Although warfarin has been the mainstay of oral anticoagulation therapy for decades, evidence-based methods for improving the quality of warfarin therapy remain underused. The arrival of new anticoagulants that do not require routine laboratory monitoring and lack the significant dietary and drug interaction potential that are seen with warfarin is an important evolutionary step in the management of thromboembolic disease. However, it will be years before the efficacy and long-term safety of these new agents are defined. Newer oral anticoagulants will be more expensive than generic warfarin. This article examines various approaches to optimize the clinical use of warfarin. For patients able to achieve stable anticoagulation control, warfarin remains an important therapeutic option, delivering similar clinical outcomes at a fraction of the cost to the health care system.
For decades, vitamin K antagonists (VKAs) like warfarin sodium have served well as the oral anticoagulant drugs of choice for prevention and treatment of thromboembolic disease. Despite excellent clinical efficacy, warfarin remains a difficult treatment to deliver. Because of wide intra- and interindividual variability and the small differential separating beneficial and toxic therapeutic effects, warfarin is classified as a narrow therapeutic index drug. Consequently, frequent assessment of the effect of warfarin on the coagulation system, as measured clinically by the international normalized ratio (INR), is required for the duration of treatment. Frequent INR monitoring and follow-up have potential negative effects on quality of life. The pharmacokinetics and pharmacodynamics of warfarin are altered by several factors, including diet, alcohol use, many medications, and concurrent illnesses. Because of these challenges and fear of bleeding complications, warfarin remains underused despite an increasing number of patients who might benefit from its use. The many liabilities associated with warfarin therapy have fueled ongoing efforts to develop effective oral anticoagulants that are clinically easier to use.
New oral anticoagulants (eg, dabigatran and rivaroxaban) have been introduced for selected indications, namely orthopedic thromboprophylaxis, in Canada and Europe and are in different phases of testing for other indications and in preparation for introduction in the United States. There is speculation that the introduction of newer, easier-to-use anticoagulants will eliminate the need for warfarin. Although the cost of newer agents is yet to be defined in the US market, they will be more expensive than warfarin, which is available as a generic drug. Results of clinical trials comparing new anticoagulants with adjusted-dose warfarin therapy have largely reported similar efficacy and safety, particularly when warfarin therapy is well managed. Patients with stable INR control have been shown to experience significantly fewer anticoagulation therapy-related complications compared with patients with less stable INR control. Data from retrospective studies further support the use of INR stability to accurately predict reductions in adverse events. Therefore, before a tried-and-true therapeutic modality like warfarin with decades of accumulated clinical experience is abandoned in favor of novel newer agents, measures to ensure optimal use of warfarin should be fully explored. In addition, warfarin remains the therapy of choice for patients with mechanical heart valves and for those who experience therapeutic failure on the newer agents. This article examines various approaches to optimize the clinical use of warfarin.
Initiation of therapy
Selecting appropriate candidates for warfarin therapy is an important first step in achieving optimal anticoagulation. A valid indication for anticoagulation therapy should exist. Although the preceding statement should be intuitive, patients receiving atrial fibrillation with low underlying stroke risk likely receive minimal net benefit from warfarin therapy. Therefore, before initiating therapy, careful weighing of the risk and benefits of warfarin therapy is required.
Before initiating therapy a thorough patient assessment should be performed, including a comprehensive medical, family, medication history (including dietary supplements and over-the-counter drugs); social, lifestyle, and employment profile; and health beliefs and attitudes, level of understanding, health literacy, personal health motivation, and health care resources. The risks of warfarin therapy may outweigh benefits in patients with a previous history of medication nonadherence, bleeding risk factors, history of falls, significant alcohol consumption, memory impairment, and lack of adequate support from family members or caregivers. Validated tools exist for conducting formal bleeding risk assessment. Patients and/or their caregivers should be involved in the discussion of the risks and benefits associated with warfarin therapy and should agree with the decision to initiate therapy. Some anticoagulation providers require new patients to sign a contract indicating their commitment to adhere to the requirements of warfarin therapy.
Patient education
When patients are actively involved in, understand, and take responsibility for their care the likelihood of INR stability is improved. Patient education is an essential component in quality management of the anticoagulated patient. Because it is time consuming for clinicians and overwhelming for patients, educating the anticoagulated patient is often neglected. A formalized warfarin education curriculum based on established models may be more likely to improve patient’s knowledge level compared with an ad hoc approach. Specific warfarin knowledge-assessment tools have been developed to help assess patients’ educational needs. Efforts to educate patients regarding warfarin therapy should continue throughout treatment.
Patient education
When patients are actively involved in, understand, and take responsibility for their care the likelihood of INR stability is improved. Patient education is an essential component in quality management of the anticoagulated patient. Because it is time consuming for clinicians and overwhelming for patients, educating the anticoagulated patient is often neglected. A formalized warfarin education curriculum based on established models may be more likely to improve patient’s knowledge level compared with an ad hoc approach. Specific warfarin knowledge-assessment tools have been developed to help assess patients’ educational needs. Efforts to educate patients regarding warfarin therapy should continue throughout treatment.
Induction of therapy
Various algorithms aimed at quickly achieving therapeutic INR values during warfarin therapy induction have been developed. The size of the initial warfarin dose is a key differentiation between the various available algorithms. Regardless of the size of the initial warfarin dose, a key component of successful warfarin initiation is a structured initiation process that incorporates frequent INR assessments (at least 2–3 times per week) with subsequent warfarin dose titration.
Genetic variability among patients, specifically variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1), plays a role in determining the eventual required therapeutic warfarin dose. Determining CYP2C9 and VKORC1 status before initiating warfarin therapy has been enthusiastically promoted as a means to improve the accuracy of initial warfarin dose selection. However, the promise of genotype-guided initial warfarin dosing remains largely unfulfilled and current evidence does not support its routine use.
Maintenance of therapy
Standardization of follow-up procedures using checklists, flow diagrams, or computerized tracking systems should be used to ensure consistency of warfarin management. Before determining warfarin dose instructions, a thorough assessment of the various factors that influence warfarin dosing requirements (eg, diet, concurrent illness, other medications, alcohol use, and adherence to dosing instructions) should be completed, especially for out-of-range INRs. Patients should also be assessed regularly for signs and symptoms of bleeding or clotting complications.
Maintenance Dosing Algorithms
Validated algorithms for adjusting warfarin doses should be incorporated into operating procedures. Using algorithms reduces clinician variation in the management of warfarin doses and can improve the stability of INR control. Frequent warfarin dose changes in response to slightly out-of-range INRs (eg, 1.8–1.9 or 3.1–3.2 for target INR range of 2.0–3.0) perturbs INR control, setting up a cycle of dose adjustment and readjustment. It has been suggested that for target INR range of 2.0 to 3.0, an optimal maintenance dose management strategy would be to change warfarin doses only when the INR is 1.7 or less or 3.3 or greater. It has been further suggested that INR reductions greater than 20% be avoided in most circumstances. Target INR ranges should be evidence based (eg, 2.0–3.0 and 2.5–3.5 in most cases).
It is common practice to instruct patients with otherwise stable INR control who present with a slightly out-of-range INR to skip or boost the dose of warfarin one time before reverting back to the usual dosing schedule. Although this behavior may bring the INR more rapidly back into the therapeutic range, a recent study showed the net effect on the next measured INR was unimportant compared with simply continuing the usual warfarin dose alone. Furthermore, the clinical benefit of this practice is probably negligible because of the low risk of bleeding or thromboembolic complications associated with short periods outside the therapeutic range.
Studies of computer-assisted warfarin dosing have consistently shown improvements in INR control compared with manual dosing. When possible, computer-assisted or paper-based algorithms are preferred to an ad hoc dosing approach. Evidence-based guidelines should be used to establish a systematic approach to responding to extreme INR values (eg, >5.0 and <1.5).
INR Recall Interval
Likewise, a systematic approach should be used to determine the interval between INR tests that maximizes the amount of time patients spend within their therapeutic range. The 4-week maximum recall interval between INR measurements recommended by consensus guidelines is not evidence based, having evolved instead from routine clinical practice and expert opinion. The weekly INR testing that has been suggested for patients who self-monitor INRs using portable fingerstick INR monitors is probably unnecessary for patients showing long-term INR stability. High-frequency INR testing raises the likelihood of measuring slightly out-of-range INR values (which as discussed previously can lead to unnecessary warfarin dose changes) and unnecessarily increases the costs associated with warfarin therapy. Evidence supports less frequent INR monitoring for patients with stable INR control. Recent studies have shown that a stable subgroup of patients treated with warfarin can be identified, in whom allowing 8-week INR recall intervals would be reasonable. Stable INR control in these studies was associated with age greater than 70 years, target INRs less than 3.0, and lower chronic disease burden. In the United Kingdom INR recall intervals of up to 90 days are routinely used in patients with stable INR control. Therefore, INR recall intervals should be individually tailored based on proven INR control rather than being fixed at some arbitrary minimum frequency, such as 4 weeks.
Drug and Dietary Interactions
Warfarin therapy is complicated by administration of drugs that interfere with its pharmacokinetic and pharmacodynamic properties, leading to loss of INR control. Avoidance of interacting drug therapy is preferred, but not always feasible. Although there is no clinical standard for managing warfarin therapy when interacting drugs are coadministered, 2 strategies are generally used. The conventional approach involves increasing INR monitoring frequency with reactive warfarin dose adjustment based on INR response. Alternatively, the warfarin dose can be preemptively increased or decreased on initiation of the interacting medication in addition to increasing the frequency of INR monitoring in anticipation of subsequent INR increase or decrease. When drugs with a known strong tendency to affect the INR, such as cotrimoxazole, are coadministered, preemptive warfarin dose alteration may reduce the likelihood of subsequent nontherapeutic INRs. Conversely, using timely INR monitoring to identify patients with altered INR response then reactively adjusting the warfarin dose may be preferred for interacting medications with less predictable effects on the INR, such as levofloxacin. The value of the first follow-up INR following initiation of an interacting drug may be less important than longitudinal INR control during the weeks that follow. Evidence indicates that the risk of major bleeding in patients with INRs between 4.5 and 10.0 and the risk of thromboembolism associated with isolated subtherapeutic INRs are low provided steps are taken to rapidly restore therapeutic anticoagulation. Therefore, ensuring timely INR monitoring and adjusting doses of warfarin when necessary is of primary importance. Application of pharmacokinetic and pharmacodynamic principles is necessary to determine how long increased INR monitoring frequency is required. For interacting drugs like rifampin and amiodarone, prolonged effects on the INR response of warfarin are possible, necessitating careful INR monitoring for weeks or months.
Some warfarin drug interactions do not alter the INR response but rather increase the risk for bleeding complications; this is perhaps best illustrated by concomitant administration of warfarin and aspirin therapy. Many patients receiving warfarin therapy also have indications for antiplatelet therapy, for example coronary artery and cerebrovascular disease, and some patients take a daily aspirin without knowledge of their anticoagulant provider. One study showed that concurrent administration of antiplatelet therapy was present in nearly 40% of patients receiving warfarin enrolled in an anticoagulation monitoring service. In most cases, adding aspirin to warfarin therapy merely increases the risk of significant bleeding without further reducing thromboembolic risk. Clinicians should carefully consider whether adding antiplatelet therapy to warfarin therapy is warranted and should clearly document aspirin use or nonuse in all patients prescribed warfarin.
Dietary vitamin K intake can affect the INR response to warfarin. This drug-food interaction can be clinically relevant and independently interfere with INR stability. The precise amount of dietary vitamin K that should be ingested by patients receiving warfarin has not been definitively established and this component of achieving optimal INR stability is frequently overlooked. A recent study reported that a dietary vitamin K-guided strategy for adjusting oral anticoagulation therapy, in lieu of the conventional approach of altering oral anticoagulant doses, was feasible, safe, and may result in increased INR control. The strategy involved an assessment of vitamin K intake using a validated instrument that evaluated usual consumption of 16 vitamin K-rich foods. Based on this assessment, patients with low or high INR values were instructed to half or double the consumption frequency of vitamin K-rich foods. Oral anticoagulant dose remained unaltered. Patients randomized to the vitamin K-guided strategy had the same magnitude and direction of INR variation as patients randomized to the conventional anticoagulant medication dose adjustment arm. A higher proportion of patients in the vitamin K-guided strategy group reached a prespecified INR target at study conclusion compared with conventional management (74%, vs 58%, respectively, P = .04). A separate approach involving daily administration of vitamin K supplements (100 to 200 μg/d) has also been shown to improve INR control for patients with unexplained variability in response to warfarin. Daily vitamin K supplementation in this manner is believed to override any variability in dietary vitamin K intake, allowing eventual stabilization of the INR response following a period of careful monitoring and warfarin dose titration. In determining whether a patient with variable INR control is a candidate for daily supplemental vitamin K, known causes of INR variability (eg, poor adherence to warfarin therapy, drug interactions, changes in health status, and alcohol abuse), should be first excluded. Although more study is required to clarify the role of vitamin K-based strategies for improving INR control, for patients with persistently unstable INR control, efforts targeting vitamin K intake may yield improvement.
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