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Joachim Stangier - One of the best experts on this subject based on the ideXlab platform.
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A: Pharmacology, pharmacokinetics, and pharmacodynamics of Dabigatran Etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009, 15(Suppl 1):9S–16S
2016Co-Authors: Joachim Stangier, Andreas ClemensAbstract:Dabigatran Etexilate is a novel, oral reversible direct thrombin inhibitor that is rapidly absorbed and converted to its active form, Dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible inhibitor of thrombin, inhibiting both thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of Dabigatran are reached approximately 2 hours after oral administration. The elimina-tion half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug–drug interac-tions. The pharmacokinetic profile of Dabigatran is consistent across a broad range of different patient populations and is unaf-fected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in Dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran Etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes
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an open label study of the pharmacokinetics and pharmacodynamics of Dabigatran Etexilate 150 mg once daily in caucasian patients with moderate renal impairment undergoing primary unilateral elective total knee or hip replacement surgery
Thrombosis Research, 2016Co-Authors: Bengt I Eriksson, Joachim Stangier, Sebastian Haertter, Martin Feuring, Gerhard Nehmiz, Zsolt Mikuska, Jean Amiral, Jeffrey I WeitzAbstract:Abstract Background In adults with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of Dabigatran Etexilate is 150 mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. Methods Single-arm, open-label phase 4 study ( NCT01184989 ) in Caucasian patients receiving Dabigatran Etexilate 75 mg 1–4 h after surgery and 150 mg qd on days 2–10 (TKR) or days 2–35 (THR). Plasma total Dabigatran concentrations (day 6 ± 1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). Results Of 112 patients (mean CrCl 42.5 mL/min, age 79.1 years, 69.6% female), 100 completed the study. Geometric mean trough and peak Dabigatran concentrations were 47.5 ng/mL (10th–90th percentile 19.7–120) and 166 ng/mL (49.1–364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50–500 ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ± 15%. Conclusions These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150 mg qd dose of Dabigatran Etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of Dabigatran levels would be helpful.
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influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral Dabigatran Etexilate an open label parallel group single centre study
Clinical Pharmacokinectics, 2010Co-Authors: Joachim Stangier, Hildegard Stahle, Karin Rathgen, Dago MazurAbstract:Background and Objective: Dabigatran Etexilate is an oral direct thrombin inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Following oral administration, Dabigatran Etexilate is rapidly absorbed and converted into its active form, Dabigatran. The aim of this study was to investigate the effect of renal impairment on the pharmacokinetics and pharmacodynamics of Dabigatran following administration of a single oral dose of Dabigatran Etexilate in subjects with renal impairment (150 mg) or end-stage renal disease (ESRD) on maintenance haemodialysis (50 mg). Methods: This open-label, parallel-group, single-centre study enrolled 23 subjects with mild, moderate or severe renal impairment (creatinine clearance >50 to ≤80, >30 to ≤50 and ≤30 mL/min, respectively), 6 patients with ESRD and 6 healthy subjects. Blood and urine samples were collected up to 96 hours after dosing for determination of Dabigatran pharmacokinetic and pharmacodynamic parameters. Results: Compared with the values in healthy subjects, the area under the plasma concentration-time curve from time zero to infinity (AUC∞) values were 1.5-, 3.2- and 6.3-fold higher in subjects with mild, moderate and severe renal impairment. Changes in the maximum plasma concentration (Cmax) were modest, and the time to reach the Cmax was unchanged. In subjects with severe renal impairment, the mean terminal elimination half-life was doubled (28 hours vs 14 hours for control). The AUC for prolongation of pharmacodynamic parameters (the activated partial thromboplastin time and ecarin clotting time) increased in line with the pharmacokinetic changes. In patients with ESRD, the dose-normalized AUC∞ was approximately twice the value in the control group. Haemodialysis removed 62–68% of the dose. Dabigatran Etexilate was well tolerated in all groups. Conclusions: Exposure to Dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction. A decrease in the dose and/or an increase in the administration interval in these patients may be appropriate. In patients with ESRD, Dabigatran can be partly removed from the plasma by haemodialysis.
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Dabigatran Etexilate a novel reversible oral direct thrombin inhibitor interpretation of coagulation assays and reversal of anticoagulant activity
Thrombosis and Haemostasis, 2010Co-Authors: Joachim Stangier, Sebastian Haertter, Karlheinz Liesenfeld, Wolfgang Wienen, Martin Feuring, Andreas ClemensAbstract:Summary 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
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pharmacology pharmacokinetics and pharmacodynamics of Dabigatran Etexilate an oral direct thrombin inhibitor
Clinical and Applied Thrombosis-Hemostasis, 2009Co-Authors: Joachim Stangier, Andreas ClemensAbstract:Dabigatran Etexilate is a novel, oral reversible direct thrombin inhibitor that is rapidly absorbed and converted to its active form, Dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible inhibitor of thrombin, inhibiting both thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of Dabigatran are reached approximately 2 hours after oral administration. The elimination half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug-drug interactions. The pharmacokinetic profile of Dabigatran is consistent across a broad range of different patient populations and is unaffected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in Dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran Etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes.
Bengt I Eriksson - One of the best experts on this subject based on the ideXlab platform.
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an open label study of the pharmacokinetics and pharmacodynamics of Dabigatran Etexilate 150 mg once daily in caucasian patients with moderate renal impairment undergoing primary unilateral elective total knee or hip replacement surgery
Thrombosis Research, 2016Co-Authors: Bengt I Eriksson, Joachim Stangier, Sebastian Haertter, Martin Feuring, Gerhard Nehmiz, Zsolt Mikuska, Jean Amiral, Jeffrey I WeitzAbstract:Abstract Background In adults with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of Dabigatran Etexilate is 150 mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. Methods Single-arm, open-label phase 4 study ( NCT01184989 ) in Caucasian patients receiving Dabigatran Etexilate 75 mg 1–4 h after surgery and 150 mg qd on days 2–10 (TKR) or days 2–35 (THR). Plasma total Dabigatran concentrations (day 6 ± 1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). Results Of 112 patients (mean CrCl 42.5 mL/min, age 79.1 years, 69.6% female), 100 completed the study. Geometric mean trough and peak Dabigatran concentrations were 47.5 ng/mL (10th–90th percentile 19.7–120) and 166 ng/mL (49.1–364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50–500 ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ± 15%. Conclusions These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150 mg qd dose of Dabigatran Etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of Dabigatran levels would be helpful.
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thromboprophylaxis with Dabigatran Etexilate in patients over seventy five years of age with moderate renal impairment undergoing or knee replacement
International Orthopaedics, 2012Co-Authors: Ola E Dahl, Andreas Clemens, Nadia Rosencher, Andreas A Kurth, Herbert Noack, Bengt I ErikssonAbstract:Purpose Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor Dabigatran Etexilate (hereafter referred to as Dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation.
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efficacy and safety of Dabigatran Etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty a meta analysis
Thrombosis and Haemostasis, 2008Co-Authors: Sorrel Wolowacz, Neil Roskell, Jonathan M Plumb, Joseph A Caprini, Bengt I ErikssonAbstract:Dabigatran Etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a metaanalysis of efficacy and safety data for the recommended dose of Dabigatran Etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared Dabigatran Etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared Dabigatran Etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between Dabigatran Etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p>0.15), or when all three trials were combined ( all p>0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 – 1.10] and 1.05 [0.87 – 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that Dabigatran Etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.
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oral Dabigatran Etexilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement the re model randomized trial
Journal of Thrombosis and Haemostasis, 2007Co-Authors: Bengt I Eriksson, Ola E Dahl, Nadia Rosencher, Andreas A Kurth, Simon P Frostick, Stefan Hantel, C N Van Dijk, Peter Kalebo, Anita Vedel Christiansen, Rohan HettiarachchiAbstract:Summary. Background: Oral anticoagulants, such as Dabigatran Etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. Methods: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received Dabigatran Etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6–10 days. Patients were followed up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. Results: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group vs. 36.4% (183 of 503) of the Dabigatran Etexilate 220-mg group (absolute difference, −1.3%; 95% CI, −7.3 to 4.6) and 40.5% (213 of 526) of the 150-mg group (2.8%; 95% CI,−3.1 to 8.7). Both doses were non-inferior to enoxaparin on the basis of the prespecified non-inferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% vs. 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. Conclusions: Dabigatran Etexilate (220 mg or 150 mg) was at least as effective as enoxaparin and had a similar safety profile for prevention of VTE after total knee replacement surgery.
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Dabigatran Etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement a randomised double blind non inferiority trial
The Lancet, 2007Co-Authors: Bengt I Eriksson, Ola E Dahl, Martin H Prins, Nadia Rosencher, Andreas A Kurth, Niek C Van Dijk, Simon P Frostick, Rohan Hettiarachchi, Stefan Hantel, Janet SchneeAbstract:Summary Background After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor Dabigatran Etexilate for such prophylaxis. Methods In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28–35 days with Dabigatran Etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7·7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. Findings Median treatment duration was 33 days. 880 patients in the Dabigatran Etexilate 220 mg group, 874 in the Dabigatran Etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6·7%) of 897 individuals in the enoxaparin group versus 53 (6·0%) of 880 patients in the Dabigatran Etexilate 220 mg group (absolute difference −0·7%, 95% CI −2·9 to 1·6%) and 75 (8·6%) of 874 people in the 150 mg group (1·9%, −0·6 to 4·4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of Dabigatran Etexilate compared with enoxaparin (p=0·44 for 220 mg, p=0·60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. Interpretation Oral Dabigatran Etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.
Andreas Clemens - One of the best experts on this subject based on the ideXlab platform.
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A: Pharmacology, pharmacokinetics, and pharmacodynamics of Dabigatran Etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009, 15(Suppl 1):9S–16S
2016Co-Authors: Joachim Stangier, Andreas ClemensAbstract:Dabigatran Etexilate is a novel, oral reversible direct thrombin inhibitor that is rapidly absorbed and converted to its active form, Dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible inhibitor of thrombin, inhibiting both thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of Dabigatran are reached approximately 2 hours after oral administration. The elimina-tion half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug–drug interac-tions. The pharmacokinetic profile of Dabigatran is consistent across a broad range of different patient populations and is unaf-fected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in Dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran Etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes
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observational study of Dabigatran Etexilate 150 mg in patients with moderate renal impairment undergoing elective total hip or knee replacement
Thrombosis Research, 2016Co-Authors: Charlesmarc Samama, Martin Feuring, Andreas Clemens, Martina Brueckmann, Nadia Rosencher, Eva Kleine, Jenny Gullberg, Simon P FrostickAbstract:Abstract Introduction The standard Dabigatran Etexilate dosage for prevention of venous thromboembolism (VTE) after elective total hip or knee replacement (THR/TKR) is 220mg once daily (qd), with 150mg qd for patients with moderate renal impairment. As clinical trial experience in patients with moderate renal impairment was limited at the time of approval, we conducted an observational study to evaluate the 150mg qd dose. Materials and methods This open-label, prospective, uncontrolled, observational study in patients with creatinine clearance (CrCl) 30–50mL/min was conducted in seven European countries. Patients received 75mg Dabigatran Etexilate 1–4h after surgery and 150mg qd on days 2–10 (TKR) or 2–35 (THR), per the European Summary of Product Characteristics. Coprimary outcomes were major bleeding events (MBEs) and a composite of symptomatic VTE and all-cause mortality. Results 428 renally impaired patients with median CrCl 43.4mL/min (range 30.0–49.9), and median age 80years (range 32–96) received Dabigatran Etexilate: median treatment duration THR 31days, TKR 28days. Ten MBEs occurred in nine patients (2.1%; 95% confidence interval [CI]: 1.0–4.0; THR 1.8%; TKR 2.4%); none were fatal or involved a critical organ. Symptomatic VTE and all-cause mortality occurred in three patients (0.7%; 95% CI: 0.1–2.0; THR 0.9%; TKR 0.5%). Overall, 54 patients discontinued treatment prematurely, including 35 due to an adverse event (nine bleeding-related) and 16 switching to another anticoagulant. Conclusions Dabigatran Etexilate 150mg qd had a good safety profile and was efficacious in fragile, elderly, renally impaired patients undergoing THR or TKR. These findings from the clinical practice setting add to the existing clinical trial data.
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Dabigatran Etexilate in atrial fibrillation patients with severe renal impairment dose identification using pharmacokinetic modeling and simulation
The Journal of Clinical Pharmacology, 2012Co-Authors: Thorsten Lehr, Sebastian Haertter, Karlheinz Liesenfeld, Andreas Clemens, Alexander Staab, Paul A Reilly, Jeffrey FriedmanAbstract:Dabigatran, administered orally as the prodrug Dabigatran Etexilate (DE), is a direct thrombin inhibitor shown to be effective in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The aim of this analysis was to derive a modeling and simulation-based dose and dosing regimen for AF patients with severe renal failure who could potentially benefit from the use of DE. The exposure was simulated for AF patients with severe renal impairment for several combinations of doses (75, 110, 150 mg) and posologies (BID, QD, Q2D). Simulations were based on a population pharmacokinetic model derived from data from 9522 patients from the pivotal phase III study (RE-LY). Atrial fibrillation patients with a creatinine clearance (CRCL) of 30 mL/min receiving 150 mg BID. This dosing algorithm was also confirmed and supported by the United States Food and Drug Administration Clinical Pharmacology Division using their model based on the data from the dedicated renal impairment study and taking into account the safety and efficacy information from RE-LY.
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thromboprophylaxis with Dabigatran Etexilate in patients over seventy five years of age with moderate renal impairment undergoing or knee replacement
International Orthopaedics, 2012Co-Authors: Ola E Dahl, Andreas Clemens, Nadia Rosencher, Andreas A Kurth, Herbert Noack, Bengt I ErikssonAbstract:Purpose Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor Dabigatran Etexilate (hereafter referred to as Dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation.
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Dabigatran Etexilate for stroke prevention in patients with atrial fibrillation resolving uncertainties in routine practice
Thrombosis and Haemostasis, 2012Co-Authors: Menno V Huisman, Martina Brueckmann, Gregory Y H Lip, Joanne Van Ryn, Hanschristoph Diener, Andreas ClemensAbstract:Dabigatran Etexilate is a new oral anticoagulant recently approved in Europe for the prevention of stroke or systemic embolism in adult patients with non-valvular atrial fibrillation (AF) and at least one risk factor for stroke. With a fast onset of action and a predictable anticoagulant effect obviating the need for coagulation monitoring, Dabigatran Etexilate offers practical advantages over vitamin K antagonists in clinical practice. However, clinicians may have questions about practical aspects of Dabigatran Etexilate use including monitoring anticoagulant efficacy, interruption for surgical or invasive procedures and management of bleeding. This review article aims to address these concerns and provide guidance on the use of Dabigatran Etexilate in special situations, such as acute coronary syndromes and cardiac revascularisation. In addition, cut-off values for different coagulation assay results associated with an increased risk of bleeding are given.
Ola E Dahl - One of the best experts on this subject based on the ideXlab platform.
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thromboprophylaxis with Dabigatran Etexilate in patients over seventy five years of age with moderate renal impairment undergoing or knee replacement
International Orthopaedics, 2012Co-Authors: Ola E Dahl, Andreas Clemens, Nadia Rosencher, Andreas A Kurth, Herbert Noack, Bengt I ErikssonAbstract:Purpose Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor Dabigatran Etexilate (hereafter referred to as Dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation.
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oral Dabigatran Etexilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement the re model randomized trial
Journal of Thrombosis and Haemostasis, 2007Co-Authors: Bengt I Eriksson, Ola E Dahl, Nadia Rosencher, Andreas A Kurth, Simon P Frostick, Stefan Hantel, C N Van Dijk, Peter Kalebo, Anita Vedel Christiansen, Rohan HettiarachchiAbstract:Summary. Background: Oral anticoagulants, such as Dabigatran Etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. Methods: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received Dabigatran Etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6–10 days. Patients were followed up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. Results: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group vs. 36.4% (183 of 503) of the Dabigatran Etexilate 220-mg group (absolute difference, −1.3%; 95% CI, −7.3 to 4.6) and 40.5% (213 of 526) of the 150-mg group (2.8%; 95% CI,−3.1 to 8.7). Both doses were non-inferior to enoxaparin on the basis of the prespecified non-inferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% vs. 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. Conclusions: Dabigatran Etexilate (220 mg or 150 mg) was at least as effective as enoxaparin and had a similar safety profile for prevention of VTE after total knee replacement surgery.
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Dabigatran Etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement a randomised double blind non inferiority trial
The Lancet, 2007Co-Authors: Bengt I Eriksson, Ola E Dahl, Martin H Prins, Nadia Rosencher, Andreas A Kurth, Niek C Van Dijk, Simon P Frostick, Rohan Hettiarachchi, Stefan Hantel, Janet SchneeAbstract:Summary Background After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor Dabigatran Etexilate for such prophylaxis. Methods In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28–35 days with Dabigatran Etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7·7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. Findings Median treatment duration was 33 days. 880 patients in the Dabigatran Etexilate 220 mg group, 874 in the Dabigatran Etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6·7%) of 897 individuals in the enoxaparin group versus 53 (6·0%) of 880 patients in the Dabigatran Etexilate 220 mg group (absolute difference −0·7%, 95% CI −2·9 to 1·6%) and 75 (8·6%) of 874 people in the 150 mg group (1·9%, −0·6 to 4·4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of Dabigatran Etexilate compared with enoxaparin (p=0·44 for 220 mg, p=0·60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. Interpretation Oral Dabigatran Etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.
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pharmacokinetic profile of the oral direct thrombin inhibitor Dabigatran Etexilate in healthy volunteers and patients undergoing total hip replacement
The Journal of Clinical Pharmacology, 2005Co-Authors: Joachim Stangier, Hildegard Stahle, Karin Rathgen, Gerhard Nehmiz, Bengt I Eriksson, Ola E Dahl, Lennart Ahnfelt, Robbyna SvardAbstract:Dabigatran Etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, Dabigatran Etexilate is rapidly converted to its active form, Dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of Dabigatran Etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, Dabigatran Etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of Dabigatran Etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of Dabigatran Etexilate, although there was reduced interindividual variability for Dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean Dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of Dabigatran occurring after 6 hours. The AUC(0-24) of Dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the Dabigatran Etexilate capsule with food has no effect on the extent of Dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of Dabigatran were seen with early postoperative administration of the Dabigatran Etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.
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a new oral direct thrombin inhibitor Dabigatran Etexilate compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement the bistro ii randomized trial
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Bengt I Eriksson, Joachim Stangier, Ola E Dahl, Lennart Ahnfelt, Nadia Rosencher, Rohan Hettiarachchi, Harry R Buller, M L Bravo, F Piovella, Peter KaleboAbstract:Summary. Background: Dabigatran Etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. Methods: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6–10 days of oral Dabigatran Etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1–4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. Results: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to Dabigatran Etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of Dabigatran Etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). Conclusions: Oral administration of Dabigatran Etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.
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an open label study of the pharmacokinetics and pharmacodynamics of Dabigatran Etexilate 150 mg once daily in caucasian patients with moderate renal impairment undergoing primary unilateral elective total knee or hip replacement surgery
Thrombosis Research, 2016Co-Authors: Bengt I Eriksson, Joachim Stangier, Sebastian Haertter, Martin Feuring, Gerhard Nehmiz, Zsolt Mikuska, Jean Amiral, Jeffrey I WeitzAbstract:Abstract Background In adults with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of Dabigatran Etexilate is 150 mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. Methods Single-arm, open-label phase 4 study ( NCT01184989 ) in Caucasian patients receiving Dabigatran Etexilate 75 mg 1–4 h after surgery and 150 mg qd on days 2–10 (TKR) or days 2–35 (THR). Plasma total Dabigatran concentrations (day 6 ± 1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). Results Of 112 patients (mean CrCl 42.5 mL/min, age 79.1 years, 69.6% female), 100 completed the study. Geometric mean trough and peak Dabigatran concentrations were 47.5 ng/mL (10th–90th percentile 19.7–120) and 166 ng/mL (49.1–364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50–500 ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ± 15%. Conclusions These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150 mg qd dose of Dabigatran Etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of Dabigatran levels would be helpful.
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oral bioavailability of Dabigatran Etexilate pradaxa after co medication with verapamil in healthy subjects
British Journal of Clinical Pharmacology, 2013Co-Authors: Sebastian Hartter, Gerhard Nehmiz, Regina Sennewald, Paul A ReillyAbstract:Aim To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of Dabigatran Etexilate (DE).
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decrease in the oral bioavailability of Dabigatran Etexilate after co medication with rifampicin
British Journal of Clinical Pharmacology, 2012Co-Authors: S Hartter, Michael Koenenbergmann, Ashish Sharma, Gerhard Nehmiz, Ute Lemke, Wolfgang TimmerAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Dabigatran Etexilate is an oral prodrug that is rapidly converted to Dabigatran, a direct and reversible thrombin inhibitor. • Dabigatran Etexilate and Dabigatran are not metabolized by the cytochrome P450 system, and Dabigatran does not affect the metabolism of other drugs that utilize this system, leading to a low potential for drug–drug interactions. • Dabigatran Etexilate, but not Dabigatran, is a P-glycoprotein (P-gp) substrate, and the bioavailability of Dabigatran may be altered by P-gp inhibitors or inducers. WHAT THIS STUDY ADDS • Administration of rifampicin (a strong P-gp inducer) for 7 days before a single dose of Dabigatran Etexilate resulted in a significant reduction in the bioavailability of Dabigatran compared with administration of Dabigatran Etexilate alone. • Within 7 days following the cessation of rifampicin administration, the bioavailability of Dabigatran returned almost to baseline values. • Rifampicin is not recommended for use with Dabigatran Etexilate because of the potential for reduced systemic exposure to Dabigatran. AIMS This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of Dabigatran following oral administration of the prodrug, Dabigatran Etexilate. METHODS This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of Dabigatran Etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2–8, and single doses of Dabigatran Etexilate on days 9, 16 and 23. RESULTS Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of Dabigatran Etexilate alone; treatment A), administration of Dabigatran Etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration–time curve (AUC0–∞) and maximal plasma concentration (Cmax) of total Dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC0–∞ and 34.5% (90% confidence interval 26.9, 44.1%) for Cmax, indicating a significant effect on total Dabigatran exposure (total pharmacologically active Dabigatran represents the sum of nonconjugated Dabigatran and Dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC0–∞ and Cmax of Dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good. CONCLUSIONS Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of Dabigatran, which returned almost to baseline after 7 days washout.
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pharmacokinetic profile of the oral direct thrombin inhibitor Dabigatran Etexilate in healthy volunteers and patients undergoing total hip replacement
The Journal of Clinical Pharmacology, 2005Co-Authors: Joachim Stangier, Hildegard Stahle, Karin Rathgen, Gerhard Nehmiz, Bengt I Eriksson, Ola E Dahl, Lennart Ahnfelt, Robbyna SvardAbstract:Dabigatran Etexilate is an oral low-molecular-weight direct thrombin inhibitor. Following oral administration, Dabigatran Etexilate is rapidly converted to its active form, Dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of Dabigatran Etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, Dabigatran Etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of Dabigatran Etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of Dabigatran Etexilate, although there was reduced interindividual variability for Dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean Dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of Dabigatran occurring after 6 hours. The AUC(0-24) of Dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the Dabigatran Etexilate capsule with food has no effect on the extent of Dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of Dabigatran were seen with early postoperative administration of the Dabigatran Etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.
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dose escalating safety study of a new oral direct thrombin inhibitor Dabigatran Etexilate in patients undergoing total hip replacement bistro i
Journal of Thrombosis and Haemostasis, 2004Co-Authors: Bengt I Eriksson, Joachim Stangier, Gerhard Nehmiz, Ola E Dahl, Lennart Ahnfelt, Peter Kalebo, Karin Hermansson, V KohlbrennerAbstract:Summary. Background: Dabigatran Etexilate (BIBR 1048) is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, Dabigatran Etexilate is rapidly converted to its active form Dabigatran (BIBR 953 ZW). Objectives: To determine the safe therapeutic range of Dabigatran Etexilate following total hip replacement. Methods: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of Dabigatran Etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4–8 h after surgery, for 6–10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose–response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the Dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher Dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran Etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.