Warfarin (coumadin) differs from most other drugs in that the dosage required to achieve a desired therapeutic effect varies greatly among individuals. This variability can lead to therapeutic failure, potentially resulting in new thrombosis, or, at the other extreme, to life-threatening bleeding.
Further, there is no reliable means to identify patients who require unusually high doses of warfarin, although genetic testing may become available in the future.
Warfarin, a coumarin derivative first synthesized in 1948, is still the only oral anticoagulant available for long-term use in the United States. Indications for its use include the treatment and, to a lesser extent, the prevention of arterial and venous thromboembolism. It is also used for long-term anticoagulation in patients with atrial arrhythmias (atrial fibrillation and atrial flutter) and mechanical heart valves.
In the paragraphs that follow, we review the causes of warfarin resistance and how to recognize and manage it.
WHAT IS WARFARIN RESISTANCE?
Resistance to warfarin has been described as the inability to prolong the prothrombin time or raise the international normalized ratio (INR) into the therapeutic range when the drug is given at normally prescribed doses.1
However, a higher warfarin requirement does not itself establish the diagnosis of warfarin resistance. The prevalence of warfarin resistance varies by patient population and is difficult to determine. The difficulty lies largely in accounting for dietary factors and in defining normal metabolic variations among individuals.
The range of normally recommended daily or weekly warfarin doses to maintain a therapeutic prothrombin time or INR depends on the study population. Nevertheless, patients who need more than 105 mg per week (15 mg/day) should be considered warfarin-resistant. These patients are likely to be in the top 5% for warfarin doses within an anticoagulated cohort.
Warfarin resistance is different than warfarin failure, which is defined as a new thrombotic event despite a therapeutic prothrombin time and INR. This situation is commonly seen in patients with malignant diseases.
An important characteristic of warfarin resistance is that patients need much smaller doses of vitamin K to reverse the effect of warfarin.2 Thijssen3 showed that, in warfarin-resistant rats, warfarin did not irreversibly inhibit vitamin K1 2,3-epoxide reductase (VKORC1) activity. This is consistent with the vitamin K hypersensitivity observed in warfarin-resistant people.2,3
WHAT CAUSES WARFARIN RESISTANCE?
Warfarin resistance can be classified in practical terms as acquired vs hereditary, or in mechanistic terms as pharmacokinetic vs pharmacodynamic.
Acquired vs hereditary resistance
Hulse4 categorizes warfarin resistance as either acquired or hereditary.
Acquired resistance to warfarin may result from:
- Poor patient compliance (the most common cause)
- High consumption of vitamin K
- Increased clearance (see Warfarin is metabolized by P450 enzymes5–11)
- Drug interactions (Table 1).12,13
Hereditary resistance has been postulated to be caused by genetic factors that result either in faster metabolism of the drug (a form of pharmacokinetic resistance) or in lower activity of the drug (pharmacodynamic resistance). Polymorphisms may play a role, as some VKORC1 and CYP2C9 variant alleles are known to be associated with increased sensitivity to warfarin.14
However, the genetic mechanisms of warfarin resistance are not clearly understood, despite several case reports of hereditary resistance confirmed by similar patterns of resistance in immediate family members.15–19 More than one mechanism is likely. There is ample room for further insight into genetic polymorphisms underlying hereditary warfarin resistance. More on this topic is included in the sections below.