amount of atherosclerosis was estimated as the ratio of the atherosclerotic area to the total aortic intimal area. In addition, we used immunohistochemistry to analyze the expression of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and endothelial nitric oxide synthase (eNOS) in atherosclerotic regions. To evaluate thrombolysis, we used a He–Ne laser to induce thrombosis in vessels of the cremaster muscle and then measured the thrombus volume over time.ResultsThe atherosclerotic area was smaller and thrombolytic activity greater in the dabigatran-treated group than in the placebo group. Furthermore, according to the thrombolysis model, spontaneous thrombolytic activity was increased in the dabigatran-treated mice compared with the placebo mice. In support of these results, immunohistochemistry demonstrated decreased expression of PAI-1 and TAFI but increased expression of eNOS in the dabigatran group compared with the placebo group. However, t-PA expression did not differ between groups.ConclusionsDirect long-term inhibition by dabigatran etexilate of thrombin led to an increase in spontaneous thrombolytic activity decreasing the expression of PAI-1 and TAFI.

Preliminary Observations on the Antihypertension Action of Dabigatran Etexilate in Patients With Nonvalvular Atrial Fibrillation: A Prospective Multicenter Single-Arm Interventional Study.

BackgroundIn Japan, the number of patients with atrial fibrillation continues to grow with the aging of the population. Prevention of cardiogenic cerebral embolism is extremely important in patients with atrial fibrillation. While warfarin has long played a major role for this purpose, a new oral anticoagulant, dabigatran etexilate (dabigatran), has demonstrated superior efficacy and safety in recent years. We conducted a multicenter prospective interventional study to examine whether dabigatran could demonstrate superiority over warfarin in practical clinical situation.MethodsAmong outpatients attending Fukuoka University Chikushi Hospital or clinics registered with the Chikushi Cardiovascular Disease Clinical Research Network (Chikushi-JRN), 143 patients with nonvalvular atrial fibrillation (NVAF) were enrolled in this study and followed up for 12 months after initiation of dabigatran therapy. The primary endpoint was occurrence of cerebral embolism or systemic embolism, while secondary endpoints were: 1) Bleeding events; 2) Changes in the activated partial thromboplastin time (aPTT); 3) Adverse events; and 4) Changes in blood pressure and pulse rate.ResultsDuring the follow-up period, none of the patients developed cerebral or systemic embolism (the primary endpoint). In addition, there were no bleeding events or other adverse events (the secondary endpoints). aPTT remained stable throughout the 12-month observation period. A significant decrease in systolic blood pressure was observed at 1 month after initiation of dabigatran therapy, and blood pressure was reduced up to 12 months. Blood pressure showed a significant decrease in patients with paroxysmal atrial fibrillation, but not in patients with chronic atrial fibrillation.ConclusionsDabigatran showed a stable anticoagulant effect, and its safety was confirmed. Dabigatran also reduced blood pressure, which may help to explain why it causes fewer major bleeding events than warfarin.

Analysis of Risk Factors Associated with Cognitive Dysfunction in Patients with Atrial Fibrillation

Objective: To discuss the risk factors of cognitive dysfunction in patients with atrial fibrillation. Methods: The 150 cases of patients with atrial fibrillation were analyzed in the first affiliated hospital of Nanchang University who were treated in the cardiovascular department, general medicine department and gerontology department from August 2018 to June 2019. We used Mini-Mental State Examination (MMSE) score to evaluate cognitive function of patients with atrial fibrillation. According to the level of education and MMSE score, patients with atrial fibrillation were divided into three groups: normal cognitive function group, mild cognitive impairment group (MCI) and dementia group. And then the demographic data, the previous use of taking drugs, the results of ultrasonic cardiogram (UCG) and laboratory test were analyzed. Results: 1) The basic situation of research object: a total of 150 patients with atrial fibrillation were enrolled in the study, and the average age of these patients was 65.05 ± 8.74 years old, which included 78 males (52%) and 72 females (48%). The mean MMSE score was 23.42 ± 4.65. According to MMSE score, 86 cases (57.3%) of cognitive dysfunction occurred in 150 patients with atrial fibrillation, which included 41 cases (27.3%) of mild cognitive impairment and 45 cases (30%) of dementia. 2) The comparison of general clinical data: there were significant differences in age, smoking, level of education, left ventricular ejection fraction, left atrial diameter, D-dimer, fibrinogen, homocysteine, platelet and previous use of taking warfarin, dabigatran, CCB, statins among the three groups (P < 0.05). 3) The linear correlational analysis between risk factors of cognitive function and MMSE score in patients with atrial fibrillation: there was a positive correlation between left ventricular ejection fraction and MMSE score, but age, left atrial diameter, homocysteine, low density lipoprotein, platelet, BMI, NT-proBNP, D-dimer were negatively correlated with MMSE score. 4) The risk factors with statistical significance in ANOVA were analyzed by ordinal and multinomial logistic regression, which showed that age (OR = 1.174, 95% CI: 0.091 - 0.231), the level of education (illiteracy OR = 4.162, 95% CI: -0.032 - 2.955, primary school OR = 2.751, 95% CI: -0.172 - 2.197, junior high school OR = 3.539, 95% CI: -0.048 - 2.577, senior high school and special secondary school OR = 1.332, 95% CI: -1.080 - 1.655), no CCB (OR = 1.174, 95% CI: 0.091 - 0.231), no warfarin (OR = 13.749, 95% CI: 1.480 - 3.762), no dabigatran (OR = 16.395, 95% CI: 1.462 - 4.131), D-dimer (OR = 2.745, 95% CI: -0.611 - 2.631), fibrinogen (OR = 3.228, 95% CI: 0.399 - 1.946) were related to the high occurrence of cognitive dysfunction. Conclusions: 1) Patients with atrial fibrillation had a higher risk of cognitive dysfunction (the incidence of 57.4%). 2) There was a positive correlation between left ventricular ejection fraction and MMSE score, but age, left atrial diameter, homocysteine, low density lipoprotein, platelet, BMI, NT-proBNP, and D-dimer were negatively correlated with MMSE score. 3) High level of education, previous use of taking warfarin and dabigatran etexilate were protective factors for cognitive function in patients with atrial fibrillation; but age, previous use of taking CCB, D-dimer and fibrinogen were the risk factors in patients with atrial fibrillation.

A composite nanocarrier to inhibit precipitation of the weakly basic drug in the gastrointestinal tract

For weakly basic drugs, the sharp decrease of drug solubility and the following drug precipitation after drugs transferring from the gastric fluid to the intestinal fluid in the gastrointestinal (GI) tract is a main reason for the poor oral bioavailability of drugs. Here, an anticoagulant dabigatran etexilate (DE) was used as a model drug, and a composite nanocarrier system of DE was developed to improve the drug dissolution by decreasing the drug leakage in the stomach and inhibiting the drug precipitation in the intestinal tract. With the encapsulation of drugs in nanocarriers, the precipitation percentage of DE in composite nanocarriers was 22.25 ± 3.88% in simulated intestinal fluid, which was far below that of the commercial formulation. Moreover, the relative bioavailability of DE-loaded composite nanocarriers (456.58%) was greatly enhanced and the peak of its activated partial thromboplastin time was also significantly prolonged (p < .01) compared with the commercial formulation, indicating that the anticoagulant effect of DE was effectively improved. Therefore, the designed composite nanocarrier system of DE presents great potentials in improving the therapeutic efficiency and expanding the clinical applications of poorly water-soluble weakly basic drugs.

Zastosowanie idarucyzumabu u pacjenta leczonego dabigatranem w przypadku konieczności wykonania pilnej operacji kardiochirurgicznej – doświadczenia ośrodka krakowskiego

Dabigatran etexilate (dabigatran), a direct, selective and reversible thrombin inhibitor, who is administered as a prodrug, being transformed into an active metabolite upon absorption from the digestive tract. Patients on dabigatran can experience serious perioperative bleeding if the emergency surgery is performed while on anticoagulation. At the end of 2015, idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, was approved for use. The RE-VERSE AD trial (NCT02104947) has shown that idarucizumab is efficacious in dabigatran reversal. The current European Heart Rhythm Association and European Association of Cardio-Thoracic Surgery guidelines recommend idarucizumab use in the setting of severe bleeding, or if an emergency surgery is needed during dabigatran treatment. This report summarizes our clinical experience with idarucizumab in dabigatran-treated patients undergoing emergency cardiac surgery.

Inhibitory effects of dabigatran etexilate, a direct thrombin inhibitor, on osteoclasts and osteoblasts

IntroductionAnticoagulants are widely used in orthopedic surgery to decrease the risk of deep vein thrombosis. While significant bone impairment is induced by long-term heparin therapy, little is known about the effects of direct oral anticoagulants (DOACs). Herein, we investigated the effects of dabigatran etexilate (Pradaxa®), a DOAC inhibitor of thrombin, on bone cells using in vitro and ex vivo cell culture models. Materials and methodsOsteoblasts and osteoclasts exposed to different concentrations of dabigatran etexilate and untreated cells were assayed for cell differentiation and activity. Favorable osteogenic conditions for osteoblasts were tested using titanium with nanotopography (Ti-Nano). In addition, mice treated with a dabigatran etexilate solution had bone marrow cells analyzed for the ability to generate osteoclasts. ResultsDabigatran etexilate at concentrations of 1 μg/mL and 2 μg/mL did not impact osteoclast or osteoblast viability. The drug inhibited osteoclast differentiation and activity as observed by the reduction of TRAP+ cells, resorption pits and gene and protein expression of cathepsin K. Consistently, osteoclasts from mice treated with dabigatran showed decreased area, resorptive activity, as well as gene and protein expression of cathepsin K. In osteoblast cultures, grown both on polystyrene and Ti-Nano, dabigatran etexilate reduced alkaline phosphatase (ALP) activity, matrix mineralization, gene expression of ALP and osteocalcin. ConclusionsDabigatran etexilate inhibited osteoclast differentiation in ex vivo and in vitro models in a dose-dependent manner. Moreover, the drug reduced osteoblast activity even under optimal osteogenic conditions. This study provides new evidence regarding the negative overall impact of DOACs on bone cells.

Ex-Vivo Absorption Study of a Novel Dabigatran Etexilate Loaded Nanostructured Lipid Carrier Using Non-Everted Intestinal Sac Model

Abstract&#x0D; The purpose of our study was to develop Dabigatran Etexilate loaded nanostructured lipid carriers (DE-NLCs) using Glyceryl monostearate and Oleic acid as lipid matrix, and to estimate the potential of the developed delivery system to improve oral absorption of low bioavailability drug, different Oleic acid ratios effect on particle size, zeta potential, entrapment efficiency and loading capacity were studied, the optimized DE-NLCs shows a particle size within the nanorange, the zeta potential (ZP) was 33.81±0.73mV with drug entrapment efficiency (EE%) of 92.42±2.31% and a loading capacity (DL%) of 7.69±0.17%. about 92% of drug was released in 24hr in a controlled manner, the ex-vivo intestinal permeation study using the non-everted sac model shows four folds increment in the permeation of DE-NLCs compared to dabigatran etexilate suspension (DE-S).

Clinically Negligible Pharmacokinetic and Pharmacodynamic Interactions Between Lanabecestat and Dabigatran Etexilate, a Prototypical P-gp Substrate.

Lanabecestat, a novel β-site amyloid precursor protein-cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P-glycoprotein (P-gp) activity in vitro. After oral 50-mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half-maximal inhibitory concentration (IC50 ), suggesting P-gp inhibition at the intestinal wall. Plasma drug concentrations following 50mg lanabecestat administered once daily are <10% of IC50 , suggesting minimal systemic P-gp interaction. Dabigatran etexilate (DE) is the prodrug of dabigatran, a thrombin inhibitor and P-gp substrate, making dabigatran exposure an intestinal P-gp activity indicator. This study (NCT02568397) was conducted in 60 healthy subjects receiving a single dose of 150mg DE alone or during a lanabecestat treatment regimen. On day 16, lanabecestat and DE were coadministered; on day 20, DE was dosed 4hours after lanabecestat. Safety was assessed using clinical labs, electrocardiogram, vital signs, Columbia Suicide Severity Rating Scale scores, adverse events, and eye and skin examinations. Pharmacokinetic/pharmacodynamic samples were collected up to 36hours postdose. Geometric mean plasma dabigatran area under the curve from time 0 to infinity (AUC0-∞ ) and the maximum plasma drug concentration (Cmax ) increased by 15% and 17%, respectively, when coadministered with lanabecestat. When DE was dosed 4hours after lanabecestat, there was no effect on plasma dabigatran AUC0-∞ , Cmax , or thrombin time. DE had no effect on lanabecestat's AUC0-∞ and Cmax at steady state (day 16) versus lanabecestat alone (day 15). No clinically relevant safety concerns were observed. Lanabecestat has no clinically meaningful effect on dabigatran exposure or on P-gp activity at the intestinal wall.

Dabigatran etexilate has favourable safety profile in children

Dabigatran etexilate has favourable safety profile in children

Dabigatran etexilate in patients with nonvalvular atrial fibrillation: benefits of application in certain clinical situations

The review discusses the problem of patient-oriented choice of anticoagulants for nonvalvular atrial fibrillation (AF). The efficacy and safety profile of dabigatran etexilate and a group of patients with advantage of dabigatran application: patients with a high risk or history of ischemic stroke, patients who are indicated for combination antithrombotic therapy, and patients with a high risk of emergency surgical interventions and procedures, as well as with a high risk of bleeding, etc. The place of idarucizumab, a direct dabigatran etexilate antagonist, is shown.

Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation

Warfarin is prescribed to patients with atrial fibrillation (AF) for the prevention of cardioembolic complications. Whether warfarin adversely affects bone health is controversial. The availability of alternate direct oral anticoagulant (DOAC) options now make it possible to evaluate the comparative safety of warfarin in association with fracture risk. To test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident fracture. This comparative effectiveness cohort study used the MarketScan administrative claims databases to identify patients with nonvalvular AF and who were prescribed oral anticoagulants from January 1, 2010, through September 30, 2015. To reduce confounding, patients were matched on age, sex, CHA2DS2-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score, and high-dimensional propensity scores. The final analysis included 167 275 patients with AF. Data were analyzed from February 27, 2019 to September 18, 2019. Warfarin and DOACs (dabigatran etexilate, rivaroxaban, and apixaban). Incident hip fracture, fracture requiring hospitalization, and all clinical fractures (identified using inpatient or outpatient claims) defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. In the study population of 167 275 patients with AF (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), a total of 817 hip fractures, 2013 hospitalized fractures, and 7294 total fractures occurred during a mean (SD) follow-up of 16.9 (13.7) months. In multivariable-adjusted, propensity score-matched Cox proportional hazards regression models, relative to new users of warfarin, new users of DOACs tended to be at lower risk of fractures requiring hospitalization (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96) and all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), whereas the association with hip fractures (HR, 0.91; 95% CI, 0.78-1.07) was not statistically significant. When comparing individual DOACs with warfarin, the strongest findings were for apixaban (HR for hip fracture, 0.67 [95% CI, 0.45-0.98]; HR for fractures requiring hospitalization, 0.60 [95% CI, 0.47-0.78]; and HR for all clinical fractures, 0.86 [95% CI, 0.75-0.98]). In subgroup analyses, DOACs appeared more beneficial among patients with AF who also had a diagnosis of osteoporosis than among those without a diagnosis of osteoporosis. In this real-world population of 167 275 patients with AF, use of DOACs-particularly apixaban-compared with warfarin use was associated with lower fracture risk. These associations were more pronounced among patients with a diagnosis of osteoporosis. Given the potential adverse effects of warfarin on bone health, these findings suggest that caution should be used when prescribing warfarin to patients with AF at high risk of fracture.

Thrombin inhibition by dabigatran attenuates endothelial dysfunction in diabetic mice

Diabetic patients have coagulation abnormalities, in which thrombin plays a key role. Whereas accumulating evidence suggests that it also contributes to the development of vascular dysfunction through the activation of protease-activated receptors (PARs). Here we investigated whether the blockade of thrombin attenuates endothelial dysfunction in diabetic mice. Induction of diabetes by streptozotocin (STZ) increased the expression of PAR1, PAR3, and PAR4 in the aorta. STZ-induced diabetic mice showed impairment of endothelial function, while the administration of dabigatran etexilate, a direct thrombin inhibitor, significantly attenuated endothelial dysfunction in diabetic mice with no alteration of metabolic parameters including blood glucose level. Dabigatran did not affect endothelium-independent vasodilation. Dabigatran decreased the expression of inflammatory molecules (e.g., MCP-1 and ICAM-1) in the aorta of diabetic mice. Thrombin increased the expression of these inflammatory molecules and the phosphorylation of IκBα, and decreased the phosphorylation of eNOSSer1177 in human umbilical endothelial cells (HUVEC). Thrombin significantly impaired the endothelium-dependent vascular response of aortic rings obtained from wild-type mice. Inhibition of NF-κB attenuated thrombin-induced inflammatory molecule expression in HUVEC and ameliorated thrombin-induced endothelial dysfunction in aortic rings. Dabigatran attenuated the development of diabetes-induced endothelial dysfunction. Thrombin signaling may serve as a potential therapeutic target in diabetic condition.

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.

The contribution of real-world evidence to cost-effectiveness analysis: case study of Dabigatran etexilate in France.

The goal of this study was to assess the differences between an ex ante and an ex post cost-effectiveness analysis of Dabigatran etexilate vs VKAs for the prevention of thromboembolic events in non-valvular atrial fibrillation patients and to draw lessons on the design and use of real-world data for decision making. The same model was used to calculate the cost-effectiveness ratio using two sets of parameters. One set included the efficacy and safety outcomes data from RE-LY, the pivotal trial comparing Dabigatran to warfarin; cost data came from an ex ante publication. Outcomes data for the second set came from real-world data studies. Cost data were a mix of real-world data and other sources. Two treatment strategies were compared: treatment initiation by either Dabigatran or VKAs, followed by either VKAs or Dabigatran. A crude comparison of results was performed; the impact of data differences was then assessed. Probabilistic sensitivity results of the two analyses were compared. With real-world evidence, Dabigatran at both dosages was more effective for the prevention of ischemic strokes, intra-cranial haemorrhages, with less major extra-cranial haemorrhages and a similar risk of myocardial infarction. Using clinical trial data, Dabigatran150mg (resp. Dabigatran110mg) as a first-line treatment vs VKAs yielded an ICER of € 8077/QALY (resp. € 13,116/QALY). Real-world evidence scenarios were cost-saving and more effective for both dosages. The reassessment of outcomes and cost data had an impact on results, improving the efficiency of Dabigatran. We identify methodological issues which should be discussed if post-launch RWE based cost-effectiveness data become a standard in HTA decision making.

Dabigatran Can Safely Be Reversed in Patients with Renal Dysfunction

Reversal of direct oral anticoagulants remains an active area of investigation. Idarucizumab, a humanized monoclonal antibody against dabigatran,