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The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Section snippets
1.0 Pharmacology and Monitoring of VKAs
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).123456 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
1.1 Pharmacokinetics and pharmacodynamics of warfarin
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.1820 Warfarin 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
1.2 The antithrombotic effect of VKAs
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
1.3 Monitoring anticoagulation intensity
The PT test75 is 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
1.4 Clinical applications of VKA therapy
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
2.0 Management of VKA Therapy
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
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
Recommendations
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).
Recommendations
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).
Recommendations
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
Recommendations
2.1.5.1 For patients with a low risk of thromboembolism, stop warfarin therapy approximately 4 days before they undergo surgery, allow the INR to return to near-normal values, briefly use postoperative prophylaxis (if the intervention increases the risk of thrombosis) with low-dose UFH (5,000 U SC) or a prophylactic dose of LMWH, and simultaneously begin warfarin therapy. Alternatively, a low dose of UFH or a prophylactic dose of LMWH also can be used preoperatively (all Grade 2C).
2.1.5.2. For
Recommendation
2.1.6.1. In patients who have a lupus inhibitor who have no additional risk factors and no lack of response to therapy, we suggest a therapeutic target INR of 2.5 (INR range, 2.0 to 3.0) [Grade 2B]. In patients who have recurrent thromboembolic events with a therapeutic INR or other additional risk factors for thromboembolic events, we suggest a target INR of 3.0 (INR range, 2.5 to 3.5) [Grade 2C].
2.1.1 The Appropriate Dose for Initiation of Oral Anticoagulants
2.1.1.1. 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 INR response (Grade 2B).
2.1.2 Anticoagulation in the Elderly
2.1.2.1. In the elderly, for 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 Oral Anticoagulation Therapy
2.1.3.1. We suggest starting INR monitoring after the initial two or three doses of oral anticoagulation
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