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KEY POINTS
■ Clinicians may choose to monitor INR more frequently, for example, in high-risk patients on multiple agents with known warfarin
interactions, in patients with a history of unstable INR response, during exacerbations of comorbid conditions, and while adjusting
codosage, but all patients should have their INR checked at least once every 4 weeks.
■ Routine monitoring of patients taking dabigatran is not required. In the event of bleeding, rapid reversal may not be required considering that the drug's therapeutic effect begins to diminish within 24 hours after the latest dose.
■ Advantages of warfarin over dabigatran include lower cost, once-daily dosing, more extensive indications and broader investigation across cardiovascular and cerebrovascular diagnoses, availability of established guidelines for use, and clarity of dosing for patients with severe renal impairment.
■ Advantages of dabigatran over warfarin include reduced need for and expense of laboratory monitoring, simplified dosage calculation and adjustment, greater predictability of dose response, fewer drug interactions, and rapid achievement of therapeutic concentrations.
Anticoagulation is commonly used for the prophylaxis and treatment of venous thrombosis and pulmonary embolism, as well as for the prevention of thromboembolism related to heart arrhythmias and valvular disorders. Current anticoagulant therapies include oral and parenteral agents that affect various elements of the coagulation cascade. Patients most commonly treated with oral anticoagulation therapy are those with persistent or paroxysmal atrial fibrillation (AF) who are at high risk for thromboembolic events, such as stroke. Atrial fibrillation affects roughly 2.5 million persons in North America and is the primary cause of cardioembolic stroke.1,2
Vitamin K antagonists have been the mainstay of oral anticoagulation for more than half a century. Warfarin (Coumadin, Jantoven, generics) is the most commonly used vitamin K antagonist, consistently ranking among the most frequently prescribed drugs in the United States. Warfarin has a narrow margin for safety, a widely variable dose-response relationship, and numerous food and drug interactions. The relative complexity in prescribing and monitoring this therapy is likely an important contributor to underprescribing for patients at high risk of cardioembolic stroke.3 When warfarin is prescribed and used responsibly, however, the benefits have clearly been shown to outweigh risk. Net treatment benefit is greatest in patients with history of previous stroke, those older than 85 years, and others with high stroke risk.4 The American College of Chest Physicians (ACCP) has developed a systematic, evidence-based approach to anticoagulation within its practice guidelines Antithrombotic and Thrombolytic Therapy.5
After many years without orally administered alternatives to warfarin, emerging anticoagulant therapies now include direct thrombin inhibitors and factor Xa inhibitors. Reported advantages of these therapies include reduced burden of frequent therapeutic laboratory monitoring, simplified dosing, and fewer clinically significant drug-drug interactions.6 Dabigatran (Pradaxa) is the first oral direct thrombin inhibitor to be approved by the FDA and is currently indicated for prophylaxis of stroke and systemic embolism in patients with nonvalvular AF.
VITAMIN K ANTAGONIST: WARFARIN
Warfarin is indicated for prophylaxis and treatment of venous thrombosis and pulmonary embolism; thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and risk of death, recurrent MI, and thromboembolic events, such as stroke or systemic embolization after MI.7 Warfarin is an oral anticoagulant that acts through inhibition of vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X).7
Considerations before prescribing Warfarin has a narrow margin for safety. Therefore, careful consideration of safety is essential when identifying appropriate patients, determining dosing and monitoring plans, and educating patients or caregivers. Contraindications are presented in Table 1. A variety of precautions exist, and long-term therapy with warfarin requires significant commitment to monitoring by patient and prescriber. Patients who are most vulnerable to drug-induced injury from warfarin include those with poor nutritional status, hepatic disorders, decreased intestinal absorption, diabetes, renal impairment, or anemia.8,9 Warfarin metabolism is also subject to genetic mutations. Screening tests are available to assess several recognized polymorphisms, specifically in the genes coding for VKORC1 and CYP2CP enzymes. The high cost of these tests currently limits use, but these assays may be particularly useful in Asian American and African American populations based on their higher susceptibility to the sensitive or resistant genotype.8
Prescribing and monitoring Dosing of warfarin is guided by laboratory measures of clotting, namely prothrombin
time (PT) or international normalized ratio (INR). Therapeutic goals differ by indication as presented in Table 2. The onset of anticoagulant effects of warfarin is delayed; thus patients with acute conditions, such as deep venous thrombosis or pulmonary embolism, should receive concurrent parenteral anticoagulation. In this case, warfarin may generally be initiated on the same day as parenteral therapy. Parenteral therapy is discontinued no sooner than 5 days and only if INR is 2.0 or higher for 24 hours. The ACCP provides more information about bridging these therapies within published guidelines.8
The ACCP recommends that starting doses be based on patient characteristics (see Table 3).8 Loading doses greater than 10 mg per day are not generally recommended because of an association with excessive anticoagulation and risk of major hemorrhage.8 The starting dose should be continued for 2 to 3 days before therapeutic monitoring with PT/INR is performed. This delay is based on the half-lives of the coagulation factors inhibited by warfarin.8 A variety of tools exist to guide prescribers in adjusting warfarin doses to attain therapeutic goal. In their 2003 paper comparing starting doses of warfarin, Kovacs and colleagues provided examples of dosing regimens.10 The standard for laboratory monitoring is an office- or laboratory-based INR; however, prescribers should be aware that home monitoring products are now available, approved by the FDA, and covered by numerous health insurance plans, including Medicare. Existing research suggests that for selected patients, home-based testing has the ability to increase time in target therapeutic range, patient satisfaction, and quality of life.11
Clinicians may choose to monitor INR more frequently, for example, in high-risk patients on multiple agents with known warfarin interactions, in patients with a history of unstable INR response, during exacerbations of comorbid conditions, and while adjusting dosage; but all patients should have their INR checked at least once every 4 weeks.8 Some patients will not tolerate dosing and may incur supratherapeutic INRs or bleeding. In the case of an emergency, vitamin K and/or fresh frozen plasma can be used to antagonize or reverse the effects of warfarin.8 Warfarin should be discontinued if bleeding risks outweigh potential anticoagulation benefits or in the event of significant bleeding. Table 4 describes dose adjustments for suboptimal INR levels or the onset of significant bleeding. Additionally, ACCP guidelines offer specific recommendations for discontinuing warfarin or when bridging is necessary prior to surgical procedures.12
Safety Bleeding is the major adverse reaction with warfarin. Several models for predicting bleeding risk, including the Outpatient Bleeding Risk Index and HEMORR2HAGES, have been developed and can be helpful for risk stratification.9 Clinical studies found the annual risk of major bleeds to be 0.3% to 0.5% and of intracranial hemorrhages (ICHs) to be 0.2% in patients who were closely monitored on warfarin when compared with controls.9 Intensity of treatment was found to be the most powerful predictor of ICH.9 In general, patients who have been on long-term established therapy have lower rates of major bleeding.8,9 Rare but potentially serious side effects include anaphylaxis, "purple toe" syndrome, tissue necrosis, and limb gangrene.7
Drug interactions are pervasive with warfarin and occur through a variety of different mechanisms.8,9 Given the broad array of potential drug-drug and drug-food interactions, providers should consult a reference or pharmacist for assistance in screening before initially prescribing warfarin or when treatments are added or discontinued for patients currently on warfarin. Some of the most commonly cited interacting agents are presented in Table 5, but this list is not all-inclusive. Patients should be educated about key food and drug interactions and encouraged to consult with their provider or a pharmacist before beginning OTC medications, dietary supplements, or vitamins. Particular attention should be given to educating patients about foods and supplements containing moderate to high levels of vitamin K, as consistency of dietary vitamin K intake will improve the provider's ability to maintain the therapeutic target. Multiple sources provide comprehensive lists of food and drug interactions with warfarin.8,13
Cost Warfarin is available in several generic formulations for less than $10 per month.14 Associated costs of therapy include laboratory monitoring with PT/INR, which costs approximately $30 per test, along with additional expenses related to office visits for medication management.15