华法林应用指南

American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy Jack Hirsh, MD, FRCP(C), FRACP, FRSC, DSc; Valentin Fuster, MD, PhD; Jack Ansell, MD; Jonathan L. Halperin, MD 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 vita- min 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 pro- teins, 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 pro- teins with reduced coagulant activity (7,8). Carboxylation promotes binding of the vitamin K–depen- dent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation (9–11). �-Carboxylation re- quires the reduced form of vitamin K (vitamin KH2). Cou- marins block the formation of vitamin KH2 by inhibiting the enzyme vitamin K epoxide reductase, thereby limiting the �-carboxylation of the vitamin K–dependent coagulant pro- teins. In addition, the vitamin K antagonists inhibit carboxy- lation 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 bioavail- ability (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 polymor- phisms in this enzyme have been described that are associated with lower dose requirements and higher bleeding complica- tion 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 pharma- codynamic 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 phar- macokinetics of warfarin by reducing gastrointestinal absorp- tion 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 nonse- lective pathways (25,26). Stereoselective interactions may The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement has been co-published in the April 1, 2003, issue of Circulation. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in October 2002 and by the American College of Cardiology Board of Trustees in February 2003. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0254. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4426, fax 410-528-4264, or e-mail klbradle@lww.com. To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400. (J Am Coll Cardiol 2003;41:1633–52.) ©2003 by the American Heart Association, Inc, and the American College of Cardiology Foundation. doi: 10.1016/S0735-1097(03)00416-9 AHA/ACC Scientific Statement 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 clear- ance 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 carbam- azepine, 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). Phylloqui- nones 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 anticoag- ulant 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 vita- min K supplementation and in states of fat malabsorption. Hepatic dysfunction potentiates the response to warfarin through impaired synthesis of coagulation factors. Hypermet- abolic states produced by fever or hyperthyroidism increase warfarin responsiveness, probably by increasing the catabo- lism of vitamin K–dependent coagulation factors (49,50). Drugs may influence the pharmacodynamics of warfarin by inhibiting synthesis or increasing clearance of vitamin K–de- pendent coagulation factors or by interfering with other pathways of hemostasis. The anticoagulant effect of warfarin is augmented by the second- and third-generation cephalo- sporins, 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 un- known 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 anticoag- ulant 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 moxolac- tam (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 Figure 1. The vitamin K cycle and its link to carboxylation of glutamic acid residues on vitamin K–dependent coagulation proteins. Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders the coagu- lation factors II, VII, IX, and X and the anticoagulant factors pro- tein C and protein S functionally active. Vit KO is then reduced to Vit K1 in a reaction catalyzed by vitamin KO reductase. By inhibiting vitamin KO reductase, warfarin blocks the formation of vitamin K1 and vitamin KH2, thereby removing the substrate (vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1, either given therapeutically or derived from food sources, can overcome the effect of warfarin by bypassing the warfarin- sensitive vitamin KO reductase step in the formation of vitamin KH2. 1634 Hirsh et al. JACC Vol. 41, No. 9, 2003 Guide to Warfarin Therapy May 7, 2003:1633–52 during high-intensity warfarin therapy (international normal- ized 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 anticoagu- lant 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 cele- coxib, 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 coag- ulation factors. More recent evidence, however, suggests that the anticoagulant and antithrombotic effects can be dissoci- ated 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 experi- ments of Wessler and Gitel (72) more than 40 years ago, which used a stasis model of thrombosis in rabbits, showed TABLE 1. Capillary Whole Blood (Point-of-Care) PT Instruments Instrument Clot Detection Methodology Type of Sample Home Use Approval Protime Monitor 1000 Coumatrak* Ciba Corning 512 Coagulation Monitor* CoaguChek Plus* CoaguChek Pro* CoaguChek Pro/DM* Clot initiation: Thromboplastin Clot detection: Cessation of blood flow through capillary channel Capillary WB Venous WB No CoaguChek CoaguChek S Thrombolytic Assessment System Rapidpoint Coag Clot initiation: Thromboplastin Clot detection: Cessation of movement of iron particles Capillary WB Venous WB Plasma Yes† (CoaguChek only) ProTIME Monitor Hemochron Jr‡ GEM PCL‡ Clot initiation: Thromboplastin Clot detection: Cessation of blood flow through capillary channel Capillary WB Venous WB Yes Avosure Pro�§ Avosure Pro§ Avosure PT§ Clot initiation: Thromboplastin Clot detection: Thrombin generations detected by fluorescent thrombin probe Capillary WB Venous WB Plasma Yes Harmony Clot initiation: Thromboplastin Clot detection: Cessation of blood flow through capillary channel Capillary WB Venous WB Yes INRatio� Clot initiation: Thromboplastin Clot detection: Change in impedance in sample Capillary WB Venous WB Yes WB indicates whole blood. *All instruments in this category are based on the original Biotrack model (Protime Monitor 1000) and licensed under different names. The latest version available is the CoaguChek Pro and Pro/DM (as models evolved, they acquired added capabilities); earlier models are no longer available. †CoaguChek not actively marketed for home use at the time of this writing. Thrombolytic Assessment System not available for home use. ‡Hemochron Jr and GEM PCL are simplified versions of the ProTIME Monitor. §Avosure instruments removed from market when manufacturer (Avocet, Inc) ceased operations (2001). Technology has since been purchased by Beckman Coulter. �INRange system manufactured by Hemosense, Inc, is currently in development. 1635JACC Vol. 41, No. 9, 2003 Hirsh et al. May 7, 2003:1633–52 Guide to Warfarin Therapy 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 pro- thrombin (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 anticoag- ulant 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 prothrom- bin 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. Management of Oral Anticoagulant Therapy Monitoring Anticoagulation Intensity The PT is the most common test used to monitor oral anticoagulant therapy (78). The PT responds to reduction of 3 of the 4 vitamin K–dependent procoagulant clotting factors (II, VII, and X) that are reduced by warfarin at a rate proportionate to their respective half-lives. Thus, during the first few days of warfarin therapy, the PT reflects mainly reduction of factor VII, the half-life of which is �6 hours. Subsequently, 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. The tradi- tional term “thromboplastin” refers to a phospholipid-protein extract of tissue (usually lung, brain, or placenta) that contains both the tissue factor and phospholipid necessary to promote activation of factor X by factor VII. Thromboplas- tins vary in responsiveness to the anticoagulant effects of warfarin according to their source, phospholipid content, and preparation (79–81). The responsiveness of a given throm- boplastin to warfarin-induced changes in clotting factors reflects the intensity of activation of factor X by the factor VIIa/tissue factor complex. 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). PT monitoring of warfarin treatment is very imprecise when expressed as a PT ratio (calculated as a simple ratio of the patient’s plasma value over that of norma