Outpatient Management of Oral Vitamin K Antagonist Therapy: Defining and Measuring High-Quality Management

Review Outpatient management of oral vitamin K antagonist therapy: defining and measuring high-quality management Expert Rev. Cardiovasc. Ther. 6(1), 57–70 (2008) Katherine W Phillips Oral anticoagulation therapy with warfarin is the mainstay of prevention and treatment of and Jack Ansell† thromboembolic disease. However, it remains one of the leading causes of harmful medication errors and medication-related adverse events. The beneficial outcomes of oral †Author for correspondence Boston University School of anticoagulation therapy are directly dependent upon the quality of dose and anticoagulation Medicine, Department of management, but the literature is not robust with regards to what constitutes such Medicine, Boston, management. This review focuses on, and attempts to define, the parameters of MA 02118, USA high-quality anticoagulation management and identifies the appropriate outcome measures Tel.: +1 617 638 7250 constituting high-quality management. Elements discussed include the most fundamental Fax: +1 616 638 8728 measure, time in therapeutic range, along with other parameters including therapy [email protected] initiation, time to therapeutic range, dosing management when patients are not in therapeutic range, perioperative dosing management, patient education, and other important outcome measures. Healthcare providers who manage oral anticoagulation therapy should utilize these parameters as a measure of their performance in an effort to achieve high-quality anticoagulation management. KEYWORDS: anticoagulation • quality • vitamin K antagonist • warfarin Oral anticoagulation therapy with the vitamin K of these agents. One such agency, the Joint antagonists (VKA), particularly warfarin, Commission, has proposed new 2008 National which is the most commonly used VKA, con- Patient Safety Goals aimed at minimizing the tinues to increase worldwide due to the aging risks associated with warfarin use and reducing population and its efficacy in preventing stroke adverse events [102]. in patients with atrial fibrillation or recurrent The beneficial outcomes of oral anticoagula- thromboembolism in patients with deep vein tion therapy are directly dependent upon thrombosis (DVT) and pulmonary embolism achieving and maintaining an optimal interna- (PE) [1]. Despite improved awareness of warfa- tional normalized ratio (INR) therapeutic range rin’s efficacy and safety, the management of which requires high-quality anticoagulation Futurewarfarin remains complex Drugsdue to its intricate management (HQACM)Ltd [1]. What constitutes pharmacokinetic and pharmacodynamic prop- HQACM of warfarin is poorly defined, as are erties and narrow therapeutic range. It is the outcome measures of HQACM. The aim of among one of the top five medications associ- this review is to identify and discuss the ele- ated with drug errors that cause harm and has ments of HQACM of warfarin and to define, been shown to be one of the most common when possible, the appropriate measures to causes of emergency room visits due to an assess HQACM. This review specifically does adverse event [2,3,101]. National healthcare regu- not address the ‘how to’ of HQACM. For latory agencies have recently targeted anticoag- detailed information on managing the VKAs, ulants, including warfarin, as high-risk medica- the reader is referred to a number of excellent tions and are focused on ensuring the safe use reviews [1,4,5]. www.future-drugs.com 10.1586/14779072.6.1.57 © 2008 Future Drugs Ltd ISSN 1477-9072 57 Review Phillips & Ansell An appropriate warfarin starting dose should generally be What constitutes high-quality 5 mg, although as little as 1–2 mg and up to 10 mg has been anticoagulation management? shown to be as effective in certain populations depending on The ultimate goals of warfarin management are to obtain the the patients’ sensitivity to warfarin. Large loading doses highest efficacy (preventing thromboembolism), while mini- (>10 mg) are not recommended [7,9,10]. Loading doses have mizing risk (preventing bleeding). This can be achieved by been associated with a high risk of early hemorrhage and a promptly reaching and maintaining a therapeutic level of false sense of complete anticoagulation in early treatment [1]. anticoagulation as measured by the INR. Various manage- A starting dose of less than 5 mg might be appropriate in the ment components, however, are required to be in place to elderly, in patients with impaired nutrition, liver disease, achieve HQACM goals. Such components include a knowl- congestive heart failure, following major surgery, and in edgeable healthcare provider, an organized system of follow- patients who are at high risk of bleeding or have had a recent up, reliable monitoring and good patient communication and heart valve replacement [1,11,12]. Many institutions have education [1,6]. adopted the use of validated warfarin dosing algorithms and nomograms (TABLE 1) as guides to dosing patients based on INR response [7,9,10]. Achieving & measuring efficacy Prompt achievement of a therapeutic INR results in Initiation of anticoagulation improved clinical outcomes. [1,13] The SPORTIF studies dem- The initiation of warfarin therapy requires an appropriate start- onstrated that good INR control at 6 months when compared ing dose, frequent INR monitoring and proper overlap with with patients who had poor INR control at 6 months, was asso- intravenous heparin or subcutaneous low-molecular-weight ciated with optimal INR control for the remainder of the study heparin (LMWH) if an immediate anticoagulant effect is period [15]. Earlier studies showed that INR control in the first required. Despite the early effect on the INR that occurs usually 30 days of warfarin therapy is predictive of subsequent INR within the first 2–3 days of initial warfarin therapy, an anti- control [16]. Thus, achieving the target INR and maintaining thrombotic effect typically requires several more days based on therapeutic anticoagulation control in patients within the first the time required for complete reduction of the vitamin K- 6 months of therapy is imperative. dependent coagulation factors (II, VII, IX, X) [7,8]. To achieve a Recent studies suggest that pharmacogenetic-based dosing rapid antithrombotic effect, heparin or LMWH is administered may improve time to reach therapeutic range, predict the concurrently and overlapped with warfarin for at least 5 days appropriate maintenance dose more accurately, reduce early until the INR has been in the therapeutic range for at least 2 days over-anticoagulation and, therefore, result in fewer hemorrhagic to allow for further reduction of Factors X and II [1]. adverse events [15,16]. Table 1. Example of a warfarin initiation nomogram. Day International normalized ratio Warfarin dose (mg) 1 - 5 2 - 5 3 <1.5 10 1.5–1.9 5 2.0–3.0 2.5 >3 0 4 <1.5 10 1.5–1.9 7.5 2.0–3.0 5 Future>3 Drugs0 Ltd 5 <2.0 10 2.0–3.0 5 >3 0 6 <1.5 12.5 1.5–1.9 10 2.0–3.0 7.5 >3 0 Data from [10]. 58 Expert Rev. Cardiovasc. Ther. 6(1), (2008) Quality of anticoagulation management Review Single nucleotide polymorphisms (SNPs) in the gene coding for CYP2C9, Prothrombin precursor Prothrombin the principal enzyme responsible for metabolizing the S-enantiomer of warfa- O O rin, will alter the metabolism rate of war- H H H H farin significantly. This polymorphism N C C N C C can influence how quickly the initial anticoagulant effects are seen, as well as the CH2 CH 2 dose required to maintain a therapeutic INR [15,17]. The target enzyme inhibited CH2 CH by warfarin is termed the vitamin K oxide HOOC COOH COOH reductase complex (VKORC) 1 (FIGURE 1). Similarly, various mutations in the gene Glutamic acid Carboxy-glutamic acid coding for VKORC1 enzyme will lead to a protein that is either sensitive or resist- Carboxylase ant to warfarin inhibition and, therefore, will also affect the initial dose required to CO 2 achieve and maintain a therapeutic INR. Retrospective analyses demonstrate that O2 CYP2C9 and VKORC1 genotype along with other patient specific clinical factors, such as age, BMI, race or concomitant medications, will account for over 50% of the variability of dose requirement [15–21]. CO 2 To date, two small prospective pilot trials Reduced vitamin K Oxidized vitamin K have been conducted and, although not powered to do so, neither were able to show a significant decrease in adverse events nor improved time in therapeutic range (TTR) [22,23]. Properly designed, randomized trials are needed to deter- mine whether pharmacogenetic-based Vitamin K oxide dosing proves to be beneficial compared reductase with high quality dose and INR management. Thus, pharmacogenetic-based dosing is not, at this time, considered to be CYP1A2 essential for HQACM. CYP2C9 CYP3A4 Measures and benchmarks of HQACM: S-warfarin R-warfarin • Proportion of patients with use of appropriate initial dose - Initial dose of warfarin with 5–10 mg, with a dose of no more than 5 mg in patients who are elderly, malnour- ished, have congestive heart failure, FutureWarfarin Drugs Ltd liver impairment or have had recent major surgery Figure 1. Vitamin K1 is reduced to vitamin KH2. The major warfarin-sensitive enzyme in this reaction is the vitamin K oxide reductase mainly inhibited by the • Proportion of patients with appropriate S-enantiomer of warfarin. S-warfarin is metabolized by the p450 cytochrome overlap of therapy with heparin enzyme, CYP2C9. - Overlap for at least 4–5 days and Warfarin exists as a racemic mixture to two stereo isomers. until two consecutive INRs are in The S-enantiomer is approximately three times more potent therapeutic range approximately 24 h apart than the R-enantiomer and is metabolized by different cyto- • Proportion of patients with prompt achievement of therapeutic chrome enzymes (FIGURE 1). INR and maintenance in therapeutic range in first month www.future-drugs.com 59 Review Phillips & Ansell - Rapid achievement and maintenance of therapeutic anti- The percent of INRs in range method utilizes the number of coagulation, but quantitative benchmarks have not been INRs within target range for all patients divided by the overall defined number of INRs during that selected time interval.

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