American College of Cardiology

HIRSH et al., AHA/ACC Expert Consensus Document on Warfarin Therapy
JACC 2003;41:1633-52

American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy  

I. Pharmacology of Warfarin

Mechanism of Action of Coumarin Anticoagulant Drugs
Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to carboxyglutamates (Gla) on the N-terminal regions of vitamin K–dependent proteins (Figure 1) (1–6). These proteins, which include the coagulation factors II, VII, IX, and X, require carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity (7,8).

Carboxylation promotes binding of the vitamin K–dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation (9–11). Carboxylation requires the reduced form of vitamin K (vitamin KH₂). Coumarins block the formation of vitamin KH₂ by inhibiting the enzyme vitamin K epoxide reductase, thereby limiting the carboxylation of the vitamin K–dependent coagulant proteins. In addition, the vitamin K antagonists inhibit carboxylation of the regulatory anticoagulant proteins C and S. The anticoagulant effect of coumarins can be overcome by low doses of vitamin K1 (phytonadione) because vitamin K1 bypasses vitamin K epoxide reductase (Figure 1). Patients treated with large doses of vitamin K1 (usually >5 mg) can become resistant to warfarin for up to a week because vitamin K1 accumulating in the liver is available to bypass vitamin K epoxide reductase.

Warfarin also interferes with the carboxylation of Gla proteins synthesized in bone (12–15). Although these effects contribute to fetal bone abnormalities when mothers are treated with warfarin during pregnancy (16,17), there is no evidence that warfarin directly affects bone metabolism when administered to children or adults.

Pharmacokinetics and Pharmacodynamics of Warfarin
Warfarin is a racemic mixture of 2 optically active isomers, the R and S forms, in roughly equal proportion. It is rapidly absorbed from the gastrointestinal tract, has high bioavailability (18,19), and reaches maximal blood concentrations in healthy volunteers 90 minutes after oral administration (18,20). Racemic warfarin has a half-life of 36 to 42 hours (21), circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where the 2 isomers are metabolically transformed by different pathways (21). The relationship between the dose of warfarin and the response is influenced by genetic and environmental factors, including common mutations in the gene coding for cytochrome P450, the hepatic enzyme responsible for oxidative metabolism of the warfarin S-isomer (18,19). Several genetic polymorphisms in this enzyme have been described that are associated with lower dose requirements and higher bleeding complication rates compared with the wild-type enzyme CYP2C9* (22–24).

In addition to known and unknown genetic factors, drugs, diet, and various disease states can interfere with the response to warfarin.

The anticoagulant response to warfarin is influenced both by pharmacokinetic factors, including drug interactions that affect its absorption or metabolic clearance, and by pharmacodynamic factors, which alter the hemostatic response to given concentrations of the drug. Variability in anticoagulant response also results from inaccuracies in laboratory testing, patient noncompliance, and miscommunication between the patient and physician. Other drugs may influence the pharmacokinetics of warfarin by reducing gastrointestinal absorption or disrupting metabolic clearance. For example, the anticoagulant effect of warfarin is reduced by cholestyramine, which impairs its absorption, and is potentiated by drugs that inhibit warfarin clearance through stereoselective or nonselective pathways (25,26). Stereoselective interactions may affect oxidative metabolism of either the S-or R-isomer of warfarin (25,26). Inhibition of S-warfarin metabolism is more important clinically because this isomer is 5 times more potent than the R-isomer as a vitamin K antagonist (25,26). Phenylbutazone (27), sulfinpyrazone (28), metronidazole (29), and trimethoprim-sulfamethoxazole (30) inhibit 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 clearance of the R-isomer, potentiate the PT only modestly in patients treated with warfarin (26,29,31). Amiodarone inhibits the metabolic clearance of both the S-and R-isomers and potentiates warfarin anticoagulation (32). The anticoagulant effect is inhibited by drugs like barbiturates, rifampicin, and carbamazepine, which increase hepatic clearance (31). Chronic 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 treated with warfarin (33). For a more thorough discussion of the effect of enzyme induction on warfarin therapy, the reader is referred to a recent critical review (34).

Warfarin pharmacodynamics are subject to genetic and environmental variability as well. Hereditary resistance to warfarin occurs in rats as well as in human beings (35–37). and patients with genetic warfarin resistance require doses 5- to 20-fold higher than average to achieve an anticoagulant effect. This disorder is attributed to reduced affinity of warfarin for its hepatic receptor.

A mutation in the factor IX propeptide that causes bleeding without excessive prolongation of PT also has been described (38). The mutation occurs in <1.5% of the population. Patients with this mutation experience a marked decrease in factor IX during treatment with coumarin drugs, and levels of other vitamin K– dependent coagulation factors decrease to 30% to 40%. The coagulopathy is not reflected in the PT, and therefore, patients with this mutation are at risk of bleeding during warfarin therapy (38 – 40). An exaggerated response to warfarin among the elderly may reflect its reduced clearance with age (41– 43).

Subjects receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary vitamin K (44,45), which is derived predominantly from phylloquinones in plant material (45). The phylloquinone content of a wide range of foodstuffs has been listed by Sadowski and associates (46). Phylloquinones counteract the anticoagulant effect of warfarin because they are reduced to vitamin KH₂ through the warfarin-insensitive pathway (47). Important fluctuations in vitamin K intake occur in both healthy and sick subjects (48). Increased intake of dietary vitamin K sufficient to reduce the anticoagulant response to warfarin (44) occurs in patients consuming green vegetables or vitamin K– containing supplements while following weight-reduction diets and in patients treated with intravenous vitamin K supplements. Reduced dietary vitamin K₁ intake potentiates the effect of warfarin in sick patients treated with antibiotics and intravenous fluids without vitamin K supplementation and in states of fat malabsorption. Hepatic dysfunction potentiates the response to warfarin through 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 (49,50). Drugs may influence the pharmacodynamics of warfarin by inhibiting synthesis or increasing clearance of vitamin K– dependent coagulation factors or by interfering with other pathways of hemostasis. The anticoagulant effect of warfarin is augmented by the second-and third-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K (51,52); by thyroxine, which increases the metabolism of coagulation factors (50); and by clofibrate, through an unknown mechanism (53). Doses of salicylates >1.5 g per day (54) and acetaminophen (55) also augment the anticoagulant effect of warfarin, possibly because these drugs have warfarin-like activity (56). Heparin potentiates the anticoagulant effect of warfarin but in therapeutic doses produces only slight prolongation of the PT.

Drugs such as aspirin (57), nonsteroidal antiinflammatory drugs (58), penicillins (in high doses) (59,60), and moxolactam (52) 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 (61). Aspirin and nonsteroidal antiinflammatory drugs also can produce gastric erosions that increase the risk of upper gastrointestinal bleeding. The risk of clinically important bleeding is heightened when high doses of aspirin are taken during high-intensity warfarin therapy (international normalized ratio [INR] 3.0 to 4.5) (57,62). In 2 studies, one involving patients with prosthetic heart valves (63) and the other involving asymptomatic individuals at high risk of coronary artery disease (64), low doses of aspirin (100 mg and 75 mg daily, combined with moderate-and low-intensity warfarin anticoagulation, respectively) also were associated with increased rates of minor bleeding.

The mechanisms by which erythromycin (65) and some anabolic steroids (66) potentiate 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 deficient in vitamin K by eliminating bacterial flora and aggravating vitamin K deficiency (67).

Wells et al (68) critically analyzed reports of possible interactions between drugs or foods and warfarin. Interactions were categorized as highly probable, probable, possible, or doubtful. There was strong evidence of interaction in 39 of the 81 different drugs and foods appraised; 17 potentiate warfarin effect and 10 inhibit it, but 12 produce no effect. Many other drugs have been reported to either interact with oral anticoagulants or alter the PT response to warfarin (69,70). A recent review highlighted the importance of postmarketing surveillance with newer drugs, such as 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 (71). This review also drew attention to potential interactions with less well-regulated herbal medicines. For these reasons, the INR should be measured more frequently when virtually any drug or herbal medicine is added or withdrawn from the regimen of a patient treated with warfarin.

The Antithrombotic Effect of Warfarin
The antithrombotic effect of warfarin conventionally has been attributed to its anticoagulant effect, which in turn is mediated by the reduction of 4 vitamin K– dependent coagulation factors. More recent evidence, however, suggests that the anticoagulant and antithrombotic effects can be dissociated and that reduction of prothrombin and possibly factor X are more important than reduction of factors VII and IX for the antithrombotic effect. This evidence is indirect and derived from the following observations: First, the experiments of Wessler and Gitel (72) more than 40 years ago, which used 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. The antithrombotic effect of warfarin requires reduction of prothrombin (factor II), which has a relatively long half-life of 60 to 72 hours, compared with 6 to 24 hours for other K-dependent factors responsible for the more rapid anticoagulant effect. Second, in a rabbit model of tissue factor– induced intravascular coagulation, the protective effect of warfarin is mainly a result of lowering prothrombin levels (73). Third, Patel and associates (74) demonstrated that clots formed from umbilical cord plasma (containing about half the prothrombin concentration of adult control plasma) generated significantly less fibrinopeptide A, reflecting less thrombin activity, 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 (75) and that reduction in prothrombin levels decreases the amount of thrombin generated and bound to fibrin, reducing thrombogenicity (74).

The suggestion that the antithrombotic effect of warfarin is reflected in lower levels of prothrombin forms the basis for overlapping heparin with warfarin until the PT (INR) is prolonged into the therapeutic range during treatment of patients with thrombosis. Because the half-life of prothrombin is 60 to 72 hours, >4 days’ overlap is necessary. Furthermore, the levels of native prothrombin antigen during warfarin therapy more closely reflect antithrombotic activity than the PT (76). These considerations support administering a maintenance dose of warfarin (5 mg daily) rather than a loading dose when initiating therapy. The rate of lowering prothrombin levels was similar with either a 5-or a 10-mg initial warfarin dose (77), but the anticoagulant protein C was reduced more rapidly and more patients were excessively anticoagulated (INR >3.0) with a 10-mg loading dose.

© 2003 by the American Heart Association, Inc., and the American College of Cardiology Foundation