Chest
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only ArticlesOral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Section snippets
Pharmacology
VKAs produce their anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the γ-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins (Fig 1).1, 2, 3, 4, 5, 6, 7, 8 The vitamin K-dependent coagulation factors II, VII, IX, and X require γ-carboxylation for their procoagulant activity, and treatment with VKAs results in the hepatic production of partially
Direct Thrombin Inhibitors: Dabigatran Etexilate
Dabigatran is a selective, reversible, direct thrombin inhibitor given as dabigatran etexilate, an orally absorbable prodrug, since dabigatran itself is a strongly polar molecule that is not absorbed from the gut. Phase 3 clinical studies reported to date have evaluated the use of dabigatran etexilate for the prevention of VTE after elective total knee or hip arthroplasty, for therapy of VTE, and to prevent stroke or systemic embolism in nonvalvular AF. The drug is approved in many countries
Direct Factor Xa Inhibitors: Rivaroxaban
Rivaroxaban is a direct factor Xa inhibitor and is currently approved in many countries, including the United States, for the prevention of VTE in patients undergoing total hip or knee replacement surgery. The drug is undergoing an extensive clinical development program in other clinical settings, including the treatment of VTE and the prevention of acute ischemic stroke in patients with AF. In phase III clinical trials, rivaroxaban was found to be more effective than the low-molecular-weight
Conclusion
Over the last decades, a large amount of research has been addressed to improve the understanding of the mechanisms of warfarin, acenocoumarol, and phenprocoumon and to improve the management of patients treated with these VKAs. Several studies have in particular identified some genetic factors associated with the individual responses to VKAs and several drugs, foods, and environmental factors that can interact with these compounds. Several induction and maintenance strategies have been
Acknowledgments
Author contributions: As Topic Editor, Dr Ageno oversaw the development of this article, including any analysis and subsequent development of the information contained herein
Dr Ageno: contributed as Topic Editor.
Dr Gallus: contributed as a panelist.
Dr Wittkowsky: contributed as a panelist.
Dr Crowther: contributed as a panelist.
Dr Hylek: contributed as a panelist.
Dr Palareti: contributed as a panelist.
Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the
References (430)
- et al.
Evidence that warfarin anticoagulant action involves two distinct reductase activities
J Biol Chem
(1982) - et al.
Normal and warfarin-resistant rat hepatocyte metabolism of vitamin K 2,3-epoxide: evidence for multiple pathways of hydroxyvitamin K formation
Arch Biochem Biophys
(1988) - et al.
The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin
J Biol Chem
(1974) The vitamin K cycle
J Thromb Haemost
(2005)- et al.
Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest
(2008) - et al.
A spectrum of partially carboxylated prothrombins in the plasmas of coumarin-treated patients
Biochim Biophys Acta
(1977) - et al.
The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins
J Biol Chem
(1985) - et al.
Role of gamma-carboxyglutamic acid. An unusual protein transition required for the calcium-dependent binding of prothrombin to phospholipid
J Biol Chem
(1976) - et al.
Differentiation of metal ion-induced transitions of prothrombin fragment 1
J Biol Chem
(1977) - et al.
Prothrombin requires two sequential metal-dependent conformational transitions to bind phospholipid. Conformation-specific antibodies directed against the phospholipid-binding site on prothrombin
J Biol Chem
(1986)
Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications
Lancet
CYP2C9 polymorphism and warfarin sensitivity in Taiwan Chinese
Clin Chim Acta
Biochemical basis of hereditary resistance to warfarin in the rat
Biochem Pharmacol
A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin
Blood
The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen
Blood
Population variation in VKORC1 haplotype structure
J Thromb Haemost
Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement
Am Heart J
Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole
Am J Cardiol
Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk
Am J Med
Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin?
Am J Med
Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
Dietary supplement use among anticoagulation clinic patients
J Thromb Haemost
Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction
Int J Cardiol
Vitamin K deficiency from dietary vitamin K restriction in humans
Am J Clin Nutr
Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition
Biochemistry
The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin
Br J Clin Pharmacol
Vitamin K dependent modifications of glutamic acid residues in prothrombin
Proc Natl Acad Sci U S A
The importance of factor Xa regulatory pathways in vascular thromboresistance: focus on protein Z
J Thromb Thrombolysis
Oral anticoagulant drugs: pharmacokinetic aspects
Semin Hematol
Vitamin K and the oral anticoagulant drugs
Annu Rev Med
Clinical pharmacokinetics of oral anticoagulants
Clin Pharmacokinet
Cytochrome P4502C9: an enzyme of major importance in human drug metabolism
Br J Clin Pharmacol
Pharmacokinetics of the enantiomers of acenocoumarol in man
Br J Clin Pharmacol
Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon
Semin Thromb Hemost
Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients
Clin Pharmacol Ther
Web site
Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance
Clin Pharmacol Ther
Pharmacology of warfarin and related anticoagulants
Individual variability in sensitivity to warfarin: nature or nurture
Clin Pharmacol Ther
Influence of CYP2C9 genotype on warfarin dose requirements—a systematic review and meta-analysis
Eur J Clin Pharmacol
Influence of CYP2C9 genetic variants on the risk of over anticoagulation and of bleeding events during warfarin therapy
JAMA
CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes
Clin Pharmacol Ther
A novel sequence variant in exon 7 of CYP2C9 gene (CYP2C9*24) in a patient on warfarin therapy
Thromb Haemost
The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon
Thromb Haemost
CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences
Clin Pharmacol Ther
Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon
Thromb Haemost
Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
Nature
Identification of the gene for vitamin K epoxide reductase
Nature
Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose
N Engl J Med
Cited by (1302)
Bleeding Risk in Hemodialysis Patients
2024, Seminars in NephrologyDirect-acting oral anticoagulants in antiphospholipid syndrome: A systematic review
2023, Medicina Clinica
Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.
Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).