An algorithm for managing warfarin resistance
ABSTRACTSome patients need higher-than-expected doses of warfarin (Coumadin) to get their international normalized ratio (INR) into the therapeutic range. The cause of warfarin resistance can be either acquired (eg, poor compliance, drug interactions, dietary interactions) or hereditary, but the genetic mechanisms of warfarin resistance are not well understood. This review offers an algorithm for the evaluation of patients with suspected warfarin resistance.
KEY POINTS
- The most common cause of warfarin resistance is noncompliance. Others include poor absorption, high vitamin K intake, hypersensitivity to vitamin K, and rapid drug deactivation.
- Patient education is necessary to improve compliance and to mitigate adverse effects of warfarin therapy, regardless of the dose.
- In time, it may be possible to individualize anticoagulant dosing on the basis of genetic testing for patients with warfarin resistance, although currently such tests are not routinely advocated and are usually done only in specialized laboratories.
- In true hereditary warfarin resistance, there are two approaches to treatment: increase the warfarin dosage (perhaps to as high as 100 mg/day or more), or switch to another anticoagulant.
DIAGNOSIS BY HISTORY AND LABORATORY STUDIES
A full drug and diet history is invaluable in diagnosing potential causes of warfarin resistance (Table 1).
Plasma warfarin levels that are subtherapeutic should raise suspicion of intestinal malabsorption or poor compliance. Poor compliance might be more appropriately seen as a mimic of warfarin resistance. Studies in humans suggest that a therapeutic total plasma warfarin level lies between 0.5 μg/mL and 3.0 μg/mL,10 though the range may vary among laboratories and patient populations.
Warfarin absorption and clearance can be evaluated by analyzing plasma levels at specific intervals after administration, eg, every 60 to 180 minutes. The drug’s half-life can be determined on the basis of its concentrations in different time samples. Normally, the S-enantiomer of warfarin is cleared at twice the rate of the R-enantiomer (5.2 vs 2.5 mL/min/70 kg).8 A normal clearance rate confirms that resistance to warfarin is not due to enhanced elimination.
Clotting assays of factors II, VII, IX, and X may be a more precise way to assess the pharmacodynamics of warfarin,10 although there is no strong evidence to support routine use of such assays. Some studies suggest targeting factor II and factor X activity levels of 10% to 30% of normal biologic activity for a therapeutic warfarin effect in patients with an unreliable or prolonged baseline prothrombin time and INR, such as those with lupus anticoagulant.
TREAT THE CAUSE
Once the type of warfarin resistance has been determined, treatment should be oriented toward the cause.
Educate the patient
The importance of compliance should be reinforced. Educating the patient about diet and other medications that may interact with warfarin is also important. (See an example of patient education material.)
Increase the warfarin dose
If the patient truly has hereditary resistance, there are two approaches to treatment.
The first is to increase the warfarin dose until the prothrombin time and INR are in the therapeutic ranges. When indicated, the warfarin dose can be safely titrated upward to more than 100 mg per day in patients who are monitored regularly—as all patients on chronic warfarin therapy should be—and whose other medications are otherwise stable. One such example is reported in a warfarinresistant patient who needed 145 mg/day to maintain a therapeutic prothrombin time.22
Try other anticoagulants?
The second approach is to change to another type of anticoagulant. However, there is no strong evidence in favor of this approach over prescribing larger dosages of warfarin.
Other anticoagulant drugs currently available in the United States include subcutaneous heparins (unfractionated and low-molecular-weight heparins) and the subcutaneous factor Xa inhibitor fondaparinux (Arixtra).
Agents not available in the United States include the following.
Dabigatran, an oral direct thrombin inhibitor, is undergoing phase 3 studies of its use for long-term anticoagulation.
Rivaroxaban (a direct factor Xa inhibitor) and dabigatran have been approved in Canada and the European Union to prevent venous thromboembolism after knee and hip arthroplasty, based on prospective comparisons with enoxaparin (Lovenox).34–37
Vitamin K antagonists other than warfarin that are not available in the United States include bishydroxycoumarin (which has limitations including slow absorption and high frequency of gastrointestinal side effects), phenprocoumon, and acenocoumarol. Another is phenindione, which has been associated with serious hypersensitivity reactions, some of which proved fatal and occurred within a few weeks of initiating therapy.
