Sensitivity To Warfarin

Approximately 10% of patients require <1.5 mg/day of warfarin to achieve an INR of 2—3. These patients are more likely to possess one or two polymorphic alleles of CYP2C9, the major enzyme responsible for converting the S-enantiomer warfarin to its inactive metabolites. In comparison with the wild-type CYP2C9*1 allele, the variant alleles CYP2C9*2 and CYP2C9*3 have been shown to inactivate S-warfarin much less efficiently in vitro. The variant alleles are present in 10—20% of Caucasians, but in <5% of African Americans or Asians. Polymorphic variations in VKORC1, which encodes a component of the Vitamin K reductase complex (see Figure 54-6), also determine warfarin sensitivity.

toxicities

Bleeding Bleeding is the major toxicity of oral anticoagulant drugs. The risk of bleeding increases with the intensity and duration of anticoagulant therapy, the use of other medications that interfere with hemostasis, and the presence of a potential anatomical source of bleeding. The incidence of major bleeding episodes is generally <5% per year in patients treated with a target INR of 2-3. The risk of intracranial hemorrhage increases dramatically with an INR >4, especially in older patients. In a large outpatient anticoagulation clinic, the most common factors associated with a transient elevation of the INR (>6) were use of a new medication known to potentiate warfarin (e.g., acetaminophen), advanced malignancy, recent diarrheal illness, decreased oral intake, and taking more warfarin than prescribed. Patients must be informed of the signs and symptoms of bleeding, and laboratory monitoring should be done at frequent intervals during intercurrent illnesses or any changes of medication or diet.

If the INR is above the therapeutic range but <5 and the patient is not bleeding or in need of a surgical procedure, warfarin can be discontinued temporarily and restarted at a lower dose once the INR is within the therapeutic range. If the INR is >5, vitamin K1 (phytonadione, mephyton, aquamephyton) can be given orally at a dose of 1-2.5 mg (for an INR of 5-9) or 3-5 mg (for an INR >9). These doses of oral vitamin K1 generally cause the INR to fall substantially within 24-48 hours without rendering the patient resistant to further warfarin therapy. Higher doses may be required if more rapid correction of the INR is necessary. The effect of vitamin K1 is delayed for at least several hours, because reversal of anticoagulation requires synthesis of fully carboxylated coagulation factors. If immediate hemostatic competence is necessary because of serious bleeding or profound warfarin overdosage (INR >20), adequate concentrations of vitamin K-dependent coagulation factors can be restored by transfusion of fresh frozen plasma (10-20 mL/kg), supplemented with 10 mg of vitamin Kp given by slow intravenous infusion. Transfusion of plasma may need to be repeated, since the transfused factors (particularly factor VII) are cleared from the circulation more rapidly than the residual oral anticoagulant. Vitamin K1 administered intravenously carries the risk of anaphylactoid reactions, and therefore should be used cautiously. Patients who receive high doses of vitamin K1 may become unresponsive to warfarin for several days, but heparin can be used if continued anticoagulation is required.

Birth Defects

Administration of warfarin during pregnancy causes birth defects and abortion. Central nervous system (CNS) abnormalities have been reported following exposure during the second and third trimesters. Fetal or neonatal hemorrhage and intrauterine death may occur, even when maternal PT values are in the therapeutic range. Oral anticoagulants should not be used during pregnancy; heparin can be used safely in this circumstance.

Toxicities

A reversible, sometimes painful, bluish discoloration of the plantar surfaces and sides of the toes that blanches with pressure and fades with elevation (purple toe syndrome) may develop 3-8 weeks after initiation of therapy with warfarin; cholesterol emboli released from atheromatous plaques have been implicated as the cause. Infrequent reactions include alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, and anorexia.

Clinical Use

Oral anticoagulants are used to prevent the progression or recurrence of acute deep vein thrombosis or pulmonary embolism following an initial course of heparin. They also are effective in preventing venous thromboembolism in patients undergoing orthopedic or gynecological surgery and in preventing systemic embolization in patients with acute myocardial infarction, prosthetic heart valves, or chronic atrial fibrillation.

Prior to initiation of therapy, laboratory tests are used in conjunction with the patient's history and physical examination to uncover hemostatic defects that might make the use of oral anticoagulant drugs more dangerous (congenital coagulation factor deficiency, thrombocytopenia, hepatic or renal insufficiency, vascular abnormalities, etc.). Thereafter, the INR calculated from the patient's PT is used to monitor efficacy and compliance. Therapeutic ranges for various clinical indications have been established empirically and reflect dosages that reduce the morbidity from thromboembolic disease while minimally increasing the risk of serious hemorrhage. For most indications the target INR is 2-3. A higher target INR (e.g., 2.5-3.5) generally is recommended for patients with mechanical prosthetic heart valves.

For treatment of acute venous thromboembolism, heparin usually is continued for at least 4-5 days after oral anticoagulation is begun and until the INR is in the therapeutic range on 2 consecutive days. This overlap allows for adequate depletion of the vitamin K-dependent coagulation factors with long half-lives, especially factor II. Daily INR measurements are indicated at the onset of therapy to guard against excessive anticoagulation in the unusually sensitive patient. The testing interval can be lengthened gradually to weekly and then to monthly for patients on long-term therapy in whom test results have been stable.

Other Oral Anticoagulants phenprocoumon and acenocoumarol These agents are not available in the U.S. but are prescribed in Europe and elsewhere. Phenprocoumon (marcumar) has a longer plasma t1/2 (5 days) than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7-14 days). It is administered in daily maintenance doses of 0.75-6 mg. Acenocoumarol (sinthrome) has a shorter t1/2 (10-24 hours), a more rapid effect on the PT, and a shorter duration of action (2 days). The maintenance dose is 1-8 mg daily.

ximelagatran Ximelagatran is a novel drug that is readily absorbed after oral administration and is rapidly metabolized to melagatran, a direct thrombin inhibitor. The drug has not yet been approved for use in the U.S.

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