2. When, and at what dosage, should i initiate warfarin?
With a medically stable patient, you can start warfarin shortly after the first dose of LMWH or fondaparinux, and overlap both therapies for at least 5 days until the patient’s international normalized ratio (INR) is ≥2 for 24 hours. If the INR does not reach 2 within 5 days, LMWH or fondaparinux should be continued. The target INR for DVT is 2.5.
The initial dose of warfarin for most patients should be between 5 and 10 mg per day for the first 2 doses, with 10-mg doses reserved for younger patients without significant drug interactions or comorbidities.4 Consider a starting dose ≤5 mg in elderly patients, those with certain medical conditions (eg, liver disease or heart failure), and patients taking medications known to significantly inhibit warfarin metabolism.3,4TABLE 3 provides a suggested method for initiation of warfarin in ambulatory patients.
Continue warfarin for at least 3 months, and possibly longer, depending on the cause of DVT/PE and underlying or ongoing risk factors. Evaluate the risk vs benefit of continued therapy 3 months after the initial thromboembolic event. Patients with cancer, whose risk for VTE is greater, should receive LMWH for the first 3 to 6 months, followed by long-term therapy with warfarin or LMWH until the cancer is resolved.3,4
TABLE 3
Average warfarin daily dosing for INR goal 2-3
| Dosage change | Patients nonsensitive to warfarin | Patients sensitive to warfarin* | |
|---|---|---|---|
| Initial dose | 5 mg/d | 2.5 mg/d | |
| First INR | 3 days after initial dose | 3 days after initial dose | |
| <1.5 | Increase dose by 50% | 7.5 mg/d | 5 mg/d |
| 1.5-1.9 | Maintain current dose | 5 mg/d | 2.5 mg/d |
| 2-3 | Decrease dose by 50% | 2.5 mg/d | 1.25 mg/d |
| 3.1-4 | Decrease dose by ~75% | 1.25 mg/d | 0.5 mg/d |
| >4 | Hold dose | Hold | Hold |
| Next INR | 2-3 days | 2-3 days | |
| INR, international normalized ratio. | |||
| *Factors that influence sensitivity to warfarin include age >75 years, clinical congestive heart failure, diarrhea, drug interactions, elevated baseline INR, hyperthyroidism, malignancy, malnutrition, or nothing by mouth for >3 days. | |||
| Source: University of Washington Medical Center. Average daily dosing method. Available at: http://vte.son.washington.edu/docs/VTE_flexible_initiation.pdf. Accessed September 26, 2010. | |||
3. Is it time to customize anticoagulant therapy based on genetic testing?
No. Currently, FDA and ACCP guidelines do not recommend genetic testing before initiating warfarin.5,6 Theoretically, genetic testing should be helpful in predicting an individual’s optimal starting warfarin dose. At present, however, no good clinical data support this practice.5 If randomized trials show improved clinical outcomes with pharmacogenetic dosing of warfarin, genotyping may become part of clinical practice in the future.
An estimated one-third of patients on warfarin therapy may be at higher risk for adverse outcomes because they carry genes that make them more or less sensitive to warfarin.5 Variants of 2 genes—cytochrome P450 2C9 (CYP2C9) and the vitamin K oxide reductase complex 1 (VKORC1)—are thought to be responsible for this variance in warfarin response.5
Patients with variations of CYP2C9 may need lower starting doses of warfarin. Mutations in the VKORC1 gene affect the enzymes that activate vitamin K, which are the target for warfarin’s inhibitory effect on clotting. Mutations in this gene therefore result in varying sensitivities to warfarin and may be the cause of hereditary warfarin resistance in some individuals. Genetic variations in VKORC1 are estimated to occur in 14% to 37% of Caucasians and African Americans and may exist in as many as 89% of Asians.5 Several tests to detect some variants in these genes have been approved by the FDA.
In August 2007, a labeling change for Coumadin and its generics detailed the influence of gene variations on warfarin sensitivity.7 A report from the American Enterprise Institute-Brookings Joint Center for Regulatory Studies estimated that genetic testing could prevent 85,000 serious bleeding events and 17,000 strokes per year, resulting in a $1.1 billion reduction in warfarin-related health care spending. Costs of genetic testing for the 2 million Americans who begin warfarin therapy each year would be approximately $1 billion.6
4. Which warfarin–drug interactions are clinically important?
Drugs, supplements, and foods that potentiate or inhibit warfarin’s anticoagulant effect or increase the risk of bleeding are clinically important. The list of such interactions has been referred to as the 8 “As”: antibiotics, antifungals, antidepressants, antiplatelets, amiodarone, anti-inflammatories, high-dose acetaminophen, and alternative remedies.8 (For details on common warfarin interactions, see TABLE W1.)
These and other medications can affect how warfarin is absorbed, distributed, and metabolized. For example, sucralfate and bile-acid sequestrants such as cholestyramine can inhibit absorption. You can minimize this interaction by staggering the time each medication is ingested. Drugs that induce cytochrome P450 enzymes (eg, rifampin, carbamazepine) enhance warfarin clearance, while drugs that inhibit CYP enzymes (amiodarone or itraconazole) decrease warfarin clearance.2 Most clinically relevant interactions affect warfarin metabolism.