Dosing
Key Points:
- Patients receiving warfarin for the first time should begin at the patient's estimated average daily dose (typically 5 mg/day; range 2.5 to 7.5 mg/day), with a recheck of INR in two to three doses.
- Steady-state INR values will not be realized for up to three weeks following a dose adjustment.
Testing must be completed and results reviewed before initiation of warfarin:
- Complete blood count (CBC)
- Platelet count
- PT/INR
- Activated partial thromboplastin time (aPTT)
- Creatinine
Obtain if there is clinical suspicion of abnormal results based on patient history and physical:
- Liver enzymes (alanine transaminase [ALT], aspartate transaminase [AST], gamma-glutamyl transferase [GGT])
- Albumin
General Principles of Warfarin Dosing
Loading doses and rapid induction of warfarin should be avoided. Warfarin (irrespective of INR) is not fully effective in the first several days of therapy because of a delayed decrease in several circulating clotting factors. Loading doses can increase a patient's risk of supratherapeutic INR and make it more difficult to determine a steady-state dose.
See "Patient Related Factors" under Annotation #3"Adverse Effect" for a discussion of the updated labeling for warfarin.
Patients at high risk of thrombosis, such as those with an active thrombotic process (e.g., venous thromboembolism [VTE]) or an underlying malignancy, should be treated with concomitant immediate-acting anticoagulant (UFH, LMWH, fondaparinux, DTIs) and warfarin therapy. Patients at lower thrombotic risk (e.g., atrial fibrillation without recurrent thromboembolism) can be initiated on warfarin alone.
A single target INR value should be used as a goal endpoint. This will decrease the odds of a patient being above or below desirable range of INR. The target INR for most conditions is 2.5 with an acceptable range of 2.0 to 3.0. Other thrombotic conditions (e.g., mitral mechanical valves) have recommended targets of 3.0 (range 2.5 to 3.5). A table of recommended therapeutic ranges for oral anticoagulant therapy is available in Annotation #8, "Recommended Therapeutic Range for Oral Anticoagulation Therapy" in the original guideline document. Also, individual disease management guidelines such as Atrial Fibrillation and Venous Thromboembolism give specific INR recommendations.
The risk of bleeding for patients on warfarin increases substantially at INR values greater than 4.0. This risk is magnified if one or more risk factors are present. Consider hemorrhagic risk in all dosing decisions. Please refer to Appendix A, "Risk Factors for Bleeding During Warfarin Therapy," of the original guideline document for more information on risk factors for bleeding during warfarin therapy.
There is a significant increase in thromboembolism as INR values decrease below INR 1.7. Clinical risk and past medical history should be considered in all dosing decisions. Higher risk may require more aggressive dosing.
In most cases, holding warfarin for 4 days prior to surgery results in an INR value of 1.2 or less. Expect advanced age and drug interactions to result in a slower decline. Patients with high risk of thromboembolism may need coverage with heparin for a portion of this time. For more information, see Annotation #65, "Anticoagulation Bridging."
Some equivalency studies have shown that substitution of generic warfarin for brand name Coumadin® may provide equivalent anticoagulation response if the manufacturer of the generic warfarin has followed the standards set for the name brand. Care must be taken to remain with either the brand name product or the same generic product. Do not switch from brand to generic or between generics.
Prescription and over-the-counter medications can adversely affect the INR response to warfarin. Dietary supplements including herbal or natural remedies can change the INR response to warfarin and/or increase a patient's risk of bleeding. In these instances, additional monitoring may be needed. See Appendices B, "Drug Interactions with Warfarin" and C, "Endogenous Interactions with Warfarin" in the original guideline document for more information on drug interactions with warfarin.
Mechanism of drug-drug interactions occur commonly by the cytochrome P450 enzyme metabolizing system. Metabolism of the object or substrate medication may either be induced or inhibited by the interacting drug. Induction will result in a diminished pharmacodynamic response, while inhibition will result in an increased pharmacodynamic response.
Foods that contain moderate amounts of vitamin K may decrease the INR response to warfarin. Patients should be encouraged to not change their diet while taking warfarin and not change the amount of foods containing vitamin K they normally eat each day. See Annotation #10, "Key Patient Education Components" for a guide to educating patients regarding warfarin therapy.
Direct thrombin inhibitors (hirudin, argatroban, bivalirudin) and heparins can affect the INR. See Annotations #35-44, "Direct Thrombin Inhibitors" for more information.
Evidence supporting this recommendation is of classes: A, B, D, R
Initiation of Warfarin
Average Daily Dosing Technique (for patients not on heparin)
Average daily dosing technique is useful for patients off UFH and LMWH.
A baseline INR value may be drawn to rule out underlying coagulopathy.
Patients previously taking warfarin can be initiated at the previous dose.
Patients receiving warfarin for the first time should begin at an average dose of 5 mg daily with a recheck of INR in two to three doses. Lower initiation doses should be considered for patients with any of the following factors: age greater than 75 years, multiple comorbid conditions, poor nutrition (low albumin), elevated INR when off warfarin, elevated liver function tests, or changing thyroid status. For patients who weigh more than 80 kg, a higher estimated average initial dose of 7.5 mg may be given. Higher initial dosing nomograms have not shown consistent benefit. Loading doses can increase a patient's risk of supratherapeutic INR and make it more difficult to determine a steady-state dose.
See "Patient Related Factors" under Annotation #3"Adverse Effect" for a discussion of the updated labeling for warfarin.
If the INR is 2.0 or greater after the first 3 doses, consider decreasing the dose by one-half. Always search for causes of rapid rise in INR such as poor nutritional status, infection, or systemic disease process. See Appendix C in the original guideline document for more information on endogenous interactions with warfarin.
Subsequent INR values are determined at two to three times weekly for one to two weeks, then less often depending on the stability of the INR result.
Steady state anticoagulation occurs between 6 to 12 days. Expect obese patients and patients of advanced age to take longer to reach steady state.
Evidence supporting this recommendation is of classes: A, B, D, R
Flexible Daily Dosing Technique (for patients on heparin)
The flexible daily dosing technique is useful for patients on concomitant UFH or a LMWH.
A baseline INR value may be drawn to rule out underlying coagulopathy.
Patients are given daily doses of warfarin, adjusted according to the daily INR, until a weekly dose can be determined.
The dose-response relationship is best interpreted when there are at least 16 hours between dose and laboratory draw.
Evidence supporting this recommendation is of class: D
Maintenance Dosing of Warfarin
An assessment of clinical variables known to affect the INR (including a change of patient adherence, change of other medications [e.g., amiodarone], change of food or alcohol consumption, change of activity level) should be made with each dose adjustment. Always search for the cause of out-of-range values and address them before adjusting the dose.
Expect a 15% dose adjustment to result in an approximately 1.0 INR change. Likewise, a 10% dose adjustment will result in an approximate 0.7 to 0.8 INR change.
Steady-state INR values will not be realized for up to 3 weeks following a dose adjustment.
Patients with INR values by + 0.5 INR out-of-range should be considered for more frequent monitoring and should have a repeat INR within seven days.
If two consecutive weekly INR values are within range and there has not been a change in clinical variables known to effect the INR, the interval between draws may be gradually increased to monthly, and not more than 6 weeks.
Options for Dosing and Management
Anticoagulation clinics have been shown to significantly reduce patients' risks of adverse events.
Though traditionally, warfarin has been monitored at a central laboratory and managed by the patient's physician, new monitoring and management options have emerged.
Anticoagulation clinics staffed by pharmacists/registered nurses (RNs) have been shown to significantly reduce patients' risks of adverse events.
Computer-assisted dosing has been slow to develop, but may someday improve the quality of anticoagulation adjustments and offer superior management for difficult or high-risk patients.
Selected point-of-care instruments have received FDA approval for patient self-testing.
While some patients may prefer self-management, clinical experience, reimbursement, and research are insufficient to support widespread implementation of patient self-management. Further research is needed to better identify appropriate candidates for self-management, and to delineate the key components of education and support.
Evidence supporting this recommendation is of classes: A, B, C, D, R