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DOI 10.1378/chest.11-2292 2012;141;e44S-e88SChest Elaine M. Hylek and Gualtiero Palareti Walter Ageno, Alexander S. Gallus, Ann Wittkowsky, Mark Crowther, Evidence-Based Clinical Practice Guidelines ed: American College of Chest Physicians Therapy and Prevention of Thrombosis, 9th Oral Anticoagulant Therapy : Antithrombotic http://chestjournal.chestpubs.org/content/141/2_suppl/e44S.full.html services can be found online on the World Wide Web at: The online version of this article, along with updated information and e44S.DC1.html http://chestjournal.chestpubs.org/content/suppl/2012/02/03/141.2_suppl. Supplemental material related to this article is available at: ISSN:0012-3692 )http://chestjournal.chestpubs.org/site/misc/reprints.xhtml( written permission of the copyright holder. this article or PDF may be reproduced or distributed without the prior Dundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2012by the American College of Chest Physicians, 3300 Physicians. It has been published monthly since 1935. is the official journal of the American College of ChestChest © 2012 American College of Chest Physicians at ZheJiang University on March 1, 2012chestjournal.chestpubs.orgDownloaded from e44S CHEST Supplement Oral Anticoagulant Therapy ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES on laboratory and clinical monitoring and on rever- sal strategies. More recently, new oral anticoagulant drugs, namely the direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitor rivaroxaban, have been approved for clinical use in several countries. A growing body of laboratory and clinical data is becoming avail- able to better understand the mechanisms of action and the optimal management of these new compounds. In this article we summarize the published literature con- cerning the pharmacokinetics and pharmacodynamics of all oral anticoagulant drugs that are currently avail- able for clinical use and other aspects related to their management. For many decades, the vitamin K antagonists (VKAs) have been the only oral anticoagulant drugs available for clinical use for the primary and secondary prevention of venous and arterial throm- boembolic events. VKAs have been consistently shown to be highly effective in many settings and are now used by millions of patients worldwide. Laboratory and clinical studies have contributed to understanding of the complex pharmacokinetics and pharmacodynamics of VKAs, their interac- tions, antithrombotic effects, and the risks associ- ated with their use. Several studies have addressed the practical issues related to the management of patients on VKAs treatment, with particular focus Background: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. Methods: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban. Results: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the mon- itoring of anticoagulation intensity are described in detail and discussed without providing spe- cifi c recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. Conclusions: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the fi rst new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban. CHEST 2012; 141(2)(Suppl):e44S–e88S Abbreviations: AC 5 anticoagulation clinic; AMS 5 anticoagulation management service; aPTT 5 activated partial thromboplastin time; AUC 5 area under the curve; Cmax 5 peak plasma concentration; ECT 5 ecarin clotting time; HR 5 hazard ratio; INR 5 international normalized ratio; ISI 5 international sensitivity index; PCC 5 prothrombin complex concentrate; PE 5 pulmonary embolism; POC 5 point of care; PSM 5 patient self-management; PST 5 patient self testing; PT 5 prothrombin time; TCT 5 thrombin clotting time; TTR 5 time in therapeutic range; UC 5 usual care; VKA 5 vitamin K antagonist; VKOR 5 vitamin K oxide reductase; WHO 5 World Health Organization Oral Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Walter Ageno , MD ; Alexander S. Gallus , MBBS ; Ann Wittkowsky , PharmD , FCCP ; Mark Crowther , MD ; Elaine M. Hylek , MD , MPH ; and Gualtiero Palareti , MD © 2012 American College of Chest Physicians at ZheJiang University on March 1, 2012chestjournal.chestpubs.orgDownloaded from www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e45S effect of the VKAs can be overcome by low doses of phytonadione (vitamin K) ( Fig 1 ). 1.2 Pharmacokinetics and Pharmacodynamics Warfarin is a racemic mixture of two optically active isomers, the R and S enantiomers. Warfarin is highly water soluble, is rapidly absorbed from the gastrointestinal tract, has high bioavailability, 15,16 and reaches maximal blood concentrations about 90 min after oral administration. 15,17 Racemic warfarin has a half-life of 36 to 42 h 18 (R-warfarin 45 h, S-warfarin 29 h), circulates bound to plasma proteins (mainly albumin), and accumulates in the liver where the two enantiomers are metabolically transformed by dif- ferent pathways ( Fig 1 ). 18 The S enantiomer of warfa- rin (2.7-3.8 times more potent than the R enantiomer) undergoes approximately 90% oxidative metabolism, primarily by the CYP2C9 enzyme of the cytochrome P450 system and to a lesser extent by CYP3A4. 19 The less potent R enantiomer undergoes approximately 60% oxidative metabolism, primarily by two cyto- chrome P450 enzymes, CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19. The remainder of the metabolism of both enantiomers involves reduction to diastereomeric alcohols. The relationship between the dose of warfarin and the response is modifi ed by genetic and environmental factors that can infl uence the absorption of warfarin, its pharmacokinetics, and its pharmacodynamics. Other available VKAs include acenocoumarol, phen- procoumon, and fl uindione. Like warfarin, aceno- coumarol and phenprocoumon also exist as optical isomers, but with different stereochemical character- istics. R-acenocoumarol has an elimination half-life of 9 h, is primarily metabolized by CYP2C9 and CYP2C19, and is more potent than S-acenocoumarol because of faster clearance of S-acenocoumarol, which has an elimination half-life of 0.5 h and is pri- marily metabolized by CYP2C9. 20 Phenprocoumon is a much longer-acting agent, with both the R- and S-isomers having elimination half-lives of 5.5 days. Both are metabolized by CYP2C9, and S-phenprocoumon is 1.5 to 2.5 times more potent than R-phenprocou- mon. 21 Finally, fl uindione is an indandione VKA with a mean half-life of 31 h. 22 Unlike warfarin, fl uindione is not a chiral compound. 22 1.3 Interactions 1.3.1 Genetic Factors: A number of point muta- tions in the gene coding for the CYP2C9 have been identifi ed. 23 These polymorphisms, the most common of which are CYP2C9*2 and CYP2C9*3, are associ- ated with an impaired ability to metabolize S-warfarin, resulting in a reduction in S-warfarin clearance and, 1.0 Vitamin K Antagonists 1.1 Pharmacology VKAs produce their anticoagulant effect by inter- fering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the g -carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins ( Fig 1 ). 1-8 The vitamin K-dependent coagula- tion factors II, VII, IX, and X require g -carboxylation for their procoagulant activity, and treatment with VKAs results in the hepatic production of partially carboxylated and decarboxylated proteins with reduced coagulant activity. 9,10 Carboxylation is required for a calcium-dependent conformational change in coagu- lation proteins 11-13 that promotes binding to cofactors on phospholipid surfaces. In addition, the VKAs inhibit carboxylation of the regulatory anticoagulant proteins C, S, and Z and thereby have the potential to be procoagulant. 14 Although the anticoagulant effect of VKAs is dominant, a transient procoagulant effect may occur when baseline protein C and protein S levels are reduced due to the start of VKA therapy and the acute phase of a thrombotic event and before the balanced decrease of vitamin K-dependent clot- ting factor levels is achieved. Carboxylation requires the reduced form of vitamin K (vitamin KH 2 ), a g -glutamyl carboxylase, molecular oxygen, and CO 2 . 1 Vitamin K epoxide can be reused by reduction to VKH 2 . The oxidation-reduction reaction involves a reductase pair. The fi rst, vitamin K epoxide reduc- tase, is sensitive to VKA, whereas vitamin K reduc- tase is less sensitive. 1-3 Therefore, the anticoagulant Revision accepted August 31, 2011 . Affi liations: From the University of Insubria (Dr Ageno), Varese, Italy; Flinders University (Dr Gallus), Adelaide, SA, Australia; the University of Washington (Dr Wittkowsky), Seattle, WA; McMas- ter University (Dr Crowther), St. Joseph’s Hospital, Hamilton, ON, Canada; the Boston University School of Medicine (Dr Hylek), Boston, MA; and the University Hospital S. Orsola-Malpighi (Dr Palareti), Bologna, Italy . 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 educa- tional grants was also provided by Bristol-Myers Squibb; Pfi zer, 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. Correspondence to: Walter Ageno, MD, Department of Clinical Medicine, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy; e-mail: walter.ageno@uninsubria.it © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/ site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2292 © 2012 American College of Chest Physicians at ZheJiang University on March 1, 2012chestjournal.chestpubs.orgDownloaded from e46S Oral Anticoagulant Therapy (VKOR) enzyme fi rst described in 1974. 36 The gene coding for the VKOR protein is located on the short arm of chromosome 16. 37,38 The gene encodes for several isoforms of a protein that are collectively termed the vitamin K oxide reductase complex 1 (VKORC1). Subsequently, mutations in this gene have been identifi ed leading to enzymes with vary- ing sensitivities to inhibition by warfarin, 38-43 thereby affecting the pharmacodynamics of warfarin. The mutations occur with differing frequencies in various ethnic populations and account, in part, for the dif- ference in warfarin doses required to maintain a ther- apeutic international normalized ratio (INR) (Table S1) (tables that contain an “S” before the number denote supplementary tables not contained in the body of the article and available instead in an online data supplement; see the “Acknowledgments” for more information). 39-41,44,45 Genetic mutations in the gene coding for the VKORC1often involve several mutations leading to various haplotypes that cause greater resistance to warfarin therapy. Harrington et al 43 found a warfarin- resistant individual who had high serum warfarin as a result, an increased S-warfarin elimination half- life. 24 Mutations in this gene occur with different frequencies in various ethnic groups (Table S1). 25,26 In comparison with patients who are homozygous for the wild-type allele (CYP2C9*1*1), patients with heterozygous (CYP2C9*1*2, CYP2C9*1*3, CYP2C9*2*3) or homozygous (CYP2C9*2*2, CYP2C9*3*3) expression of a variant allele require lower doses of warfarin, as determined by a systematic review of the literature and meta-analysis of studies that assessed the infl uence of CYP2C9 polymor- phisms on warfarin dose requirements (Table S2). 27 Several investigations 25,28,29 have shown that these mutations, as well as others, 30-32 are also associated with an increase in bleeding complications associated with warfarin therapy. Mutations in CYP2C9 also affect acenocoumarol, although to a lesser degree because the anticoagulation potencies of the R and S enantiomers are comparable. 33,34 The effects of CYP2C9 polymorphisms are least pronounced with the use of phenprocoumon. 33,35 The target for warfarin’s inhibitory effect on the vitamin K cycle is the vitamin K oxide reductase Figure 1. [Section 1.1] Vitamin K 1 is reduced to vitamin KH2. The major warfarin-sensitive enzyme in this reaction is the vitamin K oxide reductase mainly inhibited by the S-enantiomer of warfarin. S-warfarin is metabolized by the p450 cytochrome enzyme, CYP2C9. Reprinted with permission from Ansell et al. 8 © 2012 American College of Chest Physicians at ZheJiang University on March 1, 2012chestjournal.chestpubs.orgDownloaded from www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e47S tive metabolism of either the S-enantiomer or R-enantiomer of warfarin). The inhibition of S-warfarin metabolism is more important clinically, because this enantiomer is more potent than the R-enantiomer as a VKA. 50,51 Phenylbutazone, 52 sulfi npyrazone, 53 metro- nidazole, 54 and trimethoprimsulfamethoxazole 55 inhibit the clearance of S-warfarin, and each potentiates the effect of warfarin on the prothrombin time (PT). In contrast, drugs such as cimetidine and omeprazole, which inhibit the clearance of the R-isomer, poten- tiate the PT only modestly in patients who are treated with warfarin. 51,54,56 Amiodarone is a potent inhibitor of the metabolic clearance of both the S-enantiomer and the R-enantiomer and potentiates warfarin anti- coagulation. 57 The anticoagulant effect of warfarin is inhibited by drugs like barbiturates, rifampin, azathi- oprine, and carbamazepine, which increase its clear- ance by inducing hepatic metabolism. 58 Azathioprine also reduces the anticoagulant effect of warfarin, pre- sumably through a potentiating effect on hepatic clearance. 59 Long-term alcohol consumption has a similar potential to increase the clearance of warfarin, but ingestion of even relatively large amounts of wine had little infl uence on the PT in normal volunteers who were given warfarin. 60 The effect of enzyme induction on warfarin therapy has been analyzed in a critical review. 58 Ten hepatic microsomal enzyme agents were assessed. Enzyme induction of warfarin metabolism by rifampin and barbiturates was consid- ered likely, and an interaction with carbamazepine, griseofulvin, aminoglutethimide, nafcillin, and diclox- acillin was considered probable. Drugs may also infl uence the pharmacodynamics of warfarin by inhibiting the synthesis of or increas- ing the clearance of vitamin K-dependent coagula- tion factors or by interfering with other pathways of hemostasis. The anticoagulant effect of warfarin is aug- mented by second-generation and third-generation cephalosporins, which inhibit the cyclic interconver- sion of vitamin K; 61,62 by thyroxine, which increases the metabolism of coagulation factors; 63 and by clofi brate through an unknown mechanism. 64 Doses of salicylates of . 1.5 g per day 65 may augment the anticoagulant effect of warfarin. Acetaminophen potentiates the effect of warfarin when used over prolonged periods of time, as demonstrated in a recent randomized, blinded trial. 66-68 Acetaminophen possibly potentiates the anticoagulant effect of warfarin through inhibi- tion of VKOR by a toxic metabolite of the drug, 69 although the accumulation of this metabolite may vary among individuals, thus accounting for a variable potentiating effect. 70 Heparin potentiates the anti- coagulant effect of warfarin, but in therapeutic doses produces only a slight prolongation of the PT. The mechanisms by which erythromycin 71 and some ana- bolic steroids 72 potentiate the anticoagulant effect of concentrations and a 196G . A transition, predicting a Val66Met substitution in VKORC1. D’Andrea et al, 39 studying 147 patients, found that those with a 1173CC genotype required a higher mean maintenance dose compared with those with a CT or TT genotype, as did Quiteineh et al, 46 who found that a 1173 C . T poly- morphism was signifi cantly associated with the risk of anticoagulant overdose. By identifying a number of noncoding single nucleotide polymorphisms, Rieder et al 40 were able to infer that there are fi ve major haplotypes associated with different dose requirements for maintaining a therapeutic INR. The maintenance dose ranged from a low of 2.7 mg warfarin per day for the sensitive haplotypes up to a high of 6.2 mg per day for the resistant haplo- types. Asian Americans had the highest proportion of sensitive haplotypes, whereas African Americans more frequently exhibited the resistant haplotypes (Table S1). 1.3.2 Drugs: VKAs are highly susceptible to drug-drug interactions. For warfarin, for example, manufacturer-provided product information lists . 200 specifi c agents that may interfere with this agent. 47 Unfortunately, there seems to be little concordance among commonly used drug compendia and product labels with respect to interactions involving warfarin. Indeed, a major problem with the literature on this topic is that many reports are single-case reports and are not well documented. Anthony et al 44 recently reviewed three drug information compendia, Clinical Pharmacology, ePocrates, and Micromedex, and the warfarin sodium (Coumadin) product label approved by the US Food and Drug Administration, for listings of interactions between warfarin and drugs, biologics, foods, and dietary supplements and found that of a total of 648 entries from the four sources, only 50 were common to all the sources. 44 As in the previous edition of this article, 8 Table 1 summarizes a compre- hensive list of drugs that potentiate, inhibit, or have no effect on the anticoagulant effect of warfarin based on the results of a systematic review of available evi- dence completed in 2005, which rated warfarin drug interaction reports according to interaction direc- tion, clinical severity, and quality of evidence, and developed lists of warfarin drug interactions consid- ered highly prob