P&T News: June 1998

Avoid Drug Misadventures In Warfarin Therapy

Jane Blayney Chandramouli, Pharm.D. and Linda M. Schrand, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Steven Lentz, M.D., Associate Professor, Division of Hematology/Oncology, Department of Internal Medicine

Medication mishaps with warfarin are particularly problematic since the clinical ramifications can range from hemorrhagic events to stroke or thromboembolic episodes.

The incidence of complications cited in the literature following the initiation of warfarin therapy varies according to the setting of care and the length of therapy. A 28-month study by Gitter et all found that a population-based cohort of patients receiving routine medical care had incidence rates per patient-year of 8.1% for major hemorrhagic events and 3.2% for major thromboembolic occurrences. In another study by Cannegieter et al,2 1,608 mechanical heart valve patients (6,475 patient years) who were receiving coordinated anticoagulation care reported incident rates per patient-year as low as 2.68% for hemorrhagic complications and 0.71% for thromboembolism. Being aware of the risk factors (Table 1) and providing comprehensive education to the patient so that he/she will be aware of the dangers, as well as the benefits, of warfarin therapy will help minimize the frequency of adverse events.

Table 1. Risk Factors for Warfarin-Induced Adverse Drug Reactions 1,3-5

Many risk factors have been postulated to increase the incidence of bleeding while on warfarin therapy. These include:

Age 65 or more years: as age increases, risk of bleeding increases (becomes more significant at 75 years and older) Uncontrolled hypertension Prior history of cerebrovascular accident due to a bleed Higher intensity INR or unstable INR Malignancies Newly started on warfarin (first month after initiation of warfarin therapy) History of gastrointestinal bleeding Serious co-morbid condition (risk for both drug-disease and drug-drug interactions) For example, in severe congestive heart failure warfarin doses may need to be reduced when failure worsens and increased when failure improves.

Importance of Maintaining the Narrow Therapeutic Window
The importance of close therapeutic monitoring of patients receiving warfarin therapy cannot be overemphasized. The INR must be kept high enough to avoid thrombotic events, yet low enough to prevent major hemorrhage. A study by Hylek et a16 illustrates the danger of ischemic stroke in warfarin patients with non-rheumatic atrial fibrillation who have an INR less than 2. After having adjusted for other independent risk factors, the study found that a fall in INR from 2.0 to 1.7 doubled the odds of having a stroke. The results are depicted in Figure 1.

Studies2, 3, 5, 7 have evaluated the risks of higher intensity anticoagulation as well. Among the many possible bleeding 7 complications, intracranial hemorrhage carries the greatest risk. In another study by Hylek et al , the correlation of INR and intracranial hemorrhage (without head trauma) was evaluated. The results showed that the odds for subdural hemorrhage increased 7.6-fold as INR rose from 4 to 6.8 (Figure 2); for intracerebral hemorrhage, the risk rose 4-fold for each unit increase in the prothrombin time ratio.

Patient Education
The narrow therapeutic index and the many risk factors that can affect the careful management of patients taking warfarin create a challenge for all healthcare professionals. Physicians, nurses, and pharmacists are just a few of the many healthcare providers warfarin patients see on a regular basis throughout the course of their therapy. It is important that each patient receive consistent messages from all providers regarding safe and effective use of warfarin. Through consistent education and support, patients and caregivers will be more empowered to take an active role in preventing adverse drug reactions associated with warfarin therapy.

Since close monitoring and patient compliance are important to assure safe treatment with warfarin therapy, it is critical to invest the time needed to provide extensive education to patients and/or caregivers about warfarin therapy. The patient should understand the indication for anticoagulation, including the need for strict compliance with prescribed doses, and the expected duration of treatment. Figure 3 depicts a sample patient education guide for the use of warfarin. In addition, the following components of warfarin therapy should be addressed:

• Medication Identification: ensure the patient can identify his/her warfarin tablet, particularly the color and the number on the tablet that designates the milligram amount.
• Stick with Same Brand: generic warfarin is now available; it is not recommended to switch back and forth between products from different companies. Generic products do not have the same shape or markings as the Coumadin[R] brand of warfarin.
• Missed Warfarin Dose: if a dose is missed and remembered later the same day, the patient should be advised to take his/her dose at that time. If the patient has missed a dose and does not remember until the next day, do not advise the patient to double up the dose. Emphasize to the patient not to self-adjust doses. The use of a "pill box" may increase compliance.
• Alcohol Consumption: if the patient has previously been told by the physician to abstain from alcohol, that message should be reinforced. If the patient has never been instructed to avoid alcohol, two drinks/day is a reasonable limit. If the patient overindulges he/she may fall, develop gastritis, or forget to take the medication. Additionally, acute binges can raise INR. Chronic alcohol ingestion may decrease INR.
• Management of Dietary Interactions and Vitamin K: dietary consistency is the key to maintaining a sustained, stable response during warfarin therapy. Patients should be aware of vitamin K content in common foods, particularly foods high in vitamin K (green leafy vegetables, legumes, mayonnaise, canola and soybean oils), and should maintain a consistent amount of these foods in their diet. Also, changing from a diet of solid foods to an enteral liquid supplement or consuming foods rich in vitamin K for a prolonged period may lead to acquired warfarin resistance.
• Natural Coumarins/ Herbal Medications: tonka beans, sweet woodruff, and melilot are natural sources of coumarins commonly found in herbal teas. Other common herbal products that may affect INR include feverfew, garlic, and ginseng. Therefore, these herbal medications should either be avoided or used consistently while on warfarin therapy.
• Antibiotics: many serious problems with over- or under-anticoagulation can occur when patients are started on antibiotics that interact with warfarin. The most common antibiotics which interact with warfarin include: co-trimoxazole, erythromycin, fluoroquinolones, metronidazole, antifungals, isoniazid, rifampin, and nafcillin.
• Over-the-Counter (OTC) Medications: patients should be told to avoid aspirin unless prescribed by their doctor. Many OTC products may affect INR or increase risk of bleeding. These include but are not limited to: Pepto-Bismol", Alka-Seltzer[R], Tagamet HBO, Motrin", Aleve[R], Orudis KT[R], Advil", and multiple vitamins (which often contain vitamin K).
• Review Signs and Symptoms of Over-Anticoagulation: excessive nosebleeds, dark urine, bleeding gums, excessive bruising, coffee ground emesis, bleeding when brushing your teeth, more bleeding than usual during your menstrual period or unexpected menstrual bleeding, etc. The patient should be instructed to contact their prescriber if any of these symptoms occur.
• Review Signs and Symptoms of Thrombotic Events: difficulty breathing, chest pain, leg pain, dizziness, etc. The patient should be instructed to immediately contact their prescriber if any of these symptoms occur.
• Review Precautionary Measures to Prevent Injuries and Bleeding: safe stairways, safety railings, mat in bathtub or shower, immovable rugs, flat smooth carpets, stable furniture, watch for pets underfoot, use of night lights, etc.

Figure 3. Sample Patient Guide For The Use Of Warfarin

You are taking a potent medication that can prevent your body from making blood clots that you do not need and that may travel through your body to cause a heart attack or stroke. The name of this medication is warfarin, also known as Coumadin[R]. Although this medication can help prevent medical emergencies, it can also cause medical emergencies if not monitored correctly. If the medication works too well to prevent unwanted clots, it may also prevent needed clots. For example, if you cut yourself you may not be able to stop the bleeding. These medical emergencies can be avoided if you, your family and all your healthcare providers know what to do and what not to do. Your blood clotting ability will be checked fairly often (up to several times per week) at the beginning of your therapy until the time it takes your blood to clot has become stable. This test is called a protime or INR. If your clotting time falls above or below the target goal for your condition, the doctor will want to adjust your dose until the target goal is reached. Once the INR is stable, the tests to check your blood clotting ability will occur less often (about every 4 weeks). It is important to take each dose regularly and at the same time each day. If you miss a dose, do not double up your dose the next day to make up for the missed dose. Keep a record of missed doses and report them to your physician at your next visit. There are a lot of things in your everyday life that can affect your INR. Even something as basic as food that is rich in vitamin K can cause your INR to change. The most important thing is to keep your everyday routine fairly constant. Starting or stopping a diet or a medication should be discussed with your healthcare provider so that your clotting times during the change can be carefully monitored. Even herbal products or teas can sometimes cause your INR to go higher or lower than your target goal. To avoid any medical emergencies, you need to know the signs of bleeding problems. These signs include: bleeding when you brush your teeth more bleeding than usual during your menstrual period or unexpected menstrual bleeding urine that is dark brown or red red or black in your stool unusual bruising vomiting, coughing or throwing up blood diarrhea infection pain or swelling headache, dizziness, trouble breathing, chest pain, or you feel weak or more tired than usual Always inform all of your healthcare providers (physicians, nurses, pharmacists, dentists, chiropractors, etc.) that you are taking warfarin. Warfarin interacts with many medications -- both over-the-counter and prescription. Always ask your doctor or pharmacist before you self-treat any condition.

Resources Available at UIHC for Teaching Patients About Warfarin
Acting on the recommendation of the Pharmacy and Therapeutics Subcommittee, instructional materials and services (Table 2) have been compiled so that all patients newly discharged on warfarin can receive consistent education. Counseling performed by inpatient pharmacists will be documented by a pre-printed "sticker" that has been signed and dated and placed on the B-1b form in the patient's medical record. Counseling provided by ambulatory care clinical pharmacists is documented on the B-1b Clinical Notes "Nonscheduled Consultation" form.

Table 2. Educational Resources Available at the UIHC

Resources Available From the Department of Pharmaceutical Care Coumadin[R] video (approximately 10 minutes in length; will be available in the future on the hospital's closed circuit television channel) Using Coumadin[R] at Home flip chart Packets for the patient to take home that consist of a booklet entitled A Patient's Guide to Using Coumadin[R] (which includes a patient wallet card), a dosage calendar, a sheet entitled A Patient's Guide to Vitamin K, a one-page Brief Patient Guide to Coumadin[R] Therapy, and a brochure for ordering a MedicAlert[R] bracelet Ambulatory care clinical pharmacists are available in Internal Medicine's Continuity of Care clinic A patient pocketcard for use in the ambulatory care clinics A UIHC healthcare provider pocketcard entitled Guide to Warfarin Therapy in Adult Patients Resources Available From the Department of Nursing Services A folder that contains the booklet entitled A Patient's Guide to Using Coumadin[R] (which includes a patient wallet card) and patient education material from the Micromedex computer program as well as a 10-minute Coumadin[R] video are available en A packet for the patient to take home that consists of the booklet entitled A Patient's Guide to Using Coumadin[R], a dosage calendar, a sheet entitled A Patient's Guide to Vitamin K, a one-page Brief Patient Guide to Coumadin Therapy, a brochure for ordering a MedicAlert bracelet, and a one-page handout on anticoagulation and antiplatelet therapy is available. These resources can be obtained from the nursing staff for patients receiving warfarin on these units Resources Available From the Department of Food and Nutrition Services Dietary consults (informal service) Lists of foods high in vitamin K to aid the patient in maintaining a consistent diet

Drug Interactions
An important monitoring issue is anticipation of drug interactions, especially if multiple healthcare providers are involved in the patient's care. Since warfarin has a narrow therapeutic window, relatively small increases or decreases in the intensity of anticoagulation can lead to an increased risk of bleeding or an inadequate therapeutic effect. The complex variables associated with warfarin therapy often make the degree or direction of interference with the anticoagulant effect of warfarin unpredictable. The variables include individual differences in response to warfarin, multiple mechanisms for some drug interactions, simultaneous administration of several interacting drugs, drug dosages used, and sequence and duration of drug administration.

Warfarin has several properties that predispose it to drug interactions. It undergoes oxidative metabolism in the liver, a process that may be impaired by a variety of inhibitors or enzyme inducers. In general, drug interactions with warfarin are characterized as being pharmacokinetic or pharmacodynamic in nature. Examples of pharmacokinetic interactions include gastrointestinal absorption interactions, plasma protein binding interactions, enzyme induction and enzyme inhibition interactions. Pharmacodynamic mechanisms include those in which the effect. of warfarin is altered at the receptor site and often involve additive or antagonistic pharmacologic effects.8 Table 3 lists examples of various types of pharmacokinetic and pharmacodynamic drug interactions. Table 4 lists the most common drug-drug interactions that involve warfarin. This list is not all inclusive; please consult the pharmacist in your area to verity any additional drug interactions.

Table 3. Pharmacokinetic and Pharmacodynamic Drug Interactions with Warfarin

Pharmacokinetic Drug Interactions

Reduced absorption (e.g. cholestyramine, sucralfate) Displacement from plasma protein binding (e.g., salsalate, NSAIDs) Alterations in metabolism via induction of the P-450 enzyme system (e.g., rifampin, nafcillin, barbiturates) Stereoselective inhibition of S-warfarin (e.g., metronidazole, sulfonamides) Stereoselective inhibition of R-warfarin (e.g., cimetidine, omeprazole, erythromycin, ticlopidine) Nonstereoselective alterations in warfarin metabolism (e.g., azole antifungals, amiodarone, HMG-CoA reductase inhibitors)

Pharmacodynamic Drug Interactions

Drug syndegism (e.g., NSAIDs, salicylates, thyroid hormones) Drug antagonism (e.g., vitamin K, propylthiouracil, methimazole)

Table 4. Management of Common Warfarin Drug Interactions8-11
Drugs that Increase Risk of Bleeding when Used with Warfarin
Aspirin Nonsteroidal anti-inflammatory drugs Antiplatelet agents: ticlopidine, clopidogrel Anticoagulants: heparin, low molecular weight heparins Bismuth subsalicylates (more than 2 g/day)
Drugs Which May Potentiate the Effect of Warfarin and Increases INR
Major Effect	Moderate Effect	Mild Effect
Avoid combination or reduce dose of warfarin	Requires increased monitoring + dose adjustment	Routine monitoring, with possible dosage adjustment
Amiodarone Anabolic steroids Cimetidine Clarithromycin Clofibrate Co-trimoxazole Disulfiram Erythromycin Fluconazole Metronidazole Miconazole Phenylbutazone Sulfinpyrazone Sulfonamides	Acetaminophen (more than 1.3 g/day) Cisapride Fluoroquinolones (e.g., ciprofloxacin) Fluoxetine/Fluvoxamine Fluorouracil Isoniazid Itraconazole Omeprazole Propafenone Propoxyphene Quinidine Tamoxifen Tetracycline Thyroid hormones	Acarbose Allopurinol Chloral hydrate Disopyramide Ifosfamide HMG-CoA reductase inhibitors Metolazone Moricizine Nalidixic acid Propranolol Theophylline Tricyclic antidepressants
Drugs Which May Inhibit the Effect of Warfarin and Lowers INR
Major Effect	Moderate Effect	Mild Effect
Avoid combination or increase dose of warfarin	Requires increased monitoring + dose adjustment	Routine monitoring, with possible dosage adjustment
Aminoglutethimide Barbiturates (e.g., phenobarbital) Carbamazepine Cholestyramine Griseofulvin Nafcillin Rifampin	Azathioprine Cyclosporine Dicloxacillin Etretinate Methimazole Phenytoin* Propylthiouracil	Chlordiazepoxide Sucralfate Trazodone
____ *Initiation of phenytoin may transiently increase INR. This is followed within 1 to 2 weeks by a decrease in INR.

The concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin is discouraged because of the increased risk for bleeding in these patients. Some NSAIDs enhance the hypoprothrombinemic effect of warfarin by displacing warfarin from plasma binding sites or by inhibiting the hepatic metabolism of warfarin. Furthermore, most NSAIDs can prolong bleeding time by inhibiting platelet function. NSAIDs can also cause gastrointestinal erosions and/or bleeding, which can lead to GI bleeding. The net effect is an increased risk of hemorrhage. The incidence of hospitalizations for hemorrhagic peptic ulcers in patients 65 years or older taking both warfarin and NSAIDs other than aspirin has been reported to be 26.3 per 1000 person years, about 13 times that of patients not taking either drug. 12 NSAIDs which have been associated with bleeding in conjunction with warfarin include diflunisal, ibuprofen, indomethacin, ketorolac, mefenamic acid, phenylbutazone, piroxicam, sulindac, and tolmetin. In healthy subjects aspirin in larger doses (2 to 4 g/d) potentiates the anticoagulant effect of warfarin and increases the risk of bleeding in a dose-dependent manner. In patients with prosthetic heart valves, concomitant use of warfarin (INR 3.0 to 4.5) and low-dose aspirin 100 mg/d increases the risk of both minor and major bleeding episodes. If necessary, NSAIDs should be given in lower dosages where feasible and introduced slowly in patients receiving warfarin therapy. INR should be monitored closely, especially during the first two weeks of therapy. Patients should be monitored closely for any bleeding complications.

Nonacetylated salicylates (e.g., magnesium salicylate, salsalate, and choline salicylate) do not have antiplatelet activity and may cause less GI erosion and bleeding. However, these agents are highly protein bound and may displace warfarin, potentiating an increased INR. These agents may be preferred in some cases where an NSAID is indicated (e.g., arthritis pain); however, patients must be carefully instructed to watch for signs and symptoms of bleeding.

Initiation of Warfarin Therapy
The final consideration in preventing warfarin-related adverse drug reactions is to minimize inappropriate dosing. As noted previously, patients within the first month of warfarin therapy are at high risk for adverse drug reactions. Fihn et al noted that patients had an almost two-fold increased risk of bleeding within three months of initiation of therapy (relative risk 1.9). 13

Table 5. Identifying Desired INR Range* for Patients on Warfarin Therapy
Indication	INR**	Duration**
Venous Thromboembolism (VTE)
Prophylaxis	2.0 to 3.0	3 months or younger or until ambulatory
Treatment Reversible Risk Factor Spontaneous Life Threatening History of recurrent VTE	2.0 to 3.0	3 to 6 months 12 months to indefinite indefinite 12 months to indefinite
Prevention of Systemic Embolism
Chronic atrial fibrillation	2.0 to 3.0	indefinite
Acute myocardial infarction***	2.0 to 3.0	3 months or younger
Cardiomyopathy	2.0 to 3.0	indefinite
Recurrent systemic embolism	2.0 to 3.0	indefinite
Tissue cardiac valve prosthesis	2.0 to 3.0	3 months
Rheumatic mitral valve disease	2.0 to 3.0	indefinite
Mechanical cardiac valve	2.5 to 3.5	indefinite
*Adapted from Chest 1995, 108(suppl 4):225s-522s. **INR or length of therapy may vary depending on clinical presentation and presence or absence of thrombophilia (e.g., antithrombin III deficiency, factor V Leiden, protein C or protein S deficiencies; or anticardiolipin antibody syndrome). ***If warfarin is selected to prevent recurrent myocardial infarction, an INR of 2.5 to 3.5 is recommended.

When warfarin therapy is warranted and a goal INR has been established (Table 5), the following points regarding dosing should be considered. First, establish a patient baseline. This would include a history including prior bleeding and bleeding tendencies, a physical examination, a baseline measurement of PT/INR, and a complete blood count. Second, individualize the dose and avoid a loading dose; start with the expected maintenance dose. Lower maintenance doses should be considered for elderly patients, those in malnourished states or with other reasons for vitamin K depletion, and those with liver disease or serious co-morbid conditions. Third, make few dosage changes and recognize that peak anticoagulant effect of a new dose may be delayed 72 to 96 hours. It will take approximately 10 to 14 days for the M to stabilize at any given dose. Dosage regimen should be kept as simple as possible, with the fewest number of different strength tablets as possible. Warfarin dosage adjustments should be limited to 5 to 20% of total weekly dosage since there is a nonlinear relationship between warfarin dose and pharmacodynamic response. Since it takes at least three days for the effect of a change in dosage to be reflected in the INR, the minimum time to schedule a PUM test is approximately three days after therapy has been adjusted and should occur no later than two weeks. However, a hospitalized patient just initiated on warfarin therapy may require more frequent monitoring. Once a patient is stabilized on therapy, INR should be monitored once every 2 to 6 weeks. INR monitoring may be needed more frequently with changes in concomitant medications or disease states, or for less compliant patients who frequently change their diet and lifestyles or who do not take their medication as prescribed. Table 6 summarizes these key points for managing warfarin therapy.

Table 6. Practical Management of Warfarin Therapy 5

Establish a patient baseline: obtain INR/PT and check CBC. Individualize dose and avoid loading doses. Consider lower doses for patients who are elderly, malnourished, have liver disease, have serious co- morbid conditions, or take interacting medications. Make few dosage changes; peak effect of a new dose may be delayed 72 to 96 hours. Monitor INR regularly. Keep dosage regimen as simple as possible. Educate the patient.

Warfarin therapy should not be initiated with loading doses, as once recommended, since this has been shown to be associated with a high risk of early hemorrhage and false sense of full anticoagulation in early treatment. During the first 48 hours of treatment, the anticoagulant effect of warfarin is mainly caused by a reduction in the. activity of Factor VII, which has a half-life of 6 hours. In contrast, the antithrombotic effect of warfarin (which is thought to be primarily caused by a reduction in the activity of Factor II) is delayed for as long as 60 hours. In addition, because the half-life of protein C is similar to that of Factor VII, the early anticoagulant effect of warfarin (which results from a reduction of Factor VII) could be counteracted by a procoagulant effect which results from a reduction of protein C. Thus, a large loading dose of warfarin, profoundly reduces the level of Factor VU, but does not result in more rapid anticoagulation. 14,15

Summary
Warfarin is frequently utilized for a variety of conditions requiring anticoagulation. Complications of warfarin therapy can be minimized with patient education, avoiding loading doses, reliable monitoring, and appreciation of its pharmacologic properties and drug interactions. A uniform multidisciplinary approach to patient counseling will improve patient knowledge and hopefully translate into improved patient outcomes.

References
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9. Drug Interaction Facts. Facts and Comparisons. St Louis, MO, 1998.
10. Evaluation of Drug Interactions. First Databank. St. Louis, MO, 1997.
11. Warfarin Drug Monograph. Micromedex 1998.
12. Ann Pharmacother. 1995:29:1274-83.
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