Oral Anticoagulants Dabigatran Etexilate Research Articles

EFFECT OF DIRECT ORAL ANTICOAGULANTS ON THE HEMOSTASIS SYSTEM 142 IN BACTERIAL SEPSIS

The inflammatory reaction that arises in patients with sepsis is interconnected with the coagulation system and leads to the development of hypercoagulable changes in the body. Therefore, in this study, we studied the effect of direct oral anticoagulants dabigatran etexilate and apixaban on the hemostasis system without and under conditions of a systemic inflammatory response. Hypercytokinemia was created by intravenous administration of lipopolysaccharide into the tail vein of a rat. The anticoagulant activity of the studied drugs was assessed by their effect on the parameters of the rat blood coagulogram. Dabigatran etexilate showed a pronounced antithrombin effect, increasing the thrombin time by 10.5 times relative to the control in intact animals. Under conditions of hypercytokinemia, this activity increased by 12.8 times. Apixaban did not cause changes in thrombin time, but it increased the prothrombin time index both in intact animals and animals with a systemic inflammatory response by 7 and 8.6 times, respectively. Thus, an increase in the anticoagulant effect of dabigatran etexilate and apixaban under conditions of hypercytokinemia indicates that they may have anti-inflammatory activity.

Decreased M1 macrophage polarization in dabigatran-treated Ldlr-deficient mice: Implications for atherosclerosis and adipose tissue inflammation

Background and aimsThe non-vitamin K oral anticoagulant dabigatran etexilate (dabigatran) is increasingly prescribed to patients with non-valvular atrial fibrillation and venous thromboembolism. Adipose tissue (AT) inflammation during obesity plays a crucial role in the development of insulin resistance, type II diabetes and atherogenesis. The aim of the present study was to investigate the effects of thrombin inhibition by dabigatran in a combined model of diet-induced obesity and atherosclerosis. MethodsFemale Low density lipoprotein receptor knockout (Lldr−/−) mice were fed a high-fat diet containing 5 mg/g dabigatran or matching control for 20 weeks. ResultsDabigatran-treated animals showed increased adipocyte hypertrophy, but reduced numbers of pro-inflammatory M1-polarized macrophages in the adipose tissue. Abundance of pro-inflammatory M1 macrophages was also decreased in the aortic wall of dabigatran-fed mice. Multiple circulating cytokines were reduced, indicating an effect in systemically relevant secretory compartments such as the AT. ConclusionsDabigatran treatment reduces pro-inflammatory M1 macrophages in atherosclerotic lesions, thereby contributing to plaque stabilizing and atheroprotective effects of the thrombin inhibitor. This finding is not restricted to the vascular wall but is also present in AT where dabigatran treatment reduced the release of pro-inflammatory cytokines and accumulation of M1 macrophages.

Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran.

Idarucizumab is a specific antidote for the direct thrombin inhibitor oral anticoagulant dabigatran etexilate. It has been used with increasing frequency in Australia since it was granted Therapeutic Goods Administration approval in October 2016. To assess idarucizumab usage, effect on coagulation parameters and clinical outcomes in patients who received idarucizumab in Western Sydney Local Health District (WSLHD). A retrospective audit was conducted of all patients who received idarucizumab in WSLHD between September 2015 and December 2017. Of the 23 patients who received idarucizumab, 17 (74%) had bleeding, and 6 (26%) required urgent surgery/procedure. Thrombin time (TT) or activated partial thromboplastin time (APTT, when TT not available) remained prolonged at 24 h post-idarucizumab infusion in 10 of 20 (50%) patients. Renal impairment at admission was associated with prolonged TT/APTT at 24 h (P = 0.02). Of the six (26%) patients who died during hospital admission, five had raised TT/APTT at 24 h (P = 0.05). Two deaths were due to continued bleeding despite idarucizumab. Only 17% of patients received prohaemostatic treatments, and none received plasma derivatives. Despite assay availability, dabigatran drug level was only measured in eight patients. Idarucizumab helped achieve haemostasis in 15 bleeding patients and allowed 6 patients to undergo urgent surgery. Half the patients had prolonged TT/APTT at 24 h post-idarucizumab, which was more likely to occur in patients with impaired renal function.

Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study

Background and aimsPatients on parenteral nutrition for short bowel syndrome (SBS) have a high risk of thrombotic complications and are often treated with parenteral anticoagulation. Direct oral anticoagulants are absorbed proximally in the digestive tract and may represent alternative regimens in selected SBS patients. In our pilot study, we provided pharmacokinetics parameters of dabigatran etexilate and rivaroxaban in this setting and compared peak (Cmax), trough (Ctrough) concentrations, and areas-under-the-concentration-time-curve (AUC0−t) to reference values retrieved from phase I-III studies. MethodsWe enrolled 6 adults with a remaining small bowel length≤200cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150mg and once-daily rivaroxaban 20mg. ResultsAfter 5days of dabigatran dosing, Ctrough and Cmax geometric means were 39μg/L (90% CI: 23–66) and 88μg/L (90% CI: 56–137), respectively; AUC0–12h was 958μg∗h/L (90% CI: 635–1445). After 5days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9μg/L (90% CI: 1–71) and 167μg/L (90% CI: 102–276), respectively; AUC0–24h was 1720μg∗h/L (90% CI: 899–3300). Absorption was negligible in one patient with ultra-short (~15cm) bowel. For dabigatran, Cmax ratio was 0.57 (SD 0.33) and Ctrough ratio was 0.35 (SD 0.44). For rivaroxaban, the mean observed-to-reference ratios AUC0–24h and Cmax ratios were 0.73 (SD 0.32) and 0.76 (SD 0.34), respectively. ConclusionsWhile in SBS patients there is some absorption of the oral anticoagulants dabigatran etexilate and rivaroxaban, it appears to be lower than reference values. Plasma drug levels showed significant inter-individual variability.

Rationale and Design of a Phase III Single-Arm Multicenter Study of Dabigatran Etexilate for the Secondary Prevention of Venous Thromboembolism in Children

Background: In children, the incidence of venous thromboembolism (VTE) is increasing and is often associated with underlying diseases such as cancer, or risk factors such as thrombophilia. Following treatment for acute VTE, thrombosis or thromboembolic events can recur particularly if a clinical risk factor for VTE persists. The efficacy and safety of the oral anticoagulant dabigatran etexilate (DE) have been demonstrated in a number of thrombosis-related indications in adults, including for secondary VTE-prevention. There are, however, potential differences between adults and children related to developmental physiology and pharmacology and therefore trials to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of DE in children are required. To date, all pediatric phase IIa studies conducted have shown a similar PK and PK/PD relationship of DE in comparison to adult studies.Objective: To describe the design of a study to evaluate the safety and PK-PD of DE for secondary prevention of VTE in children aged 0-<18 years.Methods: This phase III, open-label, single-arm, multicenter study will be conducted at ~100 sites worldwide (NCT02197416). Eligible patients will have completed a course of initial treatment for confirmed acute VTE (for ≥ 3 months) and be considered at high risk for VTE recurrence due to the remaining presence of a clinical risk factor. Approximately 100 subjects between 0-<18 years of age will be included. Treatment with DE will extend up to 12 months, or less if the clinical risk factor resolves, with a follow-up visit 28 days after the last dose. DE will be administered twice daily as capsules, pellets or oral liquid formulation, depending on subject age and their ability to swallow capsules or pellets. A dosing nomogram will be used to scale down an adult dose based on the child’s age and weight. Initial doses calculated using the nomogram should achieve steady-state trough concentrations of DE of between 50 and < 250 ng/ml, a range which is assumed to result in safe and effective use of DE in this pediatric population; after about 3 days, trough dabigatran plasma concentration will be measured and DE may be titrated up or down to achieve the target steady-state trough plasma concentration.Results: Demographic and medical history data will be collected for all participants. The primary outcomes to be evaluated are instances at 6 and 12 months of image-proven VTE recurrence; major and minor bleeding, including clinically relevant non-major bleeding; and overall and thrombotic/thromboembolic mortality. All elements of the primary endpoints will be evaluated by an independent adjudication committee that will confirm or refute outcome events. The secondary outcomes are rates of post-thrombotic syndrome at 6 and 12 months; PK and PD (e.g., activated partial thromboplastin time and ecarin clotting time); and the number of DE dose adjustments required during the treatment period. Data on the acceptability of the age-appropriate drug formulation, the tolerability of the study medication, adverse events, treatment discontinuations due to an adverse event, and laboratory and clinical parameters will also be collected during the study. Safety and tolerability will be monitored by the independent Data Monitoring Committee.Conclusion: This phase III study has been designed to provide data on the safety and PK-PD of DE for the secondary prevention of VTE in children aged 0-<18 years. DisclosuresLuciani:Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Mitchell:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Huang:Boehringer Ingelheim: Employment. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.

Pharmacological thromboprophylaxis and total hip or knee replacement.

Pharmacological and mechanical thromboprophylaxis reduces the risk of venous thromboembolism (VTE) in patients undergoing total knee/hip replacement (TKR/THR). Nurses play a key role in VTE prevention through clinical care, before and after discharge from hospital, and patient education. Conventional pharmacological agents for VTE prophylaxis include low molecular weight heparins (LMWHs) and fondaparinux. However, parenteral administration, increased bleeding risk, and patient/physician non-adherence to treatment and guidelines, are important limitations. Three non-vitamin K antagonist oral anticoagulants--dabigatran etexilate, rivaroxaban and apixaban--are available in the UK for VTE prevention following THR/TKR. In common with LMWHs and fondaparinux, these offer rapid onset of action and fixed doses without the need for routine coagulation monitoring. An agent for emergency reversal of dabigatran is in development, while there is no antidote for fondaparinux and LMWHs can be partially neutralised by protamine. Oral administration may result in better adherence to treatment and guidelines, reducing the nurse burden after discharge, and enhancing cost-effectiveness.

Normalization of Activated Partial Thromboplastin Time Correlates with Low Levels of Dabigatran in a Patient with Severe Sepsis.

The oral anticoagulant dabigatran etexilate can be a challenge when patients need acute surgery. Sepsis and acute renal failure exacerbate the anticoagulant effect. There is no specific reversal agent for dabigatran etexilate, but it can be removed by hemodialysis. We present a case where a patient treated with dabigatran etexilate was admitted to intensive care unit with severe sepsis and acute renal failure and in need of bilateral lower limp amputation due to ischemia. The patient had severe coagulopathy and was treated with continuous venovenous hemofiltration in attempt to remove dabigatran etexilate before surgery.

PS-024 Monitoring of adverse drug reactions in patients treated with new oral anticoagulants

BackgroundData on the adverse effects of newly marketed drugs are limited. The monitoring of adverse drug reactions (ADR) through active pharmacovigilance is vital to patient safety.The new oral anticoagulants dabigatran...

Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban

The new oral anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) have predictable pharmacokinetic and pharmacodynamic profiles and are alternatives to warfarin. However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect. Management requires careful adherence to first principles of bleeding care. Unapproved and untested reversal strategies may be required in patients with life-threatening bleeding.

Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials

BackgroundThere has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin.MethodsThree previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events.ResultsGeneral, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03–1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin.ConclusionsAnaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia.Trial registrationClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.

Preoperative versus postoperative initiation of thromboprophylaxis following major orthopedic surgery: safety and efficacy of postoperative administration supported by recent trials of new oral anticoagulants.

In European countries, low-molecular-weight heparin is generally initiated preoperatively for thromboprophylaxis in hip or knee replacement surgery. The objective of this review is to compare pre- and postoperative thromboprophylaxis strategies using available evidence, and discuss the challenges and issues that arise. Surgery is the first step in the process of thrombus formation, but thrombosis is not an instant process and the formation and growth of the thrombus can take several days or weeks. Hence, it may be possible to stop this process if thromboprophylaxis is initiated after surgery. Meta-analyses or systematic reviews comparing pre- and postoperative initiation of therapy have found no consistent differences in efficacy and similar safety (bleeding rates) between the two strategies. The recently available oral anticoagulant dabigatran etexilate provides thromboprophylaxis when administered postoperatively and is as safe as preoperative enoxaparin. Further support for the use of postoperative oral thromboprophylaxis in hip or knee replacement surgery has been provided by the phase III clinical trials of rivaroxaban and apixaban versus preoperative enoxaparin. Postoperative thromboprophylaxis offers the opportunity to change management practices in Europe. As postoperative initiation may have a clinical benefit in some settings (e.g. for neuraxial anesthesia) and practical advantages (e.g. allowing same-day admission), it is a worthwhile thromboprophylactic strategy for hip or knee replacement surgery.

Prevention of Venous Thromboembolic Complications in Orthopaedic Surgery: New Possibilities

The causes of significant rate of venous thromboembolic complications after orthopaedic operations were analyzed basing on literature review and author's experience. Importance of orthopaedic surgeons' education in modern standard for such complication prevention as well as necessity of modern drugs application was presented. Data on the efficacy of new direct per oral anticoagulant Dabigatran etexilate (Pradax) were given.