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The Pharmacology and Management of the Vitamin K Antagonists : The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy FREE TO VIEW

Jack Ansell, MD; Jack Hirsh, MD, FCCP; Leon Poller, MD; Henry Bussey, PharmD, FCCP; Alan Jacobson, MD; Elaine Hylek, MD
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Correspondence to: Jack Ansell, Department of Medicine, Boston University Medical Center, 88 E Newton St, Boston, MA 02118; e-mail: jack.ansell@bmc.org



Chest. 2004;126(3_suppl):204S-233S. doi:10.1378/chest.126.3_suppl.204S
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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+).

Figures in this Article

The coumarins or vitamin K antagonists (VKAs) have been the mainstay of oral anticoagulant therapy for > 50 years. Their effectiveness has been established by well-designed clinical trials 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 primary prevention of acute myocardial infarction in high-risk men, and for the prevention of stroke, recurrent infarction, or death in patients with acute myocardial infarction. VKAs are challenging to use in clinical practice for the following reasons: (1) they have a narrow therapeutic window; (2) they exhibit considerable variability in dose response among subjects; (3) they are subject to interactions with drugs and diet; (4) they have laboratory control that can be difficult to standardize; and (5) they have problems in dosing as a result of patient nonadherence and miscommunication between the patient and physician. Since warfarin is the most commonly used VKA worldwide, warfarin will be used interchangeably with VKA or coumarin throughout the following discussion.

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 ).16 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 decarboxylated proteins with reduced coagulant activity.78 Carboxylation is required for a calcium-dependent conformational change in coagulation proteins911 that promotes binding to cofactors on phospholipid surfaces. In addition, the VKAs inhibit carboxylation of the regulatory anticoagulant proteins C and S, and thereby have the potential to be procoagulant. However, under most circumstances the anticoagulant effect of the coumarins is dominant. Carboxylation requires the reduced form of vitamin K (vitamin KH2), molecular oxygen, and carbon dioxide. The oxidation-reduction reaction between vitamin KH2 and vitamin K epoxide involves a reductase pair. The first, vitamin K epoxide reductase, is sensitive to coumarins, whereas vitamin K reductase is less sensitive.13 Therefore, the anticoagulant effect of the coumarins can be overcome by low doses of vitamin K1 (phytonadione) [Fig 1]. Patients treated with large doses of vitamin K1 can become resistant to warfarin for up to 1 week or more because the vitamin K1 accumulating in the liver is available to the coumarin-insensitive reductase.

The coumarins also interfere with the carboxylation of Gla proteins that are synthesized in bone.1215 Although these effects contribute to fetal bone abnormalities when mothers are treated with a coumarin during pregnancy,1617 there is no evidence that coumarins directly affect bone metabolism when administered to children or adults.

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.18,20Warfarin 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 pathways.21 The relationship between the dose of warfarin and the response is modified by genetic and environmental factors that can influence the absorption of warfarin, its pharmacokinetics, and its pharmacodynamics.

1.1.1 Genetic factors

Genetic factors include the following. (1) There is a common mutation in the gene coding for the cytochrome P450 2C9 hepatic microsomal enzyme that is responsible for the oxidative metabolism of the more potent warfarin S-isomer.2124 This mutation is independently responsible for the reduced warfarin requirements seen in individuals with one or more combinations of these polymorphisms (Table 1 ).,23,2526 Several investigations23,2627 have shown that these mutations are also associated with an increase in adverse clinical outcomes. (2) There is hereditary resistance to warfarin. This occurs in rats as well as in human beings,2830 and patients with genetic warfarin resistance require doses that are 5-fold to 20-fold higher than average to achieve an anticoagulant effect. This disorder is attributed to an altered affinity of the warfarin receptor, which results in an increase in the plasma warfarin levels required to achieve an anticoagulant effect. (3) A mutation in the factor IX propeptide causes selective reduction in factor IX during treatment with coumarin drugs without excessive prolongation of the prothrombin time (PT).24 Factor IX activity decreases to about 1 to 3% of normal, while levels of other vitamin K-dependent coagulation factors decrease to 30 to 40% of normal. Two distinct missense mutations involving the propeptide-coding region have been described. They are estimated to occur in < 1.5% of the population and are expressed as selectively increased sensitivity to the coumarin-mediated reduction of factor IX activity. This selective marked reduction in factor IX activity has been reported24,31 to increase the risk of bleeding during anticoagulant therapy.

1.1.2 Environmental factors

Environmental factors such as drugs, diet, and various disease states can alter the pharmacokinetics of warfarin (Table 2 ). Consequently, the international normalized ratio (INR) should be measured more frequently than the usual 4-week interval when virtually any drug or herbal medicine is added or withdrawn from the regimen of a patient treated with warfarin. Drugs such as cholestyramine can reduce the anticoagulant effect of warfarin by reducing its absorption. Many other drugs potentiate the anticoagulant effect of warfarin by inhibiting its clearance through stereoselective or nonselective pathways.3233 Stereoselective interactions may affect the oxidative metabolism of either the S-isomer or R-isomer of warfarin.3233 The inhibition of S-warfarin metabolism is more important clinically, because this isomer is five times more potent than the R-isomer as a VKA.3233 Phenylbutazone,34sulfinpyrazone,35metronidazole36and trimethoprim-sulfamethoxazole37 inhibit the clearance of S-warfarin, and each potentiates the effect of warfarin on the PT. In contrast, drugs such as cimetidine and omeprazole, which inhibit the clearance of the R-isomer, potentiate the PT only modestly in patients who have been treated with warfarin.33,36,38Amiodarone is a potent inhibitor of the metabolic clearance of both the S-isomer and the R-isomer, and potentiates warfarin anticoagulation.39The anticoagulant effect is inhibited by drugs like barbiturates, rifampin, and carbamazepine, which increase hepatic clearance. Long-term alcohol consumption has a similar potential to increase the clearance of warfarin, but ingestion of even relatively large amounts of wine has little influence on PT in subjects who have been treated with warfarin.40The effect of enzyme induction on warfarin therapy has been discussed in more detail in a critical review (Table 3 ).41

Drugs may also influence the pharmacodynamics of warfarin by inhibiting the synthesis of or increasing the clearance of vitamin K-dependent coagulation factors or by interfering with other pathways of hemostasis. The anticoagulant effect of warfarin is augmented by second-generation and third-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K,4243 by thyroxine, which increases the metabolism of coagulation factors,44and by clofibrate, through an unknown mechanism.45Doses of salicylates of > 1.5 g per day46and acetaminophen47may augment the anticoagulant effect of warfarin, possibly by interference with the P450 enzymes.48Heparin potentiates the anticoagulant effect of warfarin, but in therapeutic doses produces only a slight prolongation of the PT. The mechanisms by which erythromycin49and some anabolic steroids50potentiate the anticoagulant effect of warfarin are unknown. Sulfonamides and several broad-spectrum antibiotic compounds may augment the anticoagulant effect of warfarin in patients consuming diets that are deficient in vitamin K by eliminating bacterial flora and aggravating vitamin K deficiency.51

Drugs such as aspirin,52nonsteroidal antiinflammatory drugs,53penicillins in high doses,5455 and moxalactam43 increase the risk of warfarin-associated bleeding by inhibiting platelet function. Of these, aspirin is the most important because of its widespread use and prolonged effect.56 Aspirin and nonsteroidal antiinflammatory drugs can also produce gastric erosions that increase the risk of upper GI bleeding. The risk of clinically important bleeding is heightened when high doses of aspirin are taken during high-intensity warfarin therapy (INR, 3.0 to 4.5).52,57However, low doses of aspirin (ie, 75 to 100 mg daily) combined with moderate-intensity and low-intensity warfarin anticoagulation therapy are also associated with increased rates of bleeding.59

Wells et al60analyzed reports of possible interaction between warfarin and drugs or foods. There was evidence from observational studies of interaction in 39 of the 81 different drugs and foods appraised. Of these, 17 potentiated the warfarin effect, 10 inhibited it, and 12 produced no effect. Many other drugs have been reported either to interact with oral anticoagulants or to alter the PT response to warfarin.6162 The importance of postmarketing surveillance with newer drugs is highlighted by an experience63 with celecoxib, a drug that showed no interactions in phase 2 studies but was subsequently suspected of potentiating the effect of warfarin in several case reports. This review also drew attention to potential interactions with over-the-counter herbal medicines.

Subjects receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary vitamin K,6465 which is derived predominantly from phylloquinones in plant material.65The phylloquinone content of a wide range of foodstuffs has been listed by Sadowski and associates.66Phylloquinones act through the warfarin-insensitive pathway.67Important fluctuations in vitamin K intake can occur in both healthy and sick subjects.68 An increased intake of dietary vitamin K that is sufficient to reduce the anticoagulant response to warfarin64 occurs in patients consuming green vegetables or vitamin K-containing supplements, while following weight-reduction diets, and in patients who have been treated with vitamin K supplements. Reduced dietary vitamin K1 intake potentiates the effect of warfarin in sick patients who have been treated with antibiotics and IV fluids without vitamin K supplementation, and who have states of fat malabsorption.

Hepatic dysfunction potentiates the response to warfarin through the impaired synthesis of coagulation factors. Hypermetabolic states produced by fever or hyperthyroidism increase warfarin responsiveness, probably by increasing the catabolism of vitamin K-dependent coagulation factors.44,69

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 from the following observations. First, the experiments of Wessler and Gitel70over 40 years ago using a stasis model of thrombosis in rabbits showed that the antithrombotic effect of warfarin requires 6 days of treatment, whereas an anticoagulant effect develops in 2 days. The antithrombotic effect of warfarin requires the reduction of prothrombin (factor II), which has a relatively long half-life of about 60 to 72 h, compared with 6 to 24 h for other vitamin K-dependent factors that are responsible for the more rapid anticoagulant effect. Second, in a rabbit model of tissue factor-induced intravascular coagulation the protective effect of warfarin was mainly a result of lowering prothrombin levels.71Third, Patel and associates72demonstrated that clots formed from umbilical cord plasma containing about half the prothrombin concentration of plasma from adult control subjects generated significantly less fibrinopeptide A than clots formed from maternal plasma. The view that warfarin exerts its antithrombotic effect by reducing prothrombin levels is consistent with observations that clot-bound thrombin is an important mediator of clot growth,73 and that reduction in prothrombin levels decreases the amount of thrombin generated and bound to fibrin, thereby reducing thrombogenicity.72

The suggestion that the antithrombotic effect of warfarin is reflected in lower levels of prothrombin forms the basis for overlapping the administration of heparin with warfarin until the PT or INR is prolonged into the therapeutic range during the treatment of patients with thrombosis. Since the half-life of prothrombin is about 60 to 72 h, at least 4 days of overlap is necessary. Furthermore, the levels of native prothrombin antigen during warfarin therapy more closely reflect antithrombotic activity than the PT.74

The PT test75is 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 the PT. The PT assay is performed by adding calcium and thromboplastin to citrated plasma. Thromboplastins vary in responsiveness to a reduction of the vitamin K-dependent coagulation factors. An unresponsive thromboplastin produces less prolongation of the PT for a given reduction in vitamin K-dependent clotting factors than a responsive one. The responsiveness of a thromboplastin can be measured by assessing its international sensitivity index (ISI) [see below]. Highly sensitive thromboplastins (ISI, approximately 1.0) that are composed of human tissue factor produced by recombinant technology and defined phospholipid preparations are now available. The history of standardization of the PT has been reviewed by Poller76 and by Kirkwood,77and more detailed discussions can be found in prior editions of this article.78

PT monitoring of warfarin treatment is not standardized when expressed in seconds or as a simple ratio of the patient’s plasma value to that of plasma from a healthy control subject. A calibration model,77 which was adopted in 1982, is now used to standardize reporting by converting the PT ratio measured with the local thromboplastin into an INR, calculated as follows:

or
where ISI denotes the ISI of the thromboplastin used at the local laboratory to perform the PT measurement. The ISI reflects the responsiveness of a given thromboplastin to the reduction of the vitamin K-dependent coagulation factors compared to the primary World Health Organization (WHO) international reference preparations, so that the more responsive the reagent, the lower the ISI value.,7677 As the INR standard of reporting was widely adopted, a number of problems surfaced. These are listed in Table 4 and are reviewed briefly below.

The INR is based on ISI values derived from the plasma of patients who had received stable anticoagulant doses for at least 6 weeks.79As a result, the INR is less reliable early in the course of warfarin therapy, particularly when results are obtained from different laboratories. Even under these conditions, however, the INR is more reliable than the unconverted PT ratio,80and is thus recommended during both the initiation and maintenance of warfarin treatment. There is also evidence that the INR is a reliable measure of impaired blood coagulation in patients with liver disease.81

The INR accuracy can be influenced by reagents of different sensitivities82and also by the automated clot detectors now used in most laboratories.8390 In general, the College of American Pathologists has recommended91 that laboratories should use thromboplastin reagents that are at least moderately responsive (ie, ISI, < 1.7) and reagent/instrument combinations for which the ISI has been established.

ISI values provided by the manufacturers of thromboplastin reagents are not invariably correct when applied locally,9294 and this adversely affects the reliability of measurements. Local calibrations can be performed using plasma samples with certified PT values to determine the instrument-specific ISI. The mean normal plasma PT is not interchangeable with a laboratory control PT,95 however, the use of other than a properly defined mean normal PT can yield erroneous INR calculations, particularly when less responsive reagents are employed. The mean normal PT should be determined with each new batch of thromboplastin with the same instrument used to assay the PT.95

The concentration of citrate that is used to anticoagulate plasma affects the INR.9697 In general, higher citrate concentrations (3.8%) lead to higher INR values,96 and underfilling the blood collection tube spuriously prolongs the PT because excess citrate is present. Using collection tubes containing 3.2% concentrations of citrate for blood coagulation studies and adequately filling tubes can reduce this problem.

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 stroke, recurrent infarction, or death in patients with acute myocardial infarction. Although effectiveness has not been proven by a randomized trial, VKAs are also indicated for the prevention of systemic embolism in high-risk patients with mitral stenosis.

1.4.1 Optimal therapeutic range

The optimal target range for warfarin is not the same for all indications. Not only is it likely to be influenced by the indication for its use, but also by patient characteristics. Thus, in patients who are at very high risk of bleeding it might be prudent to sacrifice some efficacy for safety. Bleeding, the most feared and major complication of oral anticoagulant therapy, is closely related to the intensity of anticoagulation.98101 Therefore, some studies102have focused on establishing the lowest effective therapeutic range. Universal agreement has not been reached on the optimal range for the various indications. For example, in Europe higher ranges are recommended for patients with mechanical heart valves than for patients in North America.103104

In performing studies that are aimed at establishing the most appropriate range for different indications, various methodological approaches have been used. These are as follows: (1) randomized trials in which patients are randomly assigned to two different target ranges105110; (2) indirect comparisons of results of randomized trials comparing patients treated with different intensities of anticoagulants or to those treated with another antithrombotic agent (usually aspirin)111114; (3) subgroup analyses of observational studies (including within treatment groups of randomized trials) relating the observed INR or time spent in an INR range at the time of the outcome to either a bleeding event or thromboembolic event101103,115116; and (4) case-control studies in which the INR levels at the time of an event are recorded and compared with INR levels in appropriately selected control subjects.104 All of these designs have limitations, but the randomized trial, comparing two target INR ranges, provides results that are closest to the truth, because if appropriately designed, it is free of bias.117

Four randomized studies105108 have compared a moderate-intensity INR (approximately 2.0 to 3.0) to higher intensity adjusted dose oral anticoagulation, and all reported that the moderate intensity reduced the risk of clinically significant bleeding without reducing efficacy. In two of these studies, one in patients with venous thromboembolism105and the other in patients with tissue heart valves,106 patients assigned to an INR intensity of 2.0 to 3.0 experienced less bleeding without apparent loss of efficacy than those who were assigned to an INR of 3.0 to 4.5. The results of these trials influenced the decision to lower the target INR in North America to 2.0 to 3.0 for these and other indications. More recently, an INR of < 2.0 (INR target, 1.5 to 2.0) has been reported109to be effective in the long-term secondary prevention of venous thrombosis when compared to placebo. Another clinical trial,110 however, found that an INR intensity of 1.5 to 2.0 was not as effective as an INR of 2.0 to 3.0.

After a small randomized trial118reported the unexpected finding that fixed minidose warfarin (ie, 1 mg daily) was effective in preventing subclavian vein thrombosis in patients with malignancy who had indwelling catheters, two prospective cohort studies120 provided further support by showing a reduced incidence of catheter thrombosis compared to historical control subjects in patients treated with 1 mg warfarin. However, six other studies121126 all reported that a fixed dose of 1 mg warfarin was either much less effective than dose-adjusted warfarin therapy (INR, 2.0 to 3.0) or that the 1-mg dose was ineffective. Three of these studies121123 evaluated its efficacy following major orthopedic surgery, and one each evaluated its efficacy in patients with indwelling catheters,124atrial fibrillation,125or acute myocardial infarction.126 Therefore, therapy with fixed minidose warfarin should be considered much less effective than that with dose-adjusted warfarin in moderate-to-high risk situations, and in some situations it may not be effective at all. For patients with a low thrombogenic risk, the efficacy of therapy with fixed minidose warfarin remains controversial.

The results of randomized trials have demonstrated the efficacy of oral anticoagulants in preventing stroke in patients with atrial fibrillation.127131 Although moderate-intensity warfarin therapy (INR, 2.0 to 3.0) has not been directly compared with higher intensity regimens in atrial fibrillation, the recommendation of a target INR of 2.0 to 3.0 is supported by the following evidence: (1) on indirect comparison of the several randomized trials,112114 a moderate-intensity warfarin regimen (INR, 2.0 to 3.0) showed a similar risk reduction as higher intensity regimens; (2) a randomized trial132 reported that adjusted-dose warfarin therapy (INR, 2.0 to 3.0) was more effective than the combination of fixed-dose warfarin (3 mg) and aspirin; and (3) a subgroup analysis of one prospective study103,116 and the results of one case control study104 have indicated that the efficacy of oral anticoagulant agents is reduced when the INR falls to < 2.0.

In contrast to studies in the primary and secondary prevention of venous thrombosis and in the prevention of systemic embolism in patients with atrial fibrillation, an INR of 2.0 to 3.0 has not been evaluated in patients with acute myocardial infarction or in patients with prosthetic heart valves, except when the oral anticoagulant was combined with aspirin. Two randomized trials133134 have indicated that a higher intensity regimen (INR, 3.0 to 4.0) is more effective than aspirin, and is as effective and at least as safe as the combination of aspirin and a moderate-intensity anticoagulant regimen (INR, 2.0 to 2.5) following an episode of acute coronary syndrome. In contrast, the combination of a lower intensity anticoagulant regimen (INR, 1.5 to 2.5) and aspirin has been shown to be no more effective than aspirin alone.135 These secondary prevention studies contrast with those reported in the primary prevention of myocardial infarction in which low-intensity warfarin therapy (INR, 1.3 to 1.8) either used alone or in combination with aspirin was effective in high-risk men.59

In conclusion, it is clear that one single therapeutic range for coumarins will not be optimal for all indications. However, a moderate-intensity INR (2.0 to 3.0) is effective for most indications. The possible exceptions are acute myocardial infarction, in which a higher INR is likely to be superior, and the primary prevention of myocardial infarction in high-risk patients in which a lower INR is effective. In addition, a lower INR range (1.5 to 2.0) is effective in patients with venous thrombosis who have received 6 months of full-dose treatment (INR, 2.0 to 3.0), although the lower intensity is less effective than the higher intensity. Fixed-dose warfarin therapy has a reduced efficacy or none at all, depending on the indication. The optimal intensity for patients with prosthetic heart valves remains uncertain, although there is evidence that they do not require the very high-intensity regimens that have been used in the past. Defining an appropriate range is an important step in improving patient management, but it is only the first of two steps. The second is ensuring that the targeted range is achieved. In general, our success in achieving this second goal has been poor. It is better when the INR is controlled by experienced personnel in anticoagulant clinics and by using computer-assisted dosage adjustment.136 Specific recommendations regarding the optimal intensity of therapy for each of these indications can be found in the articles in this supplement that deal with each indication.

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 that affect the availability of vitamin K1, or physiologic factors that affect the synthetic or metabolic fate of the vitamin K-dependent coagulation factors. Patient-specific factors such as adherence to a therapeutic plan are also important. Last, the ability of the health-care provider to make appropriate dosage and follow-up decisions can have an impact. The comprehensive management of these variables requires a knowledgeable health-care provider, an organized system of follow-up, reliable PT monitoring, and good patient communication and education.136137

The following discussion addresses a number of management issues pertaining to the use of VKAs. A systematic review of the literature was performed based on predefined criteria for the population at risk, the intervention or exposure evaluated, the outcomes assessed, and the methodology of the trials evaluated (Table 5 ). Based on this information and, when necessary, a consensus of opinion by the authors, recommendations and/or suggestions are proposed and graded according to the conventions defined in this supplement.

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 recommended. A number of randomized studies have supported the use of a lower initiation dose. Harrison et al,138 and Crowther et al140found that in hospitalized patients, commencing with an average maintenance dose of 5 mg warfarin usually results in an INR of ≥ 2.0 in 4 or 5 days with less excessive anticoagulation compared to that with an initial 10-mg dose. Kovacs et al,141however, found that in outpatients who had been treated for venous thromboembolism, an initial 10-mg dose for the first 2 days of therapy compared to a 5-mg dose resulted in a more rapid achievement of a therapeutic INR (1.4 days earlier) without a difference in rates of excessive anticoagulation. Thus, there is room for flexibility in selecting a starting dose of warfarin. Some clinicians prefer to use a larger starting dose (eg, 7.5 to 10 mg), while a starting dose of < 5 mg might be appropriate in the elderly, in patients with impaired nutrition liver disease, or congestive heart failure, and in patients who are at high risk of bleeding. When the INR has been in the therapeutic range on two measurements approximately 24 h apart, heparin therapy is discontinued. If treatment is not urgent (eg, chronic stable atrial fibrillation), warfarin administration, without concurrent heparin administration, can be commenced out-of-hospital with an anticipated maintenance dose of 4 to 5 mg per day. In patients with a known protein C deficiency or another thrombophilic state, it would be prudent to begin heparin therapy before or at the same time as warfarin therapy to protect against a possible early hypercoagulable state caused by a warfarin-mediated reduction in the vitamin K-dependent coagulation inhibitors.142

Because dose requirements often change during maintenance therapy, physicians employ various strategies to make dosing simple and clear for the patient. Some providers prefer to use a fixed tablet strength and to use alternate dose amounts (tablets or fraction of tablets) per day. Others prefer a uniform daily amount that might require the patient to have different tablet strengths. Both methods achieve similar outcomes, although the former practice may be more confusing for the patient.143144

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).

2.1.2 Initiation of anticoagulation in the elderly

The dose required to maintain a therapeutic range for patients > 60 years of age decreases with increasing age,145147 possibly because of a reduction in the clearance of warfarin with age.148149 Therefore, in the elderly the initial dose of warfarin should not be > 5 mg,150 and in some cases (ie, in patients with a high risk of bleeding, and in those who are undernourished or have congestive heart failure or liver disease), it should be less. Other factors that may influence the response to anticoagulation in the elderly include the potential for a greater number of other medical conditions and/or concurrent drug use.,145 Consequently, it is advisable to monitor older patients more frequently in order to maximize their time in the therapeutic range (TTR).151

2.1.2.1. In the elderly, and in 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

In hospitalized patients, PT monitoring is usually performed daily starting after the second or third dose until the therapeutic range has been achieved and maintained for at least 2 consecutive days, then two or three times weekly for 1 to 2 weeks, then less often, depending on the stability of INR results. In outpatients who have started receiving warfarin therapy, initial monitoring may be reduced to every few days until a stable dose response has been achieved. When the INR response is stable, the frequency of testing can be reduced to intervals as long as every 4 weeks, although there is evidence152153 to suggest that testing more frequently than every 4 weeks will lead to greater TTR. If adjustments to the dose are required, then the cycle of more frequent monitoring should be repeated until a stable dose response can again be achieved.

The optimal frequency of long-term INR monitoring is influenced by patient compliance, transient fluctuations in comorbid conditions, the addition or discontinuation of other medications, changes in diet, the quality of dose-adjustment decisions, and whether the patient has demonstrated a stable dose response. Some investigators154 have attempted to develop predictive models with the goal of reducing the frequency of testing without sacrificing quality. Some clinical trials152153 have suggested that during long-term treatment the TTR and, presumably, fewer adverse events can be maximized by more frequent testing. This is particularly true in studies utilizing patient self-testing (PST) in which access to testing is virtually unlimited. Horstkotte et al152 addressed this issue in 200 patients with mechanical cardiac valves in which they found that the percentage of INRs within the target range increased from 48% when monitoring was performed at an average interval of 24 days to 89% when monitoring was performed at an average of every 4 days by home self-testing using a point-of-care (POC) monitor. It is suggested that patients should be monitored no less than every 4 weeks. More frequent monitoring may be advisable in patients who exhibit an unstable dose response.

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).

2.1.4 Management of nontherapeutic INRs

Fluctuations in INR may occur because of any one or more of the following conditions: inaccuracy in INR testing; changes in vitamin K1 intake; changes in vitamin K1 or warfarin absorption; changes in warfarin metabolism; changes in vitamin K1-dependent coagulation factor synthesis or metabolism; other effects of concomitant drug use; or patient noncompliance. The management of patients whose INR is outside the therapeutic range is controversial because many of the various options have not been compared. Patients whose INR is just outside the therapeutic range can be managed by either adjusting the dose up or down in increments of 5 to 20%, based on the cumulative weekly dose of warfarin or by more frequent monitoring, the latter with the expectation that the INR will return to therapeutic levels without a dosage change. Since the absolute daily risk of bleeding is low even when the INR is excessively prolonged, many physicians manage patients with minimally elevated INRs by more frequent monitoring without a dose change,155or, for higher INR values between 4.0 and 10.0, by stopping warfarin for a day or more, reducing the weekly dose, and monitoring more frequently.156Hylek et al157reported that when two doses of warfarin were withheld in patients whose INR was > 6.0, the INR returned more slowly if their maintenance dose was lower, they were of older age, had a higher initial INR, had decompensated congestive heart failure, or had active cancer. Among 562 patients with an INR between 6.0 and 10.0, the subsequent INR measurement after withholding two doses of warfarin was < 4.0 in 67% of patients, and < 2.0 in 12% of patients. If the patient is at intrinsically high risk of bleeding or if bleeding has already developed, patients also can be managed by omitting one or more doses, by more frequent monitoring, and by actively intervening to lower the INR more rapidly. The interventions include the following: administering vitamin K1; and/or infusing fresh-frozen plasma,158prothrombin concentrates,159or recombinant factor VIIa.160The choice of approach is based largely on clinical judgement, the potential risk of bleeding, the presence of active bleeding, and the level of the INR. Crowther et al161 compared either stopping warfarin or administering oral vitamin K1 in a randomized trial in patients with an INR of between 4.5 and 10. A higher rate of minor bleeding was reported in the following 3 months in those who were not treated with vitamin K1 compared to those who were (4% vs 17%, respectively; p = 0.05).

If a decision is made to use vitamin K1, it should be administered in a dose that will quickly lower the INR into a safe but not subtherapeutic range without causing resistance once warfarin is reinstated162or without exposing the patient to the risk of anaphylaxis. High doses of vitamin K1, though effective, may lower the INR more than is necessary and may lead to warfarin resistance for a week or more. IV injection may be associated with anaphylactic reactions,163164 although such reactions have even been described with non-IV routes of administration.164 Low doses of vitamin K1 and slow infusion rates are recommended, but there is no definitive evidence that this serious, but rare, complication can be avoided by using low doses or slow infusion rates.164The response to vitamin K1 administered subcutaneously (SC) is less predictable compared to oral vitamin K1 and is sometimes delayed.165167 Some studies167171 have confirmed earlier reports that oral administration is predictably effective, and has the advantages of safety and convenience over parenteral routes. A dose range of 1.0 to 2.5 mg is effective when the INR is between 5.0 and 9.0, but larger doses (ie, 5 mg), are required to correct INRs of > 9.0. Vitamin K1 also can be administered by slow IV infusion when there is a greater urgency to reverse anticoagulation.,165,172Table 6 outlines the recommendations for managing patients who are receiving coumarin anticoagulants who need their INR lowered because of actual or potential bleeding.

For patients with subtherapeutic INRs during long-term therapy, there are no specific studies examining the optimal method of correction. Since the average daily risk of thrombosis for most indications is quite small, patients do not generally need to be covered with a rapidly acting anticoagulant such as heparin or low-molecular-weight heparin (LMWH). Rather, the weekly cumulative dose of warfarin is usually increased by 10 to 20%, and more frequent monitoring is instituted until the INR is stable. In some cases, patients may be given a one-time larger dose followed by more frequent monitoring with or without a change in the cumulative weekly dose.

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 when the INR is at a therapeutic level. Alternatively, omit a dose and administer vitamin K1 (1 to 2.5 mg) orally, particularly if the patient is at increased risk of bleeding. If more rapid reversal is required because the patient requires urgent surgery, vitamin K1 (≤ 5 mg) orally can be given with the expectation that a reduction of the INR will occur in 24 h. If the INR is still high, additional vitamin K1 (1 to 2 mg) orally can be given (all Grade 2C).

2.1.4.3. For patients with INRs of ≥ 9.0 and no significant bleeding, hold warfarin therapy and administer a higher dose of vitamin K1 (5 to 10 mg) orally with the expectation that the INR will be reduced substantially in 24 to 48 h. Monitor levels more frequently and use additional vitamin K1 if necessary. Resume therapy at a lower dose when INR reaches therapeutic levels (all Grade 2C).

2.1.4.4. In patients with serious bleeding and elevated INRs, we recommend holding warfarin therapy and giving vitamin K1 (10 mg) by slow IV infusion supplemented with fresh plasma, prothrombin complex concentrate, or recombinant factor VIIa, depending on the urgency of the situation. Vitamin K1 administration can be repeated every 12 h (all Grade 1C).

2.1.4.5. In patients with life-threatening bleeding and elevated INRs, we recommend holding warfarin therapy and administering prothrombin complex concentrate or recombinant factor VIIa supplemented with vitamin K1, 10 mg by slow IV infusion. Repeat this, if necessary, depending on the INR (Grade 1C).

2.1.4.6. 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 SC (Grade 1A).

2.1.5 Management of oral anticoagulation during invasive procedures

Clinicians are often required to decide how to manage patients who are receiving long-term anticoagulant therapy who require an invasive procedure.173The decision is based on the perceived risks of continuing or stopping anticoagulant therapy and on the cost of alternative options such as hospitalization for heparin therapy perioperatively. The principal concern is the risk of thrombosis when antithrombotic therapy is discontinued. Estimating the daily risk of a thromboembolism while the patient is not receiving anticoagulation therapy is difficult because data on the subject are sparse. The reported risk of not using preoperative anticoagulants for patients with mechanical heart valves varies from very low174175 to unacceptably high.176177Table 7 summarizes the estimated risk for the most common indications based on the available literature.178The following approaches can be used: stop warfarin therapy preoperatively and perform the procedure when the INR has returned to safe levels; administer full-dose anticoagulation with IV unfractionated heparin (UFH); administer full-dose anticoagulation with LMWH; or administer prophylactic doses of UFH or LMWH. The effects of high-dose, IV UFH can be readily reversed by discontinuing treatment before a procedure, but its major drawback is the complexity and cost associated with IV therapy and hospitalization. LMWH can be administered at home to avoid the expense and inconvenience of hospitalization. Several analyses of prospective cohort studies have indicated that LMWH is a suitable and less costly alternative,179191 and that it provides therapeutic levels more rapidly and consistently than UFH.182192 Although it is not possible to draw firm conclusions on the value of different management strategies, and we must rely on observational studies or risks extrapolated from other clinical scenarios, LMWH therapy appears to be at least as effective, if not more effective, and less costly than UFH therapy.

A recent review176 on the subject summarizes the options and outcomes for a range of surgical procedures, including cataract surgery, cutaneous surgery, pacemaker and defibrillator procedures, cardiac catheterization, genitourinary surgery, GI endoscopy, and others. With each of the following options, the length of time for warfarin dosage reduction and for the duration of heparin or LMWH use preoperatively can be shortened by administering vitamin K1 24 to 48 h before surgery to reverse the warfarin effect. Table 8 outlines the recommendations for managing patients who are receiving coumarin anticoagulants and require an invasive procedure.

Dental procedures represent a particularly common intervention for patients receiving anticoagulants. A comprehensive review177 of > 700 case reports indicated in 1998 that in most cases no change in the intensity of anticoagulation therapy is needed. More recent studies193194 have reported no difference between the incidence of postprocedure bleeding at low or higher levels of the INR. If there is a need to limit local bleeding, tranexamic acid mouthwash or epsilon amino caproic acid mouthwash has been used successfully without interrupting anticoagulant therapy.195196