Practical Challenges in the Management of Oral Anticoagulation

Steven R. Kayser, PharmD

Disclosures

Prog Cardiovasc Nurs. 2005;20(2):80-85. 

In This Article

Initiation of Therapy

Many factors influence initiation of therapy with warfarin besides dosage selection. For example, when should warfarin be initiated in the hospital setting? When should warfarin therapy be "bridged" with heparin therapy? And if heparin is indicated, which form of heparin (unfractionated vs. low-molecular weight [LMW] heparin) should be utilized? How long should heparin be bridged? And what specific characteristics of a patient will be helpful in determining the dose?

The decision to use warfarin should always include an in-depth evaluation of the risks and benefits associated with its use. It qualifies as one of those drugs that is associated with very few adverse reactions (the good news), but the one adverse effect that it does have is bleeding (the bad news). Warfarin can decrease the relative risk of a stroke associated with atrial fibrillation (AF) by up to 47%-86% with an annual bleeding risk of 2%-4% when the international normalized ratio (INR) is maintained within a range of 2-3.[3] Observations from studies evaluating rate vs. rhythm control for the management of AF have confirmed the need for and efficacy of anticoagulation in both cases.[4]

If a patient has unacceptable risk factors for bleeding, is at risk for falls, has memory defects, or is unable to comply with follow-up clinic attendance, other agents, e.g., antiplatelet drugs, should be considered as an alternative. Warfarin does not require initiation in the hospital in every case, although all cases of acute thrombosis should be evaluated in the hospital or emergency department and considered for acute therapy with heparin. Stable patients with AF can be started as outpatients on warfarin alone.[3] If a patient has multiple risk factors or a demonstrated clot by transesophageal echocardiogram and requires acute anticoagulation, heparin should be the initial therapy with warfarin started simultaneously due to the delay in the onset of action of warfarin. In some patients, LMW heparins can be used for "bridging" patients until the warfarin effect is achieved. This can be accomplished outside the hospital. The decision to use LMW heparin on an outpatient basis is influenced by the stability of the patient, the indication for therapy, the patient's renal function, and the ability to self-inject or arrange administration of subcutaneous injections. LMW heparins should generally be avoided in patients with a creatinine clearance <30 mL/min. Laboratory management should include periodic platelet counts and complete blood counts. Routine coagulation tests (prothrombin time [PT]/INR, activated partial thromboplastin time [APTT]) are not useful. Anti-factor Xa levels can be used but are only necessary in patients who require long-term therapy with LMW heparins (more than 10 days), who weigh >150 kg, or have a history of recurrent thrombosis. The overall general principles are similar to those for the management of patients who require interruption of long-term oral anticoagulation therapy.[5]

There has been some concern with starting warfarin without concomitant heparin. This is due to the fact that two vitamin K dependent factors, protein C and protein S, are natural anticoagulants and they have very short half-lives of about 7 hours. If these factors are depressed to significant levels before there is an opportunity for factor IX, X, and eventually II (prothrombin) to become depressed, there is at least a theoretical chance for additional clotting to occur. Heparin, since it works quickly, can prevent this if it is started before the warfarin. Actual cases of acute depression of protein C and S leading to clotting are rare and are usually associated with the administration of large doses of warfarin, as was popular many years ago with "warfarin loading." With smaller initial and maintenance doses of warfarin (≈5 mg or less), it is unlikely for this to occur.[6]

Selection of the dose is influenced by numerous factors ( Table I ). Among the factors that have an impact are age,[7,8] ethnicity,[8] concomitant medications, comorbid conditions, diet,[9] and, to a lesser extent, weight.[8] The elderly require smaller doses of warfarin independent of other conditions. In a recent review of our anticoagulant clinic population, the average dose decreased in a linear fashion by 44% from the fourth to the ninth decade of life. Ethnicity has been observed to impact the maintenance dose and also the selection of the initial dose. Asians require 50% of the weekly dose of warfarin compared with Caucasians; African Americans required 30% more on a weekly basis. The impact of this is significant since the starting dose should be the same as the maintenance dose, and selection of too large a starting dose may lead to an increased likelihood of bleeding at a time when the risks of bleeding are already increased.

Concomitant medications are extremely important determinants of dose. Today we must also consider the impact of nontraditional or herbal medications in addition to prescribed and over-the-counter medications. There are lists of drugs that have been observed to interact with warfarin. It is important to check these whenever warfarin is prescribed, but it is also equally important to evaluate their significance, as well as their onset and extent of interaction. For example, amiodarone is commonly used for control of AF, either as a component of rate or rhythm management. It significantly interacts with warfarin, requiring up to a 50% reduction in the warfarin dose. Since the interaction may not occur immediately, but rather may be delayed for 1 week or more, failure to recognize and to monitor for the increase in INR may lead to hemorrhage. The statins which are being prescribed with increasing frequency have been reported to interact with warfarin, but actual reports and documentation for this interaction are relatively few. This should not be interpreted as lack of significance, and doses of warfarin are not usually automatically decreased, as they might be with amiodarone. Interactions of warfarin with anti-infective agents represent a class of medications that are some of the most difficult to predict. We know that some—for example, trimethoprim-sulfamethoxazole and erythromycin—are very likely to increase warfarin effect, while others may not demonstrate a direct drug interaction. Since fever may be a component of the infection, this may result in a change in response independent of the drug. The fact that a drug is not reported to interfere is no guarantee that the response to warfarin may not be influenced. Herbal and nontraditional medications are some of the most difficult to deal with since there is very poor documentation for most of these, or only isolated case reports that do not always exclude other potential confounders.[10] Close surveillance is the most important principle, and whenever a new medication is introduced into the regimen of a patient on warfarin, more frequent INR monitoring is a good idea.

Comorbid conditions can also have an impact on warfarin sensitivity and dosage selection. Congestive heart failure that is uncontrolled may lead to hepatic congestion and an independent elevation of the INR. In these patients, there is a "relative" clotting factor deficiency and the dose of warfarin may need to be decreased. Intrinsic liver disease with loss of synthetic function also presents with clotting factor deficiency. Since it is likely to progress, anticoagulation therapy requires very serious evaluation of risk vs. benefit. Nutritional deprivation with vitamin K deficiency may also lead to increased warfarin sensitivity. Any patient with a baseline elevated INR will be more sensitive to warfarin. The presence of active clotting (e.g., deep-venous thrombosis or pulmonary embolism) may increase warfarin dose requirements.

Since warfarin works by interfering with vitamin K carboxylation of precursor clotting proteins, increased or decreased dietary vitamin K intake may influence warfarin dosage requirements. Because of the multiplicity of factors that may influence warfarin, it is sometimes difficult to identify diet as the cause of an altered INR. If a patient maintains a stable diet, even if it does contain food with vitamin K, there may not be a significant difference in warfarin dose requirement. Certain foods containing large amounts of vitamin K—for example, brussel sprouts—may predictably decrease warfarin effect. The best recommendation is for patients to maintain a stable diet, not day-to-day, but rather weekly, and not to exclusively avoid vitamin K-containing foods. Of greater significance is a diet that completely excludes vitamin K—such as a liquid diet, or a weight-reduction diet that does not contain a well balanced selection of foods. If patients develop gastroenteritis, especially with a fever that persists for over 24-36 hours, they should be instructed to seek advice and have their INR followed closely since vitamin K absorption will very likely be compromised.

With each increase of 10 kg in weight, the dose requirement of warfarin was observed to increase by 1 mg per week in our clinic population. Although this did achieve clinical significance, it may be of relatively little clinical significance unless there are other conditions that result in a very low weekly dose requirement.

When warfarin therapy is started, the initial dose should rarely exceed 5 mg and, in many cases, should be less.[11,12,13] Attempts to accelerate the onset with doses greater than this, especially by 10 mg, often result in overshoot of the INR. At least one report suggested that starting with 10 mg was better than 5 mg, but this does not apply to most patients, and the risk of exceeding the desired therapeutic range is too great. Dosing guidelines and dosing cards, which can be made available to practitioners, may be helpful in assuring safe therapy.

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