Chest
Volume 126, Issue 3, Supplement, September 2004, Pages 204S-233S
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The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

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This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. The article describes the antithrombotic effect of VKAs, the monitoring of anticoagulation intensity, the clinical applications of VKA therapy, and the optimal therapeutic range of VKAs, and provides specific management recommendations. Grade 1 recommendations are strong, and indicate that the benefits do, or do not, outweigh the risks, burdens, and costs. Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this article are the following: for dosing of VKAs, we suggest the initiation of oral anticoagulation therapy with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 2B). In the elderly and in other patient subgroups with an elevated bleeding risk, we suggest a starting dose at ≤ 5 mg (Grade 2C). We recommend basing subsequent doses after the initial two or three doses on the results of INR monitoring (Grade 1C). The article also includes several specific recommendations for the management of patients with INRs above the therapeutic range and for patients requiring invasive procedures. For example, in patients with mild to moderately elevated INRs without major bleeding, we suggest that when vitamin K is to be given it be administered orally rather than subcutaneously (Grade 1A). For the management of patients with a low risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before they undergo surgery (Grade 2C). For patients with a high risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before surgery, to allow the INR to return to normal, and beginning therapy with full-dose unfractionated heparin or full-dose low-molecular-weight heparin as the INR falls (Grade 2C). In patients undergoing dental procedures, we suggest the use of tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash without interrupting anticoagulant therapy (Grade 2B) if there is a concern for local bleeding. For most patients who have a lupus inhibitor, we suggest a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 2B]. In patients with recurrent thromboembolic events with a therapeutic INR or other additional risk factors, we suggest a target INR of 3.0 (range, 2.5 to 3.5) [Grade 2C]. As models of anticoagulation monitoring and management, we recommend that clinicians incorporate patient education, systematic INR testing, tracking, and follow-up, and good communication with patients concerning results and dosing decisions (Grade 1C+).

Section snippets

1.0 Pharmacology and Monitoring of VKAs

The 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).123456 The vitamin K coagulation factors II, VII, IX, and X require γ-carboxylation for their procoagulant activity, and treatment with coumarins results in the hepatic production of partially carboxylated and

1.1 Pharmacokinetics and pharmacodynamics of warfarin

Warfarin is the most common coumarin that is in clinical use. It is a racemic mixture of two optically active isomers, the R and S forms. Warfarin is rapidly absorbed from the GI tract, has high bioavailability,1819 and reaches maximal blood concentrations about 90 min after oral administration.1820 Warfarin has a half-life of 36 to 42 h,21 circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where the two isomers are metabolically transformed by different

1.2 The antithrombotic effect of VKAs

The antithrombotic effect of VKAs has conventionally been attributed to their anticoagulant effect, which in turn is mediated by the reduction of four vitamin K-dependent coagulation factors. More recent evidence, however, suggests that the anticoagulant and antithrombotic effects can be dissociated, and that the reduction of prothrombin and possibly factor X are more important than the reduction of factors VII and IX for the antithrombotic effect. This evidence is indirect and has been derived

1.3 Monitoring anticoagulation intensity

The PT test75 is the most common test used to monitor VKA therapy. The PT responds to a reduction of three of the four vitamin K-dependent procoagulant clotting factors (ie, II, VII, and X) that are reduced by warfarin at a rate proportional to their respective half-lives. Thus, during the first few days of warfarin therapy the PT reflects mainly a reduction of factor VII, the half-life of which is approximately 6 h. Subsequently, the reduction of factors X and II contributes to prolongation of

1.4 Clinical applications of VKA therapy

The clinical effectiveness of VKAs in the treatment of a variety of disease conditions has been established by well-designed clinical trials. VKAs are effective for the primary and secondary prevention of venous thromboembolism, for the prevention of systemic embolism in patients with prosthetic heart valves or atrial fibrillation, for the prevention of acute myocardial infarction in patients with peripheral arterial disease and in men who otherwise are at high risk, and for the prevention of

2.0 Management of VKA Therapy

Utilizing the correct intensity of a coumarin anticoagulant and maintaining the patient in the therapeutic range are two of the most important determinants of its therapeutic effectiveness and safety. High-quality dose management is essential to achieve and maintain therapeutic efficacy. Attainment of this goal can be influenced by physiologic and pharmacologic factors such as interacting drugs or illnesses that affect the pharmacokinetics or pharmacodynamics of warfarin, dietary or GI factors

2.1.1 Initiation and maintenance dosing

Following the administration of warfarin, an initial effect on the PT usually occurs within the first 2 or 3 days, depending on the dose administered, and an antithrombotic effect occurs within the next several days.138139 Heparin should be administered concurrently when a rapid anticoagulant effect is required, and its administration should be overlapped with warfarin until the INR has been in the therapeutic range for at least 2 days. A loading dose (ie, > 20 mg) of warfarin is not

Recommendations

2.1.1.1. We suggest the initiation of oral anticoagulation with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the INR response (Grade 2B).

Recommendations

2.1.3.1. We suggest that INR monitoring should be started after the initial two or three doses of oral anticoagulation therapy (Grade 2C).

2.1.3.2. For patients who are receiving a stable dose of oral anticoagulants, we suggest monitoring at an interval of no longer than every 4 weeks (Grade 2C).

Recommendations

2.1.4.1. For patients with INRs above the therapeutic range, but < 5.0 and with no significant bleeding, lower the dose or omit the dose, monitor more frequently, and resume therapy at a lower dose when the INR is at a therapeutic level. If only minimally above therapeutic range, no dose reduction may be required (all Grade 2C).

2.1.4.2. For patients with INRs of ≥ 5.0 but < 9.0 and no significant bleeding, omit the next one or two doses, monitor more frequently, and resume therapy at lower dose

Recommendations

2.1.5.1 For patients with a low risk of thromboembolism, stop warfarin therapy approximately 4 days before they undergo surgery, allow the INR to return to near-normal values, briefly use postoperative prophylaxis (if the intervention increases the risk of thrombosis) with low-dose UFH (5,000 U SC) or a prophylactic dose of LMWH, and simultaneously begin warfarin therapy. Alternatively, a low dose of UFH or a prophylactic dose of LMWH also can be used preoperatively (all Grade 2C).

2.1.5.2. For

Recommendation

2.1.6.1. In patients who have a lupus inhibitor who have no additional risk factors and no lack of response to therapy, we suggest a therapeutic target INR of 2.5 (INR range, 2.0 to 3.0) [Grade 2B]. In patients who have recurrent thromboembolic events with a therapeutic INR or other additional risk factors for thromboembolic events, we suggest a target INR of 3.0 (INR range, 2.5 to 3.5) [Grade 2C].

2.1.1 The Appropriate Dose for Initiation of Oral Anticoagulants

2.1.1.1. We suggest the initiation of oral anticoagulation therapy with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the INR response (Grade 2B).

2.1.2 Anticoagulation in the Elderly

2.1.2.1. In the elderly, for patients who are debilitated, malnourished, have congestive heart failure, or have liver disease we suggest the use of a starting dose of ≤ 5 mg (Grade 2C).

2.1.3 Frequency of Monitoring Oral Anticoagulation Therapy

2.1.3.1. We suggest starting INR monitoring after the initial two or three doses of oral anticoagulation

References (329)

  • PM Mannucci

    Genetic control of anticoagulation

    Lancet

    (1999)
  • GP Aithal et al.

    Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications

    Lancet

    (1999)
  • JH Chesebro et al.

    Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole

    Am J Cardiol

    (1983)
  • JW Suttie et al.

    Vitamin K deficiency from dietary vitamin K restriction in humans

    Am J Clin Nutr

    (1988)
  • B Furie et al.

    Randomized prospective trial comparing the native prothrombin antigen with the prothrombin time for monitoring anticoagulant therapy

    Blood

    (1990)
  • J Hirsh et al.

    Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range

    Chest

    (2001)
  • M Johnston et al.

    Reliability of the international normalized ratio for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio

    J Lab Clin Med

    (1996)
  • PD Stein et al.

    Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves

    Chest

    (2001)
  • CS Landefeld et al.

    Bleeding in outpatients treated with warfarin: Relation to the prothrombin time and important remediable lesions

    Am J Med

    (1989)
  • DS Whitlon et al.

    Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition

    Biochemistry

    (1978)
  • IA Choonara et al.

    The relationship between inhibition of vitamin K 1,2,3-epoxide reductase and reduction of clotting factor activity with warfarin

    Br J Clin Pharmacol

    (1988)
  • J Stenflo et al.

    Vitamin K dependent modifications of glutamic acid residues in prothrombin

    Proc Natl Acad Sci U S A

    (1974)
  • PV Hauschka et al.

    Osteocalcin and matrix Gla protein: vitamin K dependent proteins in bone

    Phys Rev

    (1989)
  • PA Price

    Role of vitamin K-dependent proteins in bone metabolism

    Annu Rev Nutr

    (1988)
  • C Maillard et al.

    Protein S, a vitamin K-dependent protein is a bone matrix component synthesized and secreted by osteoblasts

    Endocrinology

    (1997)
  • JM Pettifor et al.

    Congenital malformations associated with the administration of oral anticoagulants during pregnancy

    J Pediatr

    (1975)
  • AM Breckenridge

    Oral anticoagulant drugs: pharmacokinetic aspects

    Semin Hematol

    (1978)
  • RA O'Reilly

    Vitamin K and other oral anticoagulant drugs

    Annu Rev Med

    (1976)
  • JG Kelly et al.

    Clinical pharmacokinetics of oral anticoagulants

    Clin Pharmacokinet

    (1979)
  • RA O'Reilly

    Warfarin metabolism and drug-drug interactions

  • H Takahashi et al.

    Pharmacogenetics of warfarin elimination and its clinical implications

    Clin Pharmacokinet

    (2001)
  • AK Wittkowsky

    Pharmacology of warfarin and related anticoagulants

  • R Loebstein et al.

    Individual variability in sensitivity to warfarin: nature or nurture

    Clin Pharmacol Ther

    (2001)
  • M Higashi et al.

    Influence of CYP2C9 genetic variants on the risk of overanticoagulation and of bleeding events during warfarin therapy

    JAMA

    (2002)
  • RA O'Reilly et al.

    Hereditary resistance to coumarin anticoagulant drugs in man and rat

    Ann NY Acad Sci

    (1968)
  • RA O'Reilly et al.

    Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs

    N Engl J Med

    (1983)
  • BM Alving et al.

    Hereditary warfarin resistance

    Arch Intern Med

    (1985)
  • J Oldenburg et al.

    Missence mutations at ALA-10 in the factor IX peopeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticaogulant therapy

    Br J Haematol

    (1997)
  • A Breckenridge et al.

    Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man

    Clin Pharmacol Ther

    (1974)
  • RA O'Reilly

    Studies on the optical enantiomorphs of warfarin in man

    Clin Pharmacol Ther

    (1974)
  • RA O'Reilly et al.

    Stereoselective interaction of phenylbutazone with 13C/12C labelled racemates of warfarin in man [abstract]

    Fed Proc

    (1978)
  • S Toon et al.

    The warfarin-sulfinpyrazone interaction: stereochemical considerations

    Clin Pharmacol Ther

    (1986)
  • RA O'Reilly

    The stereoselective interaction of warfarin and metronidazole in man

    N Engl J Med

    (1976)
  • RA O'Reilly

    Stereoselective interaction of trimethoprim-sulamethazole with the separated enantiomorphs of racemic warfarin in man

    N Engl J Med

    (1980)
  • RJ Lewis et al.

    Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone

    J Clin Invest

    (1974)
  • RA O'Reilly et al.

    Interaction of amiodorone with racemic warfarin and its separated enantimorphs in humans

    Clin Pharmacol Ther

    (1987)
  • RA O'Reilly

    Lack of effect of fortified wine ingested during fasting and anticoagulant therapy

    Arch Intern Med

    (1981)
  • JS Cropp et al.

    A review of enzyme induction of warfarin metabolism with recommendations for patient management

    Pharmacotherapy

    (1997)
  • H Bechtold et al.

    Evidence for impaired hepatic vitamin K1 metabolism in patients treated with N-methyl-thiotetrazole cephalosporins

    Thromb Haemost

    (1984)
  • M Weitkamp et al.

    Prolonged bleeding times and bleeding diathesis associated with moxalactam administration

    JAMA

    (1983)
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