Oral Anticoagulants

Warfarin

Warfarin (Coumadin®, Jantoven™) is an oral anticoagulant used for prevention and treatment of VTE, PE, atrial fibrillation with risk of embolism, and to prevent systemic embolism after MI.29 Warfarin is also used for anticoagulation therapy in patients with prosthetic heart valves. Coumarin derivatives work differently than the other parenteral anticoagulants described above, by inhibiting the synthesis of vitamin K- dependent clotting factors.

Several clotting factors are dependent upon vitamin K for their synthesis in the liver. Warfarin binds to the liver microsomal enzyme vitamin K 2,3-epoxide reductase, and inhibits the production of the reduced form of vitamin K. Reduced vitamin K is a necessary cofactor in the gamma carboxylation of the 4 vitamin K-dependent clotting factors: factors II, VII, IX, X. Precursors to these 4 clotting factors undergo vitamin K-dependent modification to produce their active forms. By inhibiting the formation of reduced vitamin K, coumarins prevent the activation of these clotting factors. Thus, the clotting factors remain as inactive molecules that cannot participate in the clotting process, thereby stopping the formation of thrombin and fibrin.

Warfarin also depresses proteins C and S, which are endogenous anticoagulants. Levels of these 2 proteins may be depressed by warfarin prior to depression of the other clotting factors, resulting in a dangerous period of hypercoagulation for a short period of time. The anticoagulant effects of warfarin are not initially evident until 8 hours to 12 hours after oral administration, and given its 36 hour half-life, if may take up to 4-7 days of dosing to reach the desired target International Normalized Ratio (INR) value.29 For this reason, heparin therapy (LDUH or LMWH) usually overlaps warfarin therapy for at least the first 2 days of oral anticoagulant therapy to allow for the warfarin to take effect and to achieve an optimal therapeutic range of anticoagulation.28,39 Heparin is discontinued after the INR has been in the therapeutic range for at least 2 measurements taken more than 24 hours apart.

Despite its widespread use, physicians often find it difficult to prescribe warfarin, given its narrow therapeutic index. It may take weeks of clinical testing (via the INR) to find the exact dose that results in the desired level of anticoagulation. Even small variations in dose can result in large clinical effects, including excess bleeding (over-anticoagulation) or inadequate anticoagulation, which places the patient at risk for developing clots.

Individuals taking warfarin vary in their response to given doses of the drug. It is known that a variation in the gene that encodes the CYP2C9 liver enzyme that metabolizes warfarin accounts for about 10% of the difference in response to the drug observed in warfarin users. Recently, investigators have identified another genetic variation in the VKORC1 gene (vitamin K epoxide reductase), which makes a protein that helps control clotting and is the target site of action of warfarin. By matching the genetic variations to the actual dose taken by study subjects, the researchers found that individuals with particular variations in the VKORC1 gene generally took similar doses of warfarin. Study results suggested that variation in this one gene accounted for 25% of the overall variance in warfarin dose. In the future, genetic testing could help to predict a person’s response to warfarin, and could be used to determine the proper initial dose.40

The major complication of anticoagulation therapy is bleeding. There is a positive relationship between the risk for hemorrhage and the intensity of anticoagulation.41 Patients on high-intensity warfarin therapy (INR>3.0) are at higher risk for hemorrhage as compared to warfarin therapy with an INR that falls between 2.0-3.0. The risk for intracranial hemorrhaging rises dramatically with an INR>4.0.41,42 The major determinants of warfarin-induced bleeding are the intensity of anticoagulation, unique patient characteristics, concurrent use of drugs that interfere with hemostasis (eg, aspirin), poorly controlled hypertension, and the duration of drug therapy.41 Multiple large, randomized controlled clinical trials support the use of combination therapy with aspirin plus warfarin (INR 2.0-2.5) in high- risk patients with atherosclerotic heart disease. Combination therapy increases the risk of both minor and major bleeding, but not intracranial bleeding in atherosclerotic patients. The most common bleeding complications include epistaxis (nosebleed), purpura (skin hemorrhages), gastrointestinal (GI) bleeding, hemoptysis (expectorating blood), and hematuria (blood in urine). 42,43,44

Unexpected elevations in the INR increase concerns for adverse bleeding events. Frequent monitoring of therapy, including the INR, is especially important in older adults, and adjustments to the treatment regimen are often necessary.45 When the INR is elevated, but no bleeding is present, warfarin therapy can be reduced or stopped, which lowers the INR within 24 hours to 48 hours without returning it to baseline levels. In patients with non-life-threatening bleeding, a small dose of vitamin K1 (1-2.5 mg) is administered orally or subcutaneously (SC). If urgent correction of the INR is needed, a larger dose of vitamin K1 (2-4 mg) is given initially, with additional 1-2 mg doses given as needed. When the INR >9.0 and/or bleeding is life-threatening, warfarin therapy is stopped and large doses of vitamin K1 (3-5 mg orally; 5-10 mg SC) are given. Fresh frozen plasma may also be given to replace the vitamin K-dependent clotting factors. Vitamin K1 may also be given by IV in life-threatening situations, but it must be administered slowly and carefully monitored, given the risk for anaphylaxis.46,47,48,49,50,51,52.

Multiple factors can contribute to alterations in the INR. Poor compliance with warfarin therapy is the most common reason for fluctuations in anticoagulation therapy.53 Switching between different brand names of warfarin product formulations has been shown to contribute to major medical complications, and patients are advised not to switch brands once the desired therapeutic effect has been achieved.29,54 Alterations in vitamin K intake, interference with intestinal bacterial synthesis of vitamin K, and impaired vitamin K absorption all cause significant fluctuations in response to warfarin.55 Many common foods, especially dark green leafy vegetables and 4 plant oils (soybean, canola, cottonseed, and olive) serve as primary dietary sources for vitamin K.56 Patients should maintain consistency in their diet and meet the recommended dietary allowance for vitamin K of 65 to 80 micrograms of phylloquinone per day.56 Patients who increase their intake of “heart-healthy” green vegetables without informing their physicians may be inadvertently increasing their warfarin requirements; sudden decreases in vitamin K intake then increases the risk for hemorrhagic events.

Other factors that contribute to alterations in anticoagulation effects include illness, fever, thyroid disease, biliary disease, liver disease, malabsorption syndromes, congestive heart failure, malignancy, and diarrhea.6,55 Warfarin is also highly affected by medication use. In fact, more food and drug interactions have been reported for warfarin than with any other prescription medication.57Alcohol consumption has also been reported to increase bleeding in warfarin users.55,58

Dental professionals should be aware that many commonly prescribed drugs used during dental treatment have the potential to alter the effects of warfarin. The dental drugs that have been reported to enhance the anticoagulant effect of warfarin include antibiotics (cephalosporins, macrolides, metronidazole, quinolones, penicillins, tetracyclines), analgesics (acetaminophen, NSAIDS), prednisone, and the systemic azole antifungals (fluconazole, ketoconazole, itraconazole).29,55,59 Single-dose antibiotic prophylaxis for the prevention of endocarditis and prosthetic joint infection is not likely to alter the effect of warfarin, although 3 case reports have been reported in the literature describing elevations in INR following prophylactic antibiotic use.60,61 Salicylates and NSAIDS should be avoided in warfarin users, given their antiplatelet activity.60 All dental professionals are encouraged to consult a drug reference guide prior to prescribing any medication to a patient taking warfarin to ensure drug compatibility and safety. Foods and herbs that alter warfarin activity are summarized in Table I.