Warfarin, which has been in use for more than 50 years, has received considerable attention because of its common use for several indications and the link to adverse events, some lifethreatening, which require close monitoring of the international normalized ratio (INR). The drug is undoubtedly effective, but has a narrow therapeutic index. In a 12-month observational study of 25 nursing homes, one sixth of the approximate 3000 residents received warfarin, which resulted in 720 adverse events1; many of the events were preventable, raising safety concerns.1
Warfarin use is on the increase and with it a higher prevalence of bleeding events, which prompted the addition of a "black box" warning by the US Food and Drug Administration (FDA).2 The Joint Commission National Patient Safety Goals requirements for 2008 have stated in goal 3E, "the need to reduce the likelihood of patient harm associated with the use of anticoagulant therapy"3; thus hospitals and long-term care institutions have to develop performance improvement processes to ensure the safe use of warfarin.
Pharmacokinetics and Pharmacodynamics
Warfarin is a racemic mixture of 2 isomers, R and S forms, in equal proportion.4 Anticoagulants of the coumarin type, such as warfarin, act by blocking the conversion of inactive vitamin K to the reduced state, a requirement to form procoagulant factors II, VII, IX, and X. Besides vitamin K–dependent clotting factors, warfarin inhibits endogenous anticoagulant proteins C and S.5 Half-lives of clotting factors vary considerably, the shortest being factor VII and the longest being factor II.
Warfarin has a narrow therapeutic index, with unpredictable and variable pharmacokinetics influenced by genetic, disease, and environmental factors. It is 99% protein-bound; variations in albumin level, particularly declines after illness, result in lower dose requirements. An exaggerated response in older patients may be caused by reduced clearance of the drug.4 Warfarin has both anticoagulant and antithrombotic effects. Anticoagulant activity results from clearance of clotting factors, the earliest being factor VII (with shortest half-life of 6 hours) manifested in the INR within 24 to 36 hours; antithrombotic effects occur by 5 days of therapy, due to clearance of factor II (prothrombin, half-life 50+ hours) (Table 1).4,5
Bleeding is the well-recognized side effect, with consequences relating to extent of bleed and location. The likelihood of bleeding increases with intensity of anticoagulation. A less-recognized and rare but bothersome side effect is skin necrosis, seen within a few days of therapy. Necrosis occurs in the extremities, penis, or the breasts, and results from a rapid drop in protein C (or with inherited protein C or S deficiency), causing thrombosis of the microvasculature. Rarely encountered is a painful blue discoloration of the toes (purple toe syndrome) attributed to cholesterol emboli from plaques.
For decades, anticoagulant effects of warfarin were monitored by measuring prothrombin time (PT) to assess decline in activity of clotting factors II, VII, and X. However, the test was fraught with variations in thromboplastin sensitivities, leading to dosing irregularities and confusion in prescribing warfarin.
The introduction of INR as the guide for anticoagulation allows comparison of test results from different laboratories and standardized therapeutic ranges. INR targets are individualized to risk and indication for anticoagulation. However, INR lacks validity during the induction and withdrawal phases of warfarin therapy.4-5 The use of PT is no longer considered safe or acceptable.
The typical initial dose of warfarin is 5 mg, followed by a maintenance dose of 2 to 5 mg/day. In the elderly, it is important to use a low loading dose; the target INR is often achieved with a smaller maintenance dose.6 Prescribers need to resist starting with higher loading doses of warfarin because not all coagulation factors inhibited by warfarin decline at the same time; factor II, with the longest half-life, drops last. Also, during induction, proteins C and S, both with anticoagulant properties, get depressed earlier, resulting in a potentially hypercoagulable situation for a brief period. Hence, heparin is added when immediate anticoagulation is required and the INR is not at therapeutic levels.6,7 Use of higher initial doses of warfarin can lead to bleeding and clotting complications.
Typical maintenance is best managed with 1 generic or brand-name preparation; switching from one to the other may lead to variations in bioavailability, which requires more frequent monitoring.8 Observations suggest it may be better to use a single tablet strength (eg, 2-mg tablet) and titrate the number of tablets daily or weekly rather than provide new prescriptions for every INR alteration.5
Periodically one encounters hereditary resistance, where patients require large doses of warfarin, up to 20 mg daily, to achieve adequate anticoagulant effect. This is possibly due to a decline in affinity of warfarin to receptors in the liver.4 In contrast, 10% of patients require smaller-than-usual doses and have greater bleeding tendencies; they inherit variant alleles of the cytochrome (CY) P450 system that cause failure of conversion of S warfarin to metabolites.4 Pharmacodynamic effects of warfarin are explained by genetic polymorphisms in the 2C9 isoform of CYP450 (CYP2C9) and vitamin K epoxide reductase (VKORC1); combined with factors such as age, sex, height, weight, and smoking status, they account for more than half the variance in warfarin dose.
Pharmacogenetic tests to guide clinical utility can help predict dosing of warfarin,9,10 but are not currently used. Initial variations in the INR with warfarin use were more strongly linked to the VKORC1 haplotype than the CYP2C9 genotype.11 However, in a randomized controlled study, pharmacogenetic-guided and standard dosing did not differ for out-of-range INRs in patients initiated with warfarin therapy.12
In August 2007, the FDA revised the prescribing information for warfarin, "to explain that people's genetic makeup may influence how they respond to the drug."10 The FDA noted that the variability in a patient's response to the drug depends on genetic variations, hence the need for genetic testing before the initiation of warfarin therapy. This labeling change, according to the FDA, would allow physicians to ensure that the initial dosing is not too large and therefore does not increase the risk for bleeding.10 Despite the FDA ruling, most health plans still do not cover genetic testing for this purpose. A recent prospective study provides further evidence in favor of genetic testing.9,13
Indications and Contraindications
A MEDLINE literature review indicates that physicians' fears of bleeding from anticoagulants are unfounded14; anticoagulant therapy is underused for stroke prophylaxis, especially in patients with atrial fibrillation (AF). Long-term warfarin use for most causes of AF is effective in significantly decreasing stroke risk, and has a low risk of intracranial bleeding.7,15 Between 1995 and 2002, trends in anticoagulation for AF have been on the rise, although many patients at risk for thromboembolic events were not anticoagulated.15,16
Warfarin (or heparin) is indicated as prophylaxis of deep-vein thrombosis in settings of restricted mobility or high-risk situations—the perioperative period (in particular orthopedic knee and hip surgery), heart failure, a history of cerebrovascular event (nonhemorrhagic, unrelated to AF), and any other hypercoagulable state. In such high-risk situations, INR is targeted to the 2 to 3 range. The presence of a mechanical prosthetic valve, depending on the type, location (mitral or aortic), and associated risk factors, will require longterm anticoagulation, with a target INR range of 2 to 3.5; with bioprosthetic valves, the presence of other risk factors dictates long-term use.4
The disadvantages of warfarin therapy include cost of testing, inconvenience from regular INR monitoring, and most important, bleeding complications. Unlike bleeding into the skin or from the gums that may be without consequence, intracranial and gastrointestinal (GI) bleeding can be life-threatening and is a basis for physician reluctance to prescribe longterm anticoagulants.14,16
Risk factors and contraindications are not universally accepted and are well-reviewed in a systematic literature search.14 Predisposition to falls and the presence of dementia are not contraindications; in a study of a longterm care resident with dementia and AF predisposed to falls, most physicians surveyed believed anticoagulation was contraindicated.14,16 Patients with mild-to-moderate dementia can use anticoagulants if supervised.
Contraindications include hazardous or sports activities associated with the risk of head trauma, noncompliance and refusal to follow regular monitoring, and excessive alcohol consumption. Current bleeding is a contraindication, but a healed peptic ulcer is not.
Control of blood pressure above 160/90 mm Hg is suggested before initiating warfarin therapy.14,17 Past GI bleeding is a risk factor for bleeding with warfarin.17 Concomitant use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs) or selective cyclooxygenase-2 inhibitors incur similar increased risk of hospitalization for upper-GI hemorrhage.18 Increasing age and intensity of anticoagulation (INR >4) are risks. Patient (caregiver) and provider preferences may influence decisions on anticoagulation.14,16 Older adults may not need closer monitoring than younger adults.19
Warfarin use is complicated by interactions with drugs, nutrients, and herbals, which potentiate or inhibit the anticoagulant effect. The mechanisms for interaction vary considerably (Table 2). Cephalosporins inhibit cyclic interconversion of vitamin K4; thyroxine enhances metabolism of clotting factors; and the mechanism involving clofibrate is unclear. Aspirin and NSAIDs inhibit platelet function, increase the prothrombin time, and augment the pharmacodynamic effect of warfarin.4,18 Sulfa and several antibiotics deplete the gut of bacterial flora and worsen vitamin K status.20 Amiodarone causes dose- and concentration-dependent inhibition of warfarin elimination. 21 Alcohol interactions are variable; acute alcoholism may inhibit warfarin metabolism, increasing the INR; long-term use may induce liver enzymes and lower the INR; further liver disease increases sensitivity to warfarin.5
Adding antiplatelet agents (clopidogrel and acetylsalicylic acid) to warfarin increases GI-bleeding risk beyond the risk with each drug alone.22 Co administration of warfarin and aspirin increases bleeding risk, but this combination increases the benefits for patients with acute coronary syndrome, a coronary stent, or a mechanical valve.23
Acetaminophen, perceived as the safest analgesic in the elderly, is an underrecognized cause of anticoagulant instability24; it slows the degradation of warfarin through the CYP450 system, increasing the active (free) fraction.
Use of complementary and alternative medicine with warfarin risks a supratherapeutic INR and bleeding events25; cranberry juice has low-level interaction potential26; oral corticosteroids can have a significant interaction.27
The effect of statins is inconsistent, requiring further evaluation.28 Clinically significant alterations in coagulation have not been observed with the influenza, pneumococcal, or tetanus vaccines.29
Patient Education, Monitoring
Every patient (or caregiver if the patient is incapacitated) should be counseled on the proper use of warfarin. Instructions should include an understanding of the interactions with warfarin. This can be simplified by the "3 Ds" mnemonic—Diet, Drug, Disease.30 Patients should be instructed to review any drug changes with their primary physician, including herbal and over-the-counter medications. Most dietary supplements affect the INR. Change in health status (even just fever) and hospitalization calls for frequent monitoring; any newly introduced medications (eg, antibiotics and analgesics) will cause changes in the INR. In addition, illness such as liver disease, malabsorption, or thyroid dysfunction cause alterations in requirement of warfarin and INR results.30 The physician should be contacted for any signs of bleeding or before switching from a branded to a generic product, or vice versa. Patients should also minimize hazardous activities prone to injury.
It is most important not to tell patients to avoid vitamin K–rich foods (spinach, greens, broccoli, and lettuce) but rather to keep dietary content consistent, avoiding indulgence. When the INR is not at target, management is focused on the INR and potential bleeding. The severity and site of bleeding may demand prompt attention. For high INR, decreasing or skipping 1 or 2 doses will usually suffice and the regimen is reevaluated; increasing the dose may be warranted for subtherapeutic INR. When vitamin K is required to counter warfarin effects, oral formulations are more predictable and effective than subcutaneous31; the intravenous (IV) slow infusion is used in the presence of bleeding relating to high INR. It is also necessary to search for the reason the INR is not at target, such as a compliance issue, an illness, or a change in diet or medication.4,6 Table 3 outlines a practical approach to the use of warfarin.
The Perioperative Period
Most patients can undergo dental procedures, cataract surgery, and endoscopy without biopsy, avoiding alterations in the warfarin regimen, although decisions should be individualized.32 For invasive or major procedures, warfarin must be withheld, and a decision must be made on the requirement for "bridging" therapy with IV or subcutaneous unfractionated heparin or low-molecular-weight heparin.4,32 The decision incorporates the indications for anticoagulation, risks and benefits of withholding warfarin, and the surgeon's preferences as well.
In high-risk situations, such as AF in valvular heart disease, previous stroke, or a mechanical prosthetic valve, it is prudent to stop warfarin 4 to 5 days before the procedure and use bridge therapy.4 Bridging anticoagulation may be considered for patients at high risk for thromboembolism.33
Although pharmacogenetic testing has the potential to allow for safer prescribing of warfarin, the FDA has not provided clear guidelines, which would encourage coverage by health plans. Patient self-testing to monitor the INR or self-management of anticoagulation instead of monitoring in the clinic has the potential to ease the burden on patients, improve control, and cut the costs associated with long-term oral anticoagulation.
The 2008 National Patient Safety Goals promote specific improvements in patient safety, such as improving the safety of using medications and reducing the likelihood of harm associated with the use of anticoagulant therapy, including warfarin, by providing healthcare organizations with proved solutions to patient safety problems; these goals apply to more than 15,000 Joint Commission–accredited and certified healthcare organizations and programs. By consistently meeting these goals, healthcare organizations can substantially improve patient safety and quality of care and reduce costs.
- Gurwitz JH, Field TS, Radford MKJ, et al. The safety of warfarin therapy in the nursing home setting. Am J Med. 2007;120:539-544.
- Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use. Arch Intern Med. 2007;167:1414-1419.
- The Joint Commission. Facts about the 2008 National Patient Safety Goals. http://www.jointcommission.org/PatientSafety/NationalPatientSafetyGoals/08_npsg_facts.htm. Accessed July 7, 2008.
- Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation. 2003;107:1692-1711.
- Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician. 1999;59:635-646.
- American Geriatrics Society Clinical Practice Committee. The use of oral anticoagulants (warfarin) in older people. American Geriatrics Society guideline. J Am Geriatr Soc. 2002;50:1439-1445.
- Fuster V, Cannom DS, Ellenbogen K, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol. 2006;48:854-906.
- Wittkowsky AK. Generic warfarin: implications for patient care. Pharmacotherapy. 1997;17:640-643.
- Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. June 23, 2008 [Epub ahead of print].
- US Food and Drug Administration. FDA approves updated warfarin (Coumadin) prescribing information. August 16, 2008. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed July 7, 2008.
- Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358:999-1008.
- Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided and standard dosing in patients initiating oral anticoagulation. Circulation. 2007;116:2563-2570.
- Flockhart DA, O'Kane D, Williams MS, et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008;10:139-150.
- Man-Son-Hing M, Laupacts A. Anticoagulant-related bleeding in older persons with atrial fibrillation. Arch Intern Med. 2003;163:1580-1586.
- Rowan SB, Bailey DN, Bublitz CE, et al. Trends in anticoagulation for atrial fibrillation in the U.S. J Am Coll Cardiol. 2007;49:1561-1565.
- Dharmarajan TS, Varma S, Norkus EP. To anticoagulate or not to anticoagulate? A common dilemma for the provider: physicians' opinion poll based on a case study of an older long-term care facility resident with dementia and atrial fibrillation. J Am Med Dir Assoc. 2006;7:23-28.
- Levine MN, Raskon G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1 suppl):108S-121S.
- Battistella M, Mamdami MM, Juurlink DN, et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165:189-192.
- Abdelhafiz AH, Wheeldon NM. Risk factors for bleeding during anticoagulation of atrial fibrillation in older and younger patients in clinical practice. Am J Geriatr Pharmacother. 2008;6:1-11.
- Glasheen JJ, Fugit RV, Prochazka AV. The risk of over-anticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20:653-656.
- Almog S, Shafran N, Halkin H, et al. Mechanism of warfarin potentiation by amiodarone: dose and concentration dependent inhibition of warfarin elimination. Eur J Clin Pharmacol. 1985;28:257-261.
- Delaney JA, Opatrny L, Brophy JM, et al. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ. 2007;177:347-351.
- Madhwal S, Lincoff AM, Rolston DDK. Should patients on longterm warfarin take aspirin for heart disease? Clev Clin J Med. 2008;75:206-208.
- Dharmarajan L, Sajjad W. Potentially lethal acetaminophen-warfarin interaction in an older adult: an under-recognized phenomenon? J Am Med Dir Assoc. 2007;8:545-547.
- Shalansky S, Lynd L, Richardson K, et al. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy. 2007;27:1237-1247.
- Pham DQ, Pham AQ. Interaction potential between cranberry juice and warfarin. Am J Health Syst Pharm. 2007;64:490-494.
- Hazlewood KA, Fugate SE, Harrison DL. Effect of oral corticosteroids on warfarin therapy. Ann Pharmacother. 2006;40:2101-2106.
- Douketis JD, Melo M, Bell CM, et al. Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin? Am J Med. 2007;120:369.e9-369.e14.
- Jackson ML, Nelson JC, Chen RT, et al. Vaccines and changes in coagulation parameters in adults on chronic warfarin therapy: a cohort study. Pharmacoepidemiol Drug Saf. 2007;16:790-796.
- Beier MT. Warfarin monitoring: consider the three Ds. J Am Med Dir Assoc. 2005;6:76.
- Crowther MA, Douketis JD, Schnurr T. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized controlled trial. Ann Intern Med. 2002;137:251-254.
- Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003;163:901-908.
- Wysokinski WE, McBane RD, Daniels PR, et al. Peri-procedural anticoagulation management of patients with nonvalvular atrial fibrillation. Mayo Clin Proc. 2008;83:639-645.