An algorithm for managing warfarin resistance - ccjm

1 REVIEW. CME EDUCATIONAL OBJECTIVE: Readers will recognize and appropriately manage warfarin resistance in patients CREDIT who need higher-than-expected doses of this drug Olusegun Osinbowale, MD, MBA, RPVI Monzr Al Malki, MD Andrew Schade, MD, PhD John R. Bartholomew, MD. Department of Cardiology, Section of Noninvasive Biotherapeutics Department Labora- Division of Pathology and Laboratory Department of Cardiovascular Cardiology, Ochsner Clinic Foundation, New Orleans, LA tory, Division of Surgical Research, Medicine, Department of Clinical Medicine, Head, Section of Vascular Boston University School of Medicine, Pathology, Cleveland Clinic Medicine, Cleveland Clinic Roger Williams Medical Center, Providence, RI. An algorithm for managing warfarin resistance Abstract Some patients need higher-than-expected doses of W arfarin (coumadin) differs from most other drugs in that the dosage required to achieve a desired therapeutic effect varies warfarin (Coumadin) to get their international normal- greatly among individuals.

2 This variability can ized ratio (INR) into the therapeutic range. The cause lead to therapeutic failure, potentially resulting of warfarin resistance can be either acquired (eg, poor in new thrombosis, or, at the other extreme, to compliance, drug interactions, dietary interactions) or life-threatening bleeding. Further, there is no reliable means to iden- hereditary, but the genetic mechanisms of warfarin tify patients who require unusually high doses resistance are not well understood. This review offers an of warfarin , although genetic testing may be- algorithm for the evaluation of patients with suspected come available in the future. warfarin resistance . Key Points See related patient information at The most common cause of warfarin resistance is non- compliance. Others include poor absorption, high vitamin K intake, hypersensitivity to vitamin K, and rapid drug warfarin , a coumarin derivative first syn- deactivation.

3 Thesized in 1948, is still the only oral anticoag- ulant available for long-term use in the United States. Indications for its use include the treat- Patient education is necessary to improve compliance ment and, to a lesser extent, the prevention and to mitigate adverse effects of warfarin therapy, of arterial and venous thromboembolism. It regardless of the dose. is also used for long-term anticoagulation in patients with atrial arrhythmias (atrial fibril- In time, it may be possible to individualize anticoagulant lation and atrial flutter) and mechanical heart dosing on the basis of genetic testing for patients with valves. warfarin resistance , although currently such tests are not In the paragraphs that follow, we review routinely advocated and are usually done only in special- the causes of warfarin resistance and how to recognize and manage it. ized laboratories. WHAT IS warfarin resistance ?

4 In true hereditary warfarin resistance , there are two approaches to treatment: increase the warfarin dosage resistance to warfarin has been described (perhaps to as high as 100 mg/day or more), or switch to as the inability to prolong the prothrom- another anticoagulant. bin time or raise the international normal- ized ratio (INR) into the therapeutic range when the drug is given at normally pre- scribed However, a higher warfarin requirement 724 C L E V E L A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 7 6 N U M B E R 1 2 D E C E M B E R 2 0 0 9. Downloaded from on September 17, 2022. For personal use only. All other uses require permission. Osinbowale and Colleagues warfarin is metabolized by P450 enzymes warfarin is a racemic mixture of R- and S- is affected by the dose, by CYP2C9-mediated enantiomers (mirror-image isomers), which metabolism of the S-enantiomer, by elimina- differ in their potency and ,6 The tion of hydroxyl metabolites, by gastrointes- left-handed S-enantiomer is three to five times tinal absorption (diminished by diarrhea or as potent as the right-handed R-enantiomer.)

5 Vomiting), by non-CYP2C9 metabolism, by the However, warfarin is hepatically metabo- patient's nutritional state and diet, and by drug lized by the cytochrome P450 complex, and although the S-isomer is more potent, the warfarin is rapidly absorbed from the gastro- R-isomer has a longer half-life. This is because intestinal tract after oral administration, with a S- warfarin is metabolized faster (via 7-hydroxy- bioavailability of 100%,10,11 and its peak absorp- lation by CYP2C9) than R- warfarin (which is tion is usually seen within 60 to 90 minutes. metabolized via 10-hydroxylation by CYP1A1, It can also be given intravenously and sublin- CYP1A2, and CYP3A4).7 Effectively, S-warfa- gually. rin accounts for 60% to 70% of the overall an- warfarin is highly (97% 99%) bound to ticoagulation response, while the R-enantiomer plasma proteins, primarily to albumin, with a is responsible for approximately 30% to 40%.

6 8 volume of distribution of to Its The steady-state concentration of warfarin mean half-life is 44 hours (range 20 60). does not itself establish the diagnosis of war- WHAT CAUSES warfarin resistance ? farin resistance . The prevalence of warfarin resistance varies by patient population and warfarin resistance can be classified in prac- is difficult to determine. The difficulty lies tical terms as acquired vs hereditary, or in largely in accounting for dietary factors and in mechanistic terms as pharmacokinetic vs defining normal metabolic variations among pharmacodynamic. Patients individuals. needing The range of normally recommended daily Acquired vs hereditary resistance or weekly warfarin doses to maintain a thera- Hulse4 categorizes warfarin resistance as either > 15 mg/day peutic prothrombin time or INR depends on acquired or hereditary. should be the study population. Nevertheless, patients Acquired resistance to warfarin may result who need more than 105 mg per week (15 mg/ from: considered day) should be considered warfarin -resistant.

7 Poor patient compliance (the most com- warfarin - These patients are likely to be in the top 5% mon cause) resistant for warfarin doses within an anticoagulated High consumption of vitamin K. cohort. Decreased absorption of warfarin warfarin resistance is different than war- Increased clearance (see warfarin is metabo- farin failure, which is defined as a new throm- lized by P450 enzymes on this page ). 5 11. botic event despite a therapeutic prothrombin Drug interactions (TABLE 1). 12,13. time and INR. This situation is commonly Hereditary resistance has been postulated seen in patients with malignant diseases. to be caused by genetic factors that result ei- An important characteristic of warfarin ther in faster metabolism of the drug (a form of resistance is that patients need much smaller pharmacokinetic resistance ) or in lower activ- doses of vitamin K to reverse the effect of war- ity of the drug (pharmacodynamic resistance ).

8 Thijssen3 showed that, in warfarin -resis- Polymorphisms may play a role, as some VKO- tant rats, warfarin did not irreversibly inhibit RC1 and CYP2C9 variant alleles are known vitamin K1 2,3-epoxide reductase (VKORC1) to be associated with increased sensitivity to activity. This is consistent with the vitamin K hypersensitivity observed in warfarin -resistant However, the genetic mechanisms of war- ,3 farin resistance are not clearly understood, C L E V E L A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 7 6 N U M B E R 1 2 D E C E M B E R 2 0 0 9 725. Downloaded from on September 17, 2022. For personal use only. All other uses require permission. warfarin resistance despite several case reports of hereditary re- TABLE 1. sistance confirmed by similar patterns of resis- tance in immediate family 19 More Drugs and supplements that than one mechanism is likely.

9 There is ample potentiate or inhibit warfarin room for further insight into genetic polymor- phisms underlying hereditary warfarin resis- Potentiate warfarin tance. More on this topic is included in the Acetaminophen (Tylenol). sections below. Alcohol Allopurinol (Zyloprim). Amiodarone (Cordarone). Pharmacokinetic resistance Amoxicillin-clavulanate (Augmentin). Pharmacokinetic resistance can result from di- Aspirin minished absorption or increased elimination Celecoxib (Celebrex). of the drug. Causes of diminished absorption Ciprofloxacin (Cipro). include emesis, diarrhea, and malabsorption Erythromycin syndrome. Fenofibrate (Tricor). The mechanism of increased warfarin Fluconazole (Diflucan). clearance has not been delineated, although Fluvastatin (Lescol). the following have been implicated. Garlic Genetic factors. Duplication or multipli- Gingko cation of cytochrome P450 enzyme genes has Levofloxacin (Levaquin).

10 Levothyroxine (Synthroid). been described as contributing to a phenotype Nonsteroidal anti-inflammatory drugs of ultrarapid metabolism. Some people may Omeprazole (Prilosec). carry multiple copies of the CYP2C9 gene, Paclitaxel (Taxol). as has already been reported for cytochrome Propafenone (Rythmol). P450 CYP2D6 and ,8 It is also plau- Ritonavir (Norvir). sible that rare allelic variants of CYP2C9 exist Tramadol (Ultram). that are associated with higher-than-normal Trimethoprim-sulfamethoxazole (Bactrim). warfarin - activity, given that there are alleles known to Vitamin E. resistant predispose to warfarin sensitivity. Hypoalbuminemia may increase the free Inhibit warfarin patients need fraction of warfarin , leading to enhanced rates Azathioprine (Imuran). Barbiturates much smaller of clearance and a shorter plasma Bosentan (Tracleer). Hyperalbuminemia may paradoxically also doses of contribute to warfarin resistance via drug bind- Carbamazepine (Tegretol).