Dabigatran Etexilate: A Possible Replacement for Heparinoids and Vitamin K Antagonists?

SummaryThe therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

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Dabigatran treatment simulation in patients undergoing maintenance haemodialysis

Thrombosis and Haemostasis ◽

10.1160/th15-07-0531 ◽

2016 ◽

Vol 115 (03) ◽

pp. 562-569 ◽

Cited By ~ 6

Author(s):

Joerg Kreuzer ◽

Martina Brueckmann ◽

Friedrich Schulze ◽

Karl-Heinz Liesenfeld ◽

Andreas Clemens

Keyword(s):

Renal Clearance ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Area Under The Curve ◽

Fold Increase ◽

Dose Selection ◽

Maintenance Haemodialysis ◽

Increased Risk

SummaryPatients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the dose-exposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

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DOACs vs Vitamin K Antagonists: a Comparison of Phase III Clinical Trials and a Prescriber Support Tool

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.289 ◽

2019 ◽

Vol 7 (7) ◽

pp. 1226-1232 ◽

Cited By ~ 1

Author(s):

Alina-Maria Pirlog ◽

Cristian Daniel Pirlog ◽

Marius Adrian Maghiar

Keyword(s):

Clinical Trials ◽

Vitamin K ◽

Primary Outcome ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Phase Iii ◽

Support Tool ◽

Phase Iii Clinical Trials

AIM: The purpose of this article was to systematically review the literature assessing the efficacy and safety of phase III clinical trials for each direct oral anticoagulant versus vitamin K antagonists and to design a ’’go-to’’ table for the prescriber. MATERIAL AND METHODS: A systematic review of specialist literature was conducted to identify RCTs which compared direct oral anticoagulants (DOACs) with standard warfarin treatment. Medline, Em-base, and the Cochrane databases were searched from January 2005- January 2019. The inclusion criteria were randomised controlled trials of oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF). Four publications were phase III randomised control trials (RCTs) included in the final analysis. RESULTS: Regarding the primary outcome in RELY the results were 1.69% per 100-year patients (p/y) for Warfarin compared to 1.11% p/y dabigatran etexilate 150mg BD (twice daily). In ROCKET AF the rates of the primary outcome were 2.2% p/y for warfarin compared to 1.7% p/y for rivaroxaban 20 mg OD (once daily). In ARISTOTLE trial the rates of the primary outcome were 1.60% p/y for warfarin compared to 1.27% p/y for apixaban 5 mg BD. In ENGAGE AF TIMI, the rates of the primary outcome were 1.50% p/y for warfarin compared to 1.18% p/y for edoxaban 60mg BD. CONCLUSION: DOACs showed to be either noninferior or superior to warfarin with regards to the primary outcome with better safety patterns. Our ’’go-to’’ table provides a supportive tool for physicians in preventing medical errors when managing patients on oral anticoagulants.

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Promising areas of research on the pharmacogenetics of dabigatran etexilate

Pharmacogenetics and Pharmacogenomics ◽

10.37489/2588-0527-2020-1-35-41 ◽

2020 ◽

pp. 35-41

Author(s):

A. V. Savinova ◽

N. A. Shnayder ◽

M. M. Petrova ◽

R. F. Nasyrova

Keyword(s):

Candidate Genes ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

P Glycoprotein ◽

Udp Glucuronosyltransferase

Dabigatran etexilate is a prodrug of dabigatran, a direct inhibitor of thrombin. Pharmacokinetics of dabigatran etexilate doesn’t have the disadvantages of vitamin K antagonists. It is considered that CES1 enzyme and P-glycoprotein (CES1 and ABCB1 genes accordingly) play important role in pharmacokinetics of dabigatran etexilate. UDP-glucuronosyltransferase enzymes UGT2B15, UGT1A9, UGT2B7 (UGT2B15, UGT1A9, UGT2B7 genes accordingly) take part in the metabolism of active dabigatran. Presence of these gene’s single-nucleotide variants (SNV) can affect effectiveness and safety of dabigatran etexilate usage. The goal of this review is analysis of promising areas of associated researches of SNV of genes CES1 and ABCB1 and search for new candidate genes that reveal effectiveness and safety of dabigatran etexilate usage.

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Abstract 11473: Dabigatran Treatment Simulation in Patients Undergoing Maintenance Hemodialysis

Circulation ◽

10.1161/circ.132.suppl_3.11473 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Karl-Heinz Liesenfeld ◽

Andreas Clemens ◽

Joerg Kreuzer ◽

Martina Brueckmann ◽

Azhar Ahmad ◽

...

Keyword(s):

Renal Clearance ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Blood Flow Rate ◽

Fold Increase ◽

Maintenance Hemodialysis ◽

Once Daily ◽

Increased Risk

Background: Patients undergoing maintenance hemodialysis (HD) with atrial fibrillation (AF) are at increased risk of ischemic stroke and bleeds. At present, vitamin K antagonists, e.g. warfarin, are predominantly used for anticoagulation in this patient population. In such patients, limited data are available on the use of non-vitamin K oral anticoagulants. Dabigatran etexilate (DE) is mainly (85%) renally eliminated, thus its half-life is prolonged in renal impairment. It has been established that 4-hour HD can remove up to 60% of dabigatran from the plasma. The aim of the presented study is to evaluate the dose-exposure relationship for DE in HD patients considering different dosages and HD modalities by pharmacokinetic modeling. The resulting data could inform DE dose selection in future clinical trials. Method: We compared modeled DE exposure at once- and twice-daily doses of 75 mg, 110 mg, 150 mg in HD patients from pre- and post-dialysis dosing, with values simulated from AF patients in the RE-LY ® trial, based on a previously characterized pharmacometric model. Furthermore, variations in non-renal clearance, and several dialysis settings were simulated. Exposure (area under the curve, AUC) was compared to those from typical clinical HD settings. Results: Twice-daily DE doses showed a 1.5- to 3.3-fold increase in AUC of dabigatran compared with a typical RE-LY ® patient. A once-daily dose of 75 mg given after dialysis or 110 mg given before dialysis achieved an AUC comparable (-13.3 and +4.4%, respectively) to typical RE-LY ® patients. Of the patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 31% change). Duration of dialysis, dialysate and blood flow rate changed exposure by ≤14%. Conclusion: Twice-daily dosing of all DE doses tested in this simulation resulted in exposures clearly above what can be seen in typical RE-LY ® patients and thus might not be recommendable, although this is based on modeling only and the clinical impact is unknown. In patients undergoing maintenance HD, DE 75 mg once daily (given after dialysis) or 110 mg once daily (given before dialysis), resulted in exposure comparable to that simulated in typical RE-LY ® patients.

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Rationale, design, and protocol of a randomized controlled trial of the safety and efficacy of dabigatran etexilate versus dose-adjusted warfarin in patients with cerebral venous thrombosis

International Journal of Stroke ◽

10.1177/1747493018778125 ◽

2018 ◽

Vol 13 (7) ◽

pp. 766-770 ◽

Cited By ~ 13

Author(s):

José M Ferro ◽

Francesco Dentali ◽

Jonathan M Coutinho ◽

Adam Kobayashi ◽

Jorge Caria ◽

...

Keyword(s):

Venous Thrombosis ◽

Vitamin K ◽

Sinus Thrombosis ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Thrombotic Event ◽

Phase Iii ◽

Dural Sinus ◽

Dural Sinus Thrombosis ◽

Exploratory Trial

Rationale To prevent recurrent venous thrombotic events after acute cerebral venous or dural sinus thrombosis, guidelines recommend long-term oral anticoagulation with vitamin K antagonists. Non-vitamin K oral anticoagulant experience in cerebral venous or dural sinus thrombosis is limited to case reports and series. Aim To compare dabigatran with dose-adjusted warfarin in patients with cerebral venous or dural sinus thrombosis for the prevention of recurrent venous thrombotic event. Sample size One hundred and twenty patients. Methods and design This study is a phase III, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded endpoint adjudication. Patients with acute cerebral venous or dural sinus thrombosis after 5–15 days of treatment with parenteral heparin are randomized to either dabigatran etexilate 150 mg twice daily or dose-adjusted (international normalized ratio 2–3) warfarin (≤24 weeks). Study outcome The primary endpoint is a composite of patients with new venous thrombotic event (recurring cerebral venous or dural sinus thrombosis, deep venous thrombosis of any limb, pulmonary embolism, and major bleeding (International Society on Thrombosis and Hemostasis definition)) during the treatment period. Statistics will be descriptive (number and frequencies). Study timelines Inclusion started in December 2016. Final results are expected by the end of 2018. Discussion This exploratory trial is the first to compare vitamin K with non-vitamin K antagonists in cerebral venous or dural sinus thrombosis. It will provide evidence to guide physicians and patients in choosing oral anticoagulants to prevent venous thrombotic event after acute cerebral venous or dural sinus thrombosis. ClinicalTrials.gov number: NCT02913326.

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Anticoagulant Therapy in Atrial Fibrillation – Time for a Change?

European Cardiology Review ◽

10.15420/ecr.2009.5.2.57 ◽

2009 ◽

Vol 5 (2) ◽

pp. 57

Author(s):

Raffaele De Caterina ◽

Giulia Renda ◽

◽

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Anticoagulation Therapy ◽

New Drugs ◽

Phase Iii ◽

Therapeutic Window ◽

Randomized Evaluation ◽

New Anticoagulants

Although to date warfarin and other vitamin K antagonists have clearly had the greatest efficacy among commonly available treatments in preventing stroke in atrial fibrillation, their use is associated with a substantial risk of major bleeding and is impractical because of their narrow therapeutic window, their interaction with drugs and foods and the need for frequent coagulation monitoring. Several new anticoagulants are undergoing phase III clinical trials in atrial fibrillation with the aim of demonstrating non-inferiority compared with vitamin K antagonists or superiority compared with aspirin in patients in whom vitamin K antagonists are contraindicated or not tolerated. In the recently released Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, the first such drug, dabigatran etexilate, was proved substantially equivalent to 2–3 international normalised ratio (INR)-adjusted warfarin at the dosage of 110mg twice a day (BID), with superior efficacy at a dosage of 150mg BID. With these new drugs, cardiologists and internists are witnessing a real revolution in the thromboprophylaxis in atrial fibrillation.

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The effect of warfarin, heparin, and modern directly acting oral anticoagulants (dabigatran etexilate, rivaroxaban, apixaban) on the level of coagulation factors: V, VII, VIII, IX, XII, WF

HERALD of North-Western State Medical University named after I I Mechnikov ◽

10.17816/mechnikov201911179-92 ◽

2019 ◽

Vol 11 (1) ◽

pp. 79-92

Author(s):

Darya E. Gulyaikhina

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Left Ventricular ◽

Therapeutic Window ◽

Thrombin Inhibitor ◽

Vascular Effects ◽

Related Factors ◽

Warfarin Sodium

Heparin is common initial therapy administered to subjects with acute venous thromboembolism. Routine clinical practice in this case consists of immediate heparin therapy initiation and administration of warfarin sodium within 24 hours; administration of heparin is usually finished in 5 days. Patients with CF-LVAD (continuous flow left ventricular assist device) are also administered intravenous unfractionated heparin. Heparin mainly serves as anticoagulant via catalyzing antithrombin, which leads to factor II (thrombin), factor X inhibition, with smaller effect on IX, XI, XII. During the last 50 years warfarin has been the most common anticoagulant from vitamin K antagonists group which is used to treat patients with high risk of developing arterial and venous thrombosis. It has narrow therapeutic window due to unfavorable pharmacokinetics, thus requiring frequent monitoring, and it’s affected by interaction with concomitant medications and foods. Apart from this, effect of warfarin is not limited to the influence on hemostasis; it also has impact on all vitamin K-related proteins. Warfarin shows its anticoagulant effect through decreasing functional levels of vitamin K-related factors II, VII, IX and X. Synthesis of two physiologic anticoagulants — C and S proteins — is blocked at the same time. Warfarin competes with vitamin K, thus blocking vitamin K effects. Modern directly acting oral anticoagulants: direct thrombin inhibitor dabigatran and Xa factor inhibitors — rivaroxaban and apixaban, were developed as an alternative to warfarin. They also show non-hemostatic vascular effects via protease activated receptors (PARs).

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Idiopathic venous thrombosis

Hämostaseologie ◽

10.1055/s-0037-1616877 ◽

2006 ◽

Vol 26 (01) ◽

pp. 52-54 ◽

Cited By ~ 3

Author(s):

P. A. Kyrle

Keyword(s):

Chronic Disease ◽

Venous Thrombosis ◽

Vitamin K ◽

Clinical Benefit ◽

Plasma Levels ◽

Vitamin K Antagonists ◽

Antithrombin Deficiency ◽

Optimal Duration ◽

Risk Of Treatment

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

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Spectrophotometric Assays of Prothrombin in Plasma of Patients Using Oral Anticoagulants

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657025 ◽

1979 ◽

Vol 42 (04) ◽

pp. 1296-1305 ◽

Cited By ~ 29

Author(s):

R M Bertina ◽

W van der Marel-van Nieuwkoop ◽

E A Loeliger

Keyword(s):

Prothrombin Time ◽

Vitamin K ◽

Oral Anticoagulation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Factor V ◽

Anticoagulant Treatment ◽

Factor Ii ◽

K Deficiency

SummaryTwo spectrophotometric assays for prothrombin have been developed and compared with a one stage coagulant and an immunological assay. One of these assays (called the XAPC assay) uses a combination of factor Xa, phospholipid, Ca2+ and factor V as activator of prothrombin, and measures only normal prothrombin. The second (the ECAR assay) uses Echis carinatus venom as activator. This assay measures both normal prothrombin and PIVKA II (protein induced by vitamin K antagonists/absence). Combination of the results obtained by the XAPC and ECAR assays provides rapid and reliable information on the degree of “subcarboxylation” of prothrombin (oral anticoagulation, vitamin K deficiency).For patients on long term anticoagulant treatment the prothrombin time (Thrombotest) shows better correlation with the ratio prothrombin/prothrombin plus PIVKA II (XAPC/ ECAR) than with the factor II concentration. For patients starting the anticoagulant treatment there is no correlation between the Thrombotest time and the XAPC/ECAR ratio.It seems doubtful that (a) spectrophotometric factor II assay(s) will be as useful as the prothrombin time in the control of oral anticoagulation.

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