UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Medline ® Abstracts for References 2,49-52

of 'Perioperative management of patients receiving anticoagulants'

2
TI
How I treat anticoagulated patients undergoing an elective procedure or surgery.
AU
Spyropoulos AC, Douketis JD
SO
Blood. 2012 Oct;120(15):2954-62. Epub 2012 Aug 28.
 
The periprocedural management of patients receiving long-term oral anticoagulant therapy remains a common but difficult clinical problem, with a lack of high-quality evidence to inform best practices. It is a patient's thromboembolic risk that drives the need for an aggressive periprocedural strategy, including the use of heparin bridging therapy, to minimize time off anticoagulant therapy, while the procedural bleed risk determines how and when postprocedural anticoagulant therapy should be resumed. Warfarin should be continued in patients undergoing selected minor procedures, whereas in major procedures that necessitate warfarin interruption, heparin bridging therapy should be considered in patients at high thromboembolic risk and in a minority of patients at moderate risk. Periprocedural data with the novel oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, are emerging, but their relatively short half-life, rapid onset of action, and predictable pharmacokinetics should simplify periprocedural use. This review aims to provide a practical, clinician-focused approach to periprocedural anticoagulant management.
AD
Department of Medicine, Division of Hematology/Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, Rochester, NY; and.
PMID
49
TI
Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
AU
Stangier J, Rathgen K, Stähle H, Mazur D
SO
Clin Pharmacokinet. 2010;49(4):259.
 
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). This open-label, parallel-group, single-centre study enrolled 23 subjects with mild, moderate or severe renal impairment (creatinine clearance>50 to<or =80,>30 to<or =50 and<or =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. Compared with the values in healthy subjects, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) 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 (C(max)) were modest, and the time to reach the C(max) wasunchanged. 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(infinity) was approximately twice the value in the control group. Haemodialysis removed 62-68% of the dose. Dabigatran etexilate was well tolerated in all groups. 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.
AD
Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach, Germany. Joachim.Stangier@boehringer-ingelheim.com
PMID
50
TI
Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.
AU
van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A
SO
Thromb Haemost. 2010;103(6):1116. Epub 2010 Mar 29.
 
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 levels. There are limited data for activated clotting time (ACT).Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.
AD
Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach an der Riss, Germany. Joanne.vanRyn@boehringer-ingelheim.com
PMID
51
TI
Dabigatran etexilate: a new oral thrombin inhibitor.
AU
Hankey GJ, Eikelboom JW
SO
Circulation. 2011;123(13):1436.
 
AD
Department of Neurology, Royal Perth Hospital, 197 Wellington St, Perth, Australia 6001. gjhankey@cyllene.uwa.edu.au
PMID
52
TI
Perioperative Management of Dabigatran: A Prospective Cohort Study.
AU
Schulman S, Carrier M, Lee AY, Shivakumar S, Blostein M, Spencer FA, Solymoss S, Barty R, Wang G, Heddle N, Douketis JD
SO
Circulation. 2015 Jul;132(3):167-73. Epub 2015 May 12.
 
BACKGROUND: The perioperative management of dabigatran in clinical practice is heterogeneous. We performed this study to evaluate the safety of perioperative management of dabigatran using a specified protocol.
METHODS AND RESULTS: Patients treated with dabigatran and planned for an invasive procedure were eligible for inclusion. The timing of the last dose of dabigatran before the procedure was based on the creatinine clearance and procedure-related bleeding risk. Resumption of dabigatran was prespecifiedaccording to the complexity of the surgery and consequences of a bleeding complication. Patients were followed up for 30 days for major bleeding (primary outcome), minor bleeding, arterial thromboembolism, and death. We included 541 cases: 324 procedures (60%) with standard risk of bleeding and 217 procedures (40%) with increased risk of bleeding. The last dose of dabigatran was at 24, 48, or 96 hours before surgery according to the protocol in 46%, 37%, and 6%, respectively, of the patients. Resumption was timed according to protocol in 77% with 75 mg as the first dose on the day of procedure in 40% of the patients. Ten patients (1.8%; 95% confidence interval, 0.7-3.0) had major bleeding, and 28 patients (5.2%; 95% confidence interval, 3.3-7.0) had minor bleeding events. The only thromboembolic complication was transient ischemic attack in 1 patient (0.2%; 95% confidence interval, 0-0.5), and there were 4 deaths unrelated to bleeding or thrombosis. Bridging was not used preoperatively but was administered in 9 patients (1.7%) postoperatively.
CONCLUSION: Our protocol for perioperative management of dabigatran appears to be effective and feasible.
AD
From Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada (S. Schulman, F.A.S., J.D.D.); Department of Hematology, Karolinska Institutet, Stockholm, Sweden (S. Schulman); Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, ON, Canada (M.C.); Division of Hematology, University of British Columbia and Vancouver Coastal Health, Canada (A.Y.Y.L.); Faculty of Medicine, Dalhousie University, Halifax, NS, Canada (S. Shivakumar); Division of Hematology, Department of Medicine, Jewish General Hospital (M.B.) and Department of Medicine (S. Solymoss), McGill University, Montreal, QC, Canada; and McMaster Transfusion Research Program, McMaster University, Hamilton, ON, Canada (R.B., G.W., N.H.). schulms@mcmaster.ca.
PMID