Vitamin K Antagonists: Biochemistry, Pharmacology, and Management
Nirmish Shah
Thomas L. Ortel
Sam Schulman
INTRODUCTION/HISTORY
Vitamin K antagonists (VKAs) are currently the most common oral anticoagulants used worldwide. The discovery of VKAs began in 1921 to 1922, with initial investigations into bleeding cattle that had eaten improperly cured hay from the sweet clovers Melilotus alba and Melilotus officinalis. These cattle were given the diagnosis of sweet clover disease and found to have an increased prothrombin time (PT).1 In 1939, crystals of the anticoagulant were isolated and the structure was subsequently identified as 3,3′-methylenebis(4-hydroxycoumarin), a conjugation of two molecules of 4-hydroxycoumarin with a methylene bridge. In addition, this dicumarol anticoagulant was found to be counteracted by vitamin K.2 Although the anticoagulant effect was not understood until the 1970s, efforts then focused on development of coumarin-type compounds.3 The development and synthesis of these compounds eventually led to patents for both dicumarol and WARF 42, which were held by the Wisconsin Alumni Research Foundation (WARF). WARF 42 was later renamed as warfarin and was initially used as a rodenticide due to its relative nontoxic effects to humans and domestic animals.4 All coumarin derivatives have a central 4-hydroxycoumarin with a substituent in the 3-position and an asymmetric carbon atom resulting in enantiomers. The anticoagulant effect of both dicoumarol and warfarin quickly became a significant weapon in the arsenal of the cardiac specialist and has remained so to this day. VKA are now used worldwide to treat patients with thrombosis or an increased risk for thrombosis. This chapter reviews the biochemistry and pharmacology of VKA, as well as issues related to the management of patients treated with VKA.
BIOCHEMISTRY
Mechanism of Action
Effect on Coagulation Factor Synthesis/Degradation
Vitamin K is a cofactor for the posttranslational γ-carboxylation of glutamate residues to γ-carboxyglutamates on the N-terminal regions of vitamin K-dependent proteins. The anticoagulant effect of VKA is due to interference of the cyclic conversion of vitamin K and its 2,3-epoxide, which blocks the regeneration of the reduced form of vitamin K (FIGURE 106.1A). The VKAs interfere by inhibiting the enzyme vitamin K epoxide reductase, subunit 1 (VKORC1). The reduced form of vitamin K (KH2) is responsible for the carboxylation of glutamic residues on the procoagulant forms of factors II, VII, IX, and X. By inhibiting vitamin K conversion, coumarins cause hepatic production of partially carboxylated and decarboxylated proteins with reduced procoagulant activity, resulting in their observed anticoagulant effect.5, 6
Conformational changes in coagulation proteins occur as a result of carboxylation and in the presence of calcium. These conformational changes are important to promoting binding to cofactors on phospholipid surfaces and procoagulant activity.7, 8 It should be noted that VKAs also inhibit carboxylation of the regulatory anticoagulant proteins C, S, and Z, which can lead to an increased procoagulant risk in certain clinical settings.
The oxidation of vitamin KH2 to vitamin K epoxide also requires molecular oxygen and carbon dioxide. Vitamin K epoxide is subsequently recycled to vitamin KH2 through two reductase steps. The first step reduces vitamin K epoxide to vitamin K1 (common in natural food) and is sensitive to VKAsΛ9, 10, 11 The second step reduces vitamin K1 to vitamin KH2 and is relatively insensitive to VKA (FIGURE 106.1A).
The use of VKAs reduces availability of vitamin KH2, which subsequently leads to decreased γ-carboxylation of the vitamin K-dependent coagulant proteins. Whereas normally about 10 glutamic acid residues on the vitamin K-dependent factors are carboxylated, only approximately seven residues undergo this posttranslational change at a therapeutic level of VKAs.12, 13 The effect of VKAs can be counteracted by vitamin K1 administered therapeutically or from ingestion in food. The counteraction is effectively due to the second reductase step, which is relatively insensitive to VKAs. In fact, the use of large doses of vitamin K1 will lead to warfarin resistance for up to a week or longer, due to its accumulation in the liver.
Procoagulant Effect
VKAs also have the potential to have a procoagulant effect in addition to their anticoagulant effect. This is due to inhibition of carboxylation of anticoagulant proteins C and S. This rare occurrence leads to complications such as skin necrosis and is discussed in detail below.
PHARMACOLOGY
Pharmacodynamics/Pharmacokinetics
Although there are several oral VKAs, warfarin is currently the most common form in clinical use. It has a high bioavailability due to its water solubility and is rapidly absorbed from the stomach and duodenum.14, 15 In addition, it has maximal blood concentrations in healthy volunteers within 90 minutes of oral administration.16 Warfarin will circulate in plasma bound to 98% to 99% to proteins, primarily to albumin, and accordingly only a minor fraction of the drug is biologically active. The drug will then accumulate in the liver, specifically in the microsomes.17 Warfarin is a racemic mixture of S and R enantiomers, which are present in almost equal proportions. Warfarin has a half-life of 36 to 42 hours, which is the result of different metabolism rates of the two enantiomers. The R enantiomer is less potent, is metabolized primarily by two microsomal cytochrome enzymes (CYP1A2 and CYP3A4) to 6- and 8-hydroxywarfarin, and has a half-life of 45 hours. The S enantiomer is 2.7 to 3.8 times more potent than the R enantiomer, is metabolized primarily by the CYP2C9 enzyme of the P450 system to 7-hydroxywarfarin, and has a half-life of 29 hours (FIGURE 106.1B).18 The inactive hydroxywarfarins are excreted renally.
FIGURE 106.1 A,B: Metabolism of vitamin K and warfarin. (From HirshJ, Dalen J, Guyatt G. The sixth [2000] ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 2001;119:1S-2S; Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:160S-198S.) |
Although warfarin is the most common VKA used, acenocoumarol, phenprocoumon, indanedione derivatives (phenindione), and rodenticides are occasionally encountered. Similar to warfarin, acenocoumarol and phenprocoumon are both composed of a racemic mixture of R- and S-isomers with different stereochemical characteristics. Although R-acenocoumarol has an elimination half-life of 9 hours, the less potent S-acenocoumarol has an elimination half-life of 0.5 hours.19 The longer acting phenprocoumon has an elimination half-life of 5.5 days, with the S-phenprocoumon isomer 1.5 to 2.5 times more potent than R-phenprocoumon.20 The most commonly used superwarfarin rodenticide is brodifacoum, a 4-hydroxycoumarin, which has higher lipid solubility and an elimination half-life of 16 to 36 days.21 Patients with accidental ingestion or overdoses of brodifacoum should be administered vitamin K daily for an extended period due to the long half-life.22
Alterations in Pharmacodynamics/Pharmacokinetics
Drugs, diet, and various disease states influence the pharmacokinetic properties of warfarin. Therefore, monitoring should occur more frequently in patients with any changes to medications or illness. The response to warfarin is also affected by multiple drugs, which lead to alterations in absorption or metabolic clearance. In addition, recently identified genetic polymorphisms can also influence the response to warfarin and should be considered in treatment protocols. Finally, anticoagulant effect may also vary based on the result of inaccurate laboratory testing, patient noncompliance, and miscommunication between patient and physician.
Pharmacokinetics of Interactions
Displacement of Warfarin from Protein-Binding Sites
Warfarin is bound to albumin at binding site I and may theoretically be displaced by compounds that are primarily albumin bound (phenylbutazone, azapropazone). Displacement may then acutely increase the effects of warfarin.23 This effect, however, seems to be transient since the rate of elimination also increases, and it is rarely of clinical importance.24
Induction/Inhibition of Metabolism
Multiple drugs reduce gastrointestinal absorption of warfarin and influence pharmacokinetics. Other drugs potentiate warfarin effect by decreasing warfarin clearance through stereoselective or nonselective pathways.25, 26, 27 Either the S-isomer or R-isomer is selectively influenced by stereoselective interactions. The influence on the S-isomer of warfarin metabolism is clinically important.26, 27 Examples of stereoselective inhibition of the S-isomer include phenylbutazone, sulfinpyrazone, metronidazole, and trimethoprim-sulfamethoxazole.28
Diet
The intake of dietary vitamin K will change daily and is an important cause of intraindividual variability over time. Vitamin K is primarily found in high amounts in foods such as green leafy vegetables and certain vegetable oils. Foods low in content can also become clinically important when ingested in large amounts. Patients need to be advised which foods contain vitamin K, as well as the variations in the international normalized ratio (INR) that can occur with warfarin use in the setting of vitamin K deficiency. The information should aim at avoiding very large amounts of these foods but make sure the patient understands that a moderate intake of vitamin K is beneficial. Reduced dietary vitamin K may arise in poor nutritional states, fat malabsorption, and sick patients treated with antibiotics and intravenous fluids without vitamin K supplementation (Table 106.1).
Genetics
Allelic variants in either CYP2C9 or VKORC1 are found in more than two-thirds of the White population and up to 90% of East Asians32, 33 (see Table 106.2). Individuals with certain polymorphisms of these genes will usually require a lower dose of warfarin to maintain a therapeutic INR, as well as need a longer time to achieve a stable dose.33, 34
The first gene identified to influence the effects of warfarin was CYP2C9, which encodes for a cytochrome P450 2C9 hepatic microsomal enzyme. Certain polymorphisms in this gene lead to an alteration in the pharmacokinetics of warfarin. The most common CYP2C9 variant alleles are designated 2C9*2 and 2C9*3 and lead to decreased metabolism of the S-warfarin, especially in those individuals who are homozygous for these mutations.35 More recently, mutations in genes encoding for the enzyme VKORC1 have been identified to lead to variable sensitivity to inhibition by warfarin, affecting the pharmacokinetics and dosing.
Rarely, patients may have a mutation affecting the factor IX propeptide that leads to a selective reduction in factor IX. This leads to a decreased factor IX level without prolonging the PT and may increase risk of bleeding.36 These mutations are estimated to affect <1.5% of the population and are phenotypically silent except when the patient is receiving warfarin therapy.
Carriers of these variant alleles are at increased risk of bleeding complications, especially at the initiation of therapy. Several studies have investigated the utility of pharmacogenetic-guided strategies for the dosing of warfarin, reviewed under Genetic Guidance below.
Drug Interactions
There are numerous drugs that alter the pharmacodynamics of warfarin by either inhibiting synthesis or increasing clearance of vitamin K-dependent factors (see Table 106.1). For example, second- and third-generation cephalosporins,37 erythromycin,38 and some anabolic steroids39 augment the effects of warfarin; thyroxine increases metabolism of coagulation factors40; sulfonamides as well as broad-spectrum antibiotics augment the warfarin effect by eliminating bacterial flora and aggravating vitamin K deficiency41; and amiodarone inhibits the metabolic clearance of both the S and R enantiomer of warfarin and potentiates the warfarin effect. Following medication changes for a patient, increased monitoring is usually required to determine the potential effect on the INR and warfarin dosing.
Dietary Supplement Interactions
A common difficulty of health care providers is the use of nutritional supplements and herbal products by patients on warfarin therapy. Most physicians do not ask about the use of these products, and patients rarely divulge this information. However, survey data would suggest that as many as 12% of the general public have used a herbal preparation or supplement within the prior year.42 Difficulty arises from little to no standardization of the contents of these products, and interactions are not well studied. Ginkgo, ginger, and coenzyme Q10 were not shown to have an effect on warfarin.24, 43 Ginseng, however, was shown to reduce the effect of warfarin.44 As expected, products containing vitamin K, such as green tea, also reduce warfarin effect. Table 106.1 details dietary supplement interactions with warfarin by level of supporting evidence.
MANAGEMENT
Warfarin Initiation
Commercially available warfarin has a half-life of approximately 36 hours; however, treatment for 4 to 5 days is usually required to stably reduce the vitamin K-dependent coagulation proteins to achieve a therapeutic INR. This is due to the >2 day half-life of factor X and prothrombin, despite the shorter half-lives of factors VII and IX (FIGURE 106.2). In addition, the therapeutic effects of warfarin seem to be primarily mitigated by decreased levels of factors X and II.45 This has been the rationale for using heparin or low molecular weight heparin (LMWH) in the initial treatment period to provide an effective anticoagulant until a therapeutic warfarin effect can be achieved.46 Treatment with warfarin should be overlapped with heparin or LMWH for at least 2 days following a therapeutic INR on two consecutive measurements 24 hours apart. This allows further reduction of factors X and II.45
Studies have evaluated the effect of an initial “loading” dose (e.g., ≥((10 mg) of warfarin, which shortens the time to reach the therapeutic range (TTR). This may be of benefit for outpatients, who have to overlap with heparin/LMWH, and was evaluated as safe in two large case series.47, 48 Loading doses lead to a more rapid decrease in factor VII and protein C levels, as well as theoretically an increased risk of warfarin skin necrosis, and should be avoided in generally ill, hospitalized patients.49, 50
Further attempts have also been made to supplement with oral vitamin K, at a dose corresponding to usual dietary intake, to improve stability of control of anticoagulation with warfarin. Supplementation seemed to decrease the variability of and increase the time of INR within the TTR.51, 52, 53 This has so far not translated into a lower risk of clinical events, and larger studies will be needed to determine any clinical benefit.
It is usually recommended to begin warfarin therapy with an average maintenance dose of 5 mg, due to this dose resulting in an INR of >2.0 in 4 to 5 days with less excessive anticoagulation.45 There are situations in which this standard dose may not be appropriate. A lower dose may be appropriate in elderly patients; in patients with impaired nutrition, liver disease, or congestive heart failure; and in patients at high risk for bleeding. For example, a patient who is undergoing heart valve replacement may begin with an initial dose of 2 to 3 mg54 and in elderly a nomogram starting with 4 mg daily and using the INR directly as predictor led to a correct decision on the maintenance dose in 88% of the patients.55
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Table 106.1 Level of evidence for drug, food, and dietary supplement interactions with warfarin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 106.2 Distribution of CYP2C9 and VKOR polymorphisms in different racial populations* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Warfarin Discontinuation
Discontinuation of warfarin will remove inhibition of vitamin K-dependent coagulation proteins and lead to a gradual normalization of INR. The rate of decrease of an INR is influenced by factors including liver dysfunction and age, with average time to normalization of 96 hours.56 For patients on chronic anticoagulation with warfarin, elective procedures require either discontinuation of warfarin or bridging therapy (see below). Current guidelines by the American College of Chest Physicians (ACCP) suggest that if the annual risk of thromboembolism is low, warfarin therapy may be held for 4 to 5 days prior to the procedure and reinitiated shortly thereafter.45
FIGURE 106.2 Effects of warfarin therapy on the plasma vitamin K-dependent procoagulant proteins. Administration of 5 to 10 mg daily of warfarin results in inhibition of synthesis of functional vitamin K-dependent proteins. The coagulant activity of these proteins in plasma declines as a function of their half-life. Half-lives of factors VII, IX, and X and prothrombin are 6,24, and 40 and 60 hours, respectively. Although 1 to 2 days of warfarin prolongs the PT assay (because of the rapid decrease in factor VII concentration), therapeutic anticoagulation requires at least 4 to 5 days. (Data from O’Reilly RA.The pharmacodynamics of the oral anticoagulant drugs. Prog Hemost Thromb 1974;2:175-213; reproduced from Greenberg PL, Negrin R, Rodgers GM. Hematologic disorders. In: Melmon KL, Morrelli HF, Hoffman BB, et al., eds. Clinical pharmacology: basic principles in therapeutics, 3rd ed. New York: McGraw-Hill, 1992:524-599, with permission; from Wintrobe MM, Greer JP. Wintrobe’s clinical hematology, 12th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009:1488, Ref. 178.) |
Temporary discontinuation of warfarin is also recommended for nonbleeding patients with a supratherapeutic INR. Once the INR is at the therapeutic level, warfarin can be resumed with more frequent monitoring. Bleeding patients with supratherapeutic INRs require additional interventions in addition to discontinuation of warfarin (see below). Discontinuation of warfarin at the end of planned therapy can be abrupt, since several trials have failed to show any benefit of a tapered regimen.57, 58, 60, 61
Monitoring
The most useful assay to monitor therapy with warfarin is the PT assay, which measures three vitamin K-dependent coagulation proteins (factors VII, X, and prothrombin). Factor VII has a half-life of 4 to 6 hours; therefore, factor VII levels often decrease significantly following only 1 day of warfarin therapy. This may lead to a prolonged PT value, but, due to the longer half-lives of the other vitamin K-dependent coagulation proteins, therapeutic anticoagulation usually takes 4 to 5 days.62
The PT is performed by adding calcium and thromboplastin to citrated plasma. Thromboplastins vary in their response to reduced levels of the vitamin K-dependent coagulation factors. PT monitoring of warfarin treatment is not standardized when expressed in seconds, as a simple ratio of the patient’s plasma value to that of plasma of a healthy control subject, or as a percentage of diluted normal plasma.45 To standardize PT assays among different laboratories, an international reference thromboplastin preparation and calibration model was adopted by the World Health Organization (WHO) in 1982. To determine the responsiveness of each thromboplastin reagent, all commercial thromboplastin reagents are calibrated against the primary WHO reference preparation. These results are used to calculate the relative sensitivity of the unknown preparation compared to the WHO standard providing an international sensitivity index (ISI).63 Once a particular thromboplastin is adjusted for the ISI, an INR is defined as the PT ratio that would be obtained if the WHO standard thromboplastin had been used. The calculation of the INR is determined by INR = (PT ratio)ISI (FIGURE 106.3).64 With the wide use of the standardized INR, several of its limitations have become apparent (Table 106.3). These include decreased precision when insensitive thromboplastins are used; there is an incorrect assignment of an ISI value by the manufacturer; a different reagent-instrument combination is used than that recommended by the manufacturer; and if an incorrect control PT value is used.45
FIGURE 106.3 Relationship between PT ratio on warfarin therapy and the corresponding INR. The slope of the line represents the ISI value of the particular thromboplastin preparation used in the laboratory’s PT assay. In this example, for low-intensity warfarin therapy (INR 2.0 to 3.0), a PT ratio between 1.50 and 1.75 would be required. Thromboplastins with higher ISI values would have slopes greater than that shown and would be less sensitive reagents for the PT assay, whereas thromboplastins with lower ISI values would have slopes less than that shown (more sensitive reagents). (From Greenberg PL, Negrin R, Rodgers GM. Hematologic disorders. In: Melmon KL, Morrelli HF, Hoffman BB, et al., eds. Clinical pharmacology: basic prìinciples in therapeutics, 3rd ed. New York: McGraw-Hill, 1992:524-599, with permission; from Wintrobe MM, Greer JP. Wintrobe’sclinical hematology, 12th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009:1490.) |
Recommendations by the ACCP are for standard-intensity warfarin therapy (INR 2.0 to 3.0) for all indications except prosthetic mechanical heart valves and prophylaxis against recurrent myocardial infarction (MI) for which a higher intensity warfarin therapy (INR 2.5 to 3.5) is suggested.45
Frequency of Monitoring
Many factors influence the response to warfarin, and as a result, the dose required to achieve a therapeutic dose will vary over time. Therefore, warfarin dosing is adjusted in response to ongoing PT measurements to maximize the proportion of time in the TTR. Appropriate anticoagulation is important because (a) subtherapeutic anticoagulation (particularly INR < 1.5) increases the risk of thromboembolism; (b) supratherapeutic anticoagulation (particularly INR > 5.0) increases the risk of bleeding; and (c) poor anticoagulation control leads to an increased burden of anticoagulation therapy and discourages patients and health care providers from continuing warfarin therapy when indicated.65 In a systematic review, the TTR was 56.7% in community practices compared to 66.4% in randomized trials.66
For hospitalized patients, although INR monitoring is usually daily, frequency is often guided by the attempt to keep patients therapeutic. Once a therapeutic INR has been obtained for two consecutive days, it is often recommended to subsequently monitor two to three times weekly for 1 to 2 weeks, then less often depending on the stability of the INR.45
As an outpatient, initial therapy is often monitored every few days until a stable dose is achieved and then frequency is often monitored at reduced intervals. It is suggested, however, that more frequent monitoring may lead to an increased TTR.67 For example, patient self-testing, in which patients have unlimited access to testing, seems to increase TTR,68 although the benefit of more frequent testing begins to decrease once testing occurs more frequently than several times per week.
The optimal frequency will ultimately be influenced by patient compliance, changes in diet, interactions with medications, as well as fluctuations in comorbid conditions. In addition, physician dose adjustment decisions will also lead to variability in obtaining a therapeutic effect. To assist health care providers in decisions of warfarin dosing adjustments, there are several predictive models being used to reduce the frequency of testing while keeping patients therapeutic. The current ACCP guidelines recommend that patients receiving a stable dose of oral anticoagulation should be monitored no less than every 4 weeks.45 A randomized trial comparing 4 versus 12 weeks interval for very stable patients indicated that the frequency can be decreased without compromising the TTR.69
Related posts:
The Field of Hemostasis and Thrombosis: Selected Translational Achievements
Structure and Function of Vitamin K-Dependent Coagulant and Anticoagulant Proteins
Integrín αIIbβ3 and Platelet Aggregation
Inherited Thrombocytopenias
Unusual Sites of Arterial Occlusion
Blood Management in the Cardiovascular Surgical Patient
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