Outpatient Oral Anticoagulant Therapy

Elaine M. Hylek

The options for oral anticoagulant therapy have expanded dramatically in recent years with the advent of direct factor × and Xa inhibitors now joining the coumarin derivatives for effective prevention of thromboembolism. Similarly, new oral platelet inhibitors have joined with aspirin in enhancing prevention of arterial thrombosis and restenosis. The importance of these agents to the management of cardiovascular disease obligates the primary care physician to know (a) their indications for use, (b) approaches to initiation and maintenance of therapy in the outpatient setting, (c) common complications, and (d) drug-drug interactions that potentiate or interfere with their action.

WARFARIN (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50)

Mechanisms of Action

Warfarin and other coumarin derivatives act by inhibiting the action of vitamin K in the γ-carboxylation of glutamic acid residues on coagulation factors II, VII, IX, and X. Without γ-carboxylation, these proteins cannot participate in coagulation. The warfarin-induced decline in active, carboxylated coagulation factors is a function of the half-life of each factor, which varies from 5 hours for factor VII to 72 hours for factor II (thrombin). The prothrombin time (PT) may be prolonged after only 2 to 3 days of therapy, but this represents primarily the depression of factor VII. The full antithrombotic effect of warfarin is achieved only after 5 to 7 days, with the depletion of factor II.

Indications

Therapy is indicated in conditions associated with a high risk for thrombus formation and subsequent embolization. These include the following:

Atrial fibrillation (AF) (see Chapters 28 and 33)
Valvular heart disease and prosthetic heart valves (see Chapter 33)
Systemic embolization (see Chapter 171)
Deep venous thrombosis (see Chapter 35)
Pulmonary embolization (see Chapter 35)
Dilated cardiomyopathy and left ventricular thrombus (see Chapter 32)
Following myocardial infarction (MI) in selected patients (see Chapter 31)

Atrial Fibrillation

AF is highly prevalent, and is found in 5% of people older than 60 years and nearly 10% of people older than 80 years. It increases the risk for stroke more than fivefold; the patient in AF has a 5% average annual risk for stroke. Patients with AF secondary to valvular heart disease are at even greater risk (see also Chapters 28 and 32).

Prosthetic Heart Valves

Prosthetic heart valves increase the risk for systemic emboli, especially stroke. The risk is higher with caged-ball and tiltingdisk valves and with valves in the mitral rather than the aortic position. Anticoagulation is continued indefinitely. Patients with bioprosthetic valves need only short-term (e.g., for 3 months) anticoagulation unless another indication, such as AF or a history of systemic embolism, is present (see also Chapter 33).

Deep Venous Thrombosis and Pulmonary Embolism

Deep venous thrombosis and pulmonary embolism are indications for anticoagulation. A 3-month course is indicated when risk factors are reversible or time limited, such as surgery, temporary immobilization, or estrogen use. Patients with a first episode of idiopathic or unprovoked deep venous thrombosis or deep venous thrombosis in the presence of an inherited thrombophilia should be treated for at least 3 months. Duration of anticoagulant therapy following the first unprovoked venous thrombosis remains controversial. For patients at low or moderate risk of bleeding, extended treatment is suggested. A risk-benefit assessment of continued anticoagulant therapy should be undertaken annually. In patients with recurrent deep venous thrombosis or pulmonary embolism, a known hypercoagulable state, or homozygosity for factor V Leiden, anticoagulation should be continued indefinitely (see also Chapter 35).

Dilated Cardiomyopathy

Dilated cardiomyopathy puts patients at risk for embolization. When accompanied by AF, the annual risk for embolic events in the absence of anticoagulation exceeds 15%. For individuals with systolic heart failure (ejection fraction <35%) in sinus rhythm, warfarin compared to aspirin significantly reduces the rate of ischemic stroke (0.72% vs. 1.36% with aspirin; hazard ratio, 0.52), but at a cost of a higher rate of major nonintracranial hemorrhage (1.78% vs. 0.87%; adjusted rate ratio, 2.05). Potential benefits and risks must be weighed for individual patients (see also Appendix 33-1-83-83).

Myocardial Infarction

Some patients may benefit from anticoagulation following MI. Anterior Q-wave infarction, particularly with evidence of mural thrombosis, or AF warrants anticoagulation. Otherwise, there is no evident advantage for warfarin over aspirin in chronic stable angina or in the secondary prevention of MI (see also Chapter 31).

Contraindications

Contraindications to the use of oral anticoagulants need to be considered in the context of urgency of anticoagulation, risk and seriousness of potential complications, and duration of therapy (Table 83-1). Patients with previous central nervous system bleeding, recent neurosurgery, or frank bleeding should not receive warfarin. Important relative contraindications include active peptic ulcer disease, chronic alcoholism, blindness (unless in supervised situations), bleeding diathesis, and severe hypertension. When taken in early pregnancy, coumarins may cause birth defects; when they are used at delivery, fetal hemorrhage can occur. Heparin should be used in place of warfarin during early pregnancy and childbirth. Embarking on oral anticoagulant therapy is unwise when follow-up cannot be readily maintained, when laboratory facilities for accurately measuring the PT are inadequate, or when the patient is not adherent to the treatment plan.

TABLE 83-1 Contraindications to Anticoagulant Therapy with Warfarin

Absolute Contraindications
	Previous central nervous system bleeding
	Recent neurosurgery
	Active frank bleeding
	Early pregnancy and delivery
Relative Contraindications
	Active peptic ulcer disease
	Chronic alcoholism
	Bleeding diathesis
	Severe hypertension

Initiating and Monitoring Therapy

Initiation for Acute Pulmonary Embolization and Systemic Thromboembolization

Patients with acute pulmonary embolization or acute systemic thrombosis should be admitted to the hospital for immediate administration of heparin to halt clot propagation. Intravenous (IV) unfractionated heparin has been the standard initial anticoagulant treatment. Evidence suggests that low molecular weight heparin (which can be administered subcutaneously twice daily and does not require continuous monitoring of the PT time) is at least as safe and effective and may be a more convenient alternative to conventional therapy in stable patients. Low molecular weight heparin should not be used in patients with significant renal impairment. Physicians should refer to the package insert for detailed dosing information.

Warfarin should be started on the first day of heparin therapy and overlapped with heparin for at least 4 days to ensure adequate reduction in prothrombin levels. Initiating warfarin therapy with 5-mg daily dose is recommended. Starting doses less than 5 mg are advised for elderly women and malnourished patients. Initiation with a 10-mg dose should be reserved for young, healthy patients. A warfarin dosing algorithm based on greater than 1,000 patients is freely available on the web and may be helpful (www.WarfarinDosing.org). Once the international normalized ratio (INR) is greater than 2.0 for at least 2 consecutive days, heparin can be discontinued.

Initiation for Acute Deep Venous Thrombosis

For patients with deep venous thrombosis, subcutaneous administration of low molecular weight heparin is an effective alternative to IV administration of unfractionated heparin for initial anticoagulation (see Chapter 35). It allows for a shortened hospital stay or an entirely at-home anticoagulant treatment program, which reduces costs. Warfarin therapy is instituted in the same fashion as for IV heparin therapy.

Initiation for Chronic Atrial Fibrillation and Other Nonacute Indications

Patients who are in less urgent need of immediate full anticoagulation (e.g., chronic stable AF) can be safely started on warfarin alone as outpatients. A generally accepted approach to initiating outpatient warfarin therapy is to give 5 mg daily, measure the INR on the fourth day, and adjust the dose accordingly. The starting dose should be set at 2.5 mg daily in patients who weigh less than 110 lb, are older than 75 years, or are at increased risk for bleeding. Warfarin is best taken on an empty stomach at a specific time each day. Administration at bedtime allows for changes to be made in the dose on the same day that the INR is measured. The U.S. Food and Drug Administration (FDA) has
approved several generic warfarins; the same generic or brand formulation should be used consistently to avoid patient confusion and INR fluctuation.

Monitoring

The intensity of anticoagulation is measured with the PT test and expressed as the prothrombin time ratio (PTR), which is the ratio of the patient’s PT to the control PT of the laboratory. Standardization of the PTR across laboratories is necessary to account for the different sensitivities of the various thromboplastin reagents used in the assay. The INR has replaced the PTR as the universally accepted measure of anticoagulation intensity. To calculate the INR, the PTR is raised to the power of the international sensitivity index (ISI) of the specific reagent used (i.e., PTR^ISI).

It can take up to 3 months to achieve a stable warfarin dose. Once stabilized, the INR can be checked every 3 to 4 weeks. The variability in the warfarin dose response mandates frequent monitoring. Changes in the warfarin requirement may be precipitated by a change in diet, particularly the intake of foods with a high content of vitamin K (e.g., most leafy vegetables) or by medications that interfere with the hepatic clearance of warfarin. Many commonly used drugs potentiate the anticoagulant effect of warfarin and should prompt close monitoring (see later discussion). Patients with lupus anticoagulants (among the antiphospholipid antibodies that can cause hypercoagulability and thrombosis; see Chapter 35) may pose a particular problem in monitoring because these antibodies can interfere with the PT assay. Both overestimation and underestimation of the degree of anticoagulation can result. Consultation with a hematologist is needed to design the anticoagulation monitoring program for such a patient.

Technologic advances have made finger-stick home monitoring an increasingly practical option. In studies of home monitoring with properly trained patients or family members, control was equal to that achieved with an anticoagulation clinic, and rates of major and minor complications were lower. When compared with a high-quality laboratory-based monitoring program, rates of adverse events were unchanged. Such findings suggest that home monitoring is an option in properly selected patients, even when high-quality monitoring laboratory services are available.

Intensity and Duration of Therapy and Adjustment of Dose

Recommended Intensity of Therapy

After the initiation of therapy, the dose should be adjusted to maintain the therapeutic range. Extensive study supports the use of lower ranges of anticoagulation intensity (INR target range of 2.0 to 3.0) for most groups of patients. Efficacy is maintained while the risk for hemorrhagic complications is reduced. Only those patients at highest risk for thromboembolism (e.g., mechanical prosthetic heart valves) should receive high-intensity anticoagulation (INR range of 2.5 to 3.5). Low-intensity therapy (INR target of 1.5 to 2.0) has been tried for deep vein thrombosis (DVT) but has been proved to be less effective and no safer than standard-intensity therapy (see Chapter 35).

Adjustment of Dose

There is wide variability in patient response to warfarin, determined in part by genetic variants of the hepatic microsomal enzyme CYP2C9, which is the principal enzyme responsible for warfarin metabolism. Genetic variants have been identified (e.g., CYP2C9*2 and CYP2C9*3) that are associated with increased risks of overanticoagulation and bleeding; however, these mutations appear to be rare. More commonly, differences in the warfarin target gene, which encodes for the vitamin K epoxide reductase complex 1 (VKORC1) appear to predict response to warfarin therapy. Whether gene typing will become a routine part of warfarin therapy remains to be established, but the mechanisms for personal differences in response to warfarin are becoming much better understood and underscore the need for dose adjustment. Cost-effectiveness study does not find warfarin genotyping worthwhile for typical nonvalvular AF patients, but suggests that it might be for patients at high risk of bleeding.

The warfarin dose can be adjusted in numerous ways when the INR is out of range. One method designed to maximize safety and avoid wide swings in the INR is based on making 10% changes in the weekly dose unless the INR is grossly out of range. For example, if the patient is taking 7.5 mg/d, the weekly dose is 52.5 mg. If the INR is too low, the weekly dose is increased by 10%, so the patient takes 10 mg on 2 days of the week and 7.5 mg on the other 5 days. The INR is then measured weekly for the next 2 weeks, with continued adjustment in dose if necessary.

Outpatient anticoagulation requires facilities for accurate INR measurement and reliable collection of blood samples and the ability to contact patients promptly. Careful monitoring and follow-up are essential for a safe and successful outpatient anticoagulation program. At the beginning of therapy, patients should attend an educational session with a nurse who can instruct them in the use of warfarin, answer questions, test their understanding, and provide informative booklets for them to take home. Patients who fail to keep an appointment for an INR test should be promptly contacted. A computer system can provide reminders so that no patient is lost to follow-up. Commercial laboratory services are sometimes used to draw samples at home for patients who have difficulty coming to the office. Home monitoring devices are another option for selective patients.

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