Usually patients switch to warfarin when long term anticoagulant treatment is recommended. The two most serious side effects of anticoagulants are bleeding and gangrene necrosis of the skin. Bleeding can occur in any organ or tissue. Bleeding in the kidneys can cause severe back pain and blood in the urine.
Bleeding in the stomach can cause weakness, fainting, black stools, or vomiting of blood. Bleeding of the brain can cause severe headache and paralysis, and bleeding of the joints can cause joint pain and swelling. Other side effects can include rash, bloating, diarrhea, jaundice yellowing of the eyes and skin , hair loss, itchy feet, pain in the toes, and, in the case of heparin, mild pain, redness, or warmth at the injection site. Bleeding gums, excessive bruising, nosebleeds, heavy menstrual bleeding, and prolonged bleeding from cuts may indicate an overdosing of medication.
Notify your doctor if these problems occur. Some people receiving heparin have experienced a reaction to the infusion, so contact your doctor immediately if you experience any abrupt and serious side effects, such as sudden numbness, confusion, swelling, or trouble breathing.
While taking anticoagulants, you should avoid supplements with vitamin K. Remember that vitamin K controls the formation of proteins in your liver involved in clotting, so taking in vitamin K can work to counteract your medication and increase your risk of blood clots. In addition, you should avoid medications that can increase your risk of bleeding. Any antibiotic may change the Coumadin INR test.
If you must take an antibiotic, notify your Coumadin clinic so that they may schedule an additional INR check. In addition, be sure to speak with your doctor before starting any new medications. Your physician may also recommend that you carry some sort of identification to alert health professionals of your use of anticoagulants should an emergency or other situation arise.
All information contained within the Johns Hopkins Lupus Center website is intended for educational purposes only. It has been shown that in many cases, low-dose heparin is effective in the prevention of both venous thrombosis and pulmonary embolism.
Although monitoring the PTT may not prevent hemorrhage, it will help prevent further thrombosis. Heparin is generally continued for seven to ten days. However, the early changes in the INR are deceptive because they do not actually affect the body's physiologic ability to halt clot expansion or form new thromboses.
Antithrombotic Effect. The antithrombotic effect of warfarin, or the inability to expand or form clots, is not present until approximately the fifth day of therapy. This effect depends on the clearance of functional factor II prothrombin , which has a half-life of approximately 50 hours in patients with normal hepatic function.
The difference between the antithrombotic and anticoagulant effects of warfarin need to be understood and applied in clinical practice. Because antithrombotic effect depends on the clearance of prothrombin which may take up to five days , loading doses of warfarin are of limited value. Loading doses of warfarin i. The administration of loading doses is a possible source of prolonged hospitalization secondary to dramatic rises in INR that necessitate increased monitoring. The practice of using loading doses should be abandoned because it has no effect on the inhibition of thrombosis.
A potential paradoxic consequence of loading doses is the development of a hypercoagulable state because of a precipitous reduction in the concentration of protein C approximate half-life of eight hours during the first 36 hours of warfarin therapy. Consequently, the concurrent use of heparin is extremely important. The initial dose of warfarin should approximate the chronic maintenance dose that is anticipated. In most patients, the average maintenance dose is 4 to 6 mg per day.
Dose has an inverse relation with age. In patients 50 years old, the average daily dose is 6. Drug interactions discussed in detail in another section need to be considered when warfarin therapy is initiated. Other factors include the patient's nutritional status and gender. Patients who are malnourished should receive lower doses of warfarin because they probably have low vitamin K intake and decreased serum albumin concentrations.
Women generally require lower doses than men. Patients at highest risk for complications should probably be given a smaller initial dose 2 to 4 mg per day. This dose is then titrated to the lower end of a given therapeutic range, depending on the indication.
For example, the goal may be an INR of 2 to 2. Current recommendations for the initiation of warfarin therapy differ based on the urgency for achieving an anticoagulant effect. While warfarin is being initiated, patients who require rapid anticoagulation should also be given unfractionated heparin or low-molecular-weight heparin intravenously or subcutaneously in doses appropriate for the given indication. Heparin and warfarin therapies should overlap for approximately four to five days. The presence of a therapeutic INR does not confer protection from clot formation and expansion during the first few days of warfarin therapy because of the delay in the therapeutic inhibition of prothrombin.
Patients who rapidly achieve a therapeutic INR may metabolize warfarin slowly and thus may require lower maintenance doses.
The opposite holds for patients who tend to respond slowly to warfarin. A small decrease in the INR is expected to occur with the discontinuation of unfractionated heparin therapy.
Patients who require nonurgent anticoagulation, such as those with stable chronic atrial fibrillation, can be started on warfarin as out-patients, without the concomitant administration of heparin. The goal of maintenance therapy is to achieve a regimen that is simple yet provides therapeutic anticoagulation.
Currently, many physicians use drug regimens that appear simple but require differing tablet strengths. These regimens can be confusing to elderly patients who are taking several other medications concurrently and who may confuse tablet colors and strengths. Effective anticoagulation can be achieved using a single tablet strength and alternating fractions or multiples of that tablet on given days of the week rather than on odd or even days.
This approach is possible because of warfarin's long half-life. It is a safe and effective way to provide sufficient anticoagulation. Algorithms for establishing a percentage change in the weekly dosage to achieve an INR of 2 to 3 or 2. Only one tablet strength 5 mg is used. Fractions or multiples of the tablet can be used for different doses, or alternative doses can be given based on the day of the week.
Dose adjustments should be made based on the total weekly dosage, with increases or decreases of 10 to 20 percent spread out over the week. Algorithm for establishing a percentage change in the weekly warfarin dosage to achieve an INR of 2 to 3. Algorithm for establishing a percentage change in the weekly warfarin dosage to achieve an INR of 2.
Questions have recently been raised about the use of generic warfarin products. Compared with the brand drug—treated patients, the 15 patients who switched products had more dosage adjustments, one hospitalization for excessive anticoagulation and one emergency department visit for epistaxis.
None of the patients maintained on the brand drug required hospitalization or emergency medical care. Generic warfarin products and Coumadin have small pharmacokinetic differences in time to peak concentration, area under the curve, absorption rate constants, half-absorption time and tablet content uniformity.
As noted in the Boston City Hospital study, 19 the slight cost advantage of the generic product may be outweighed by increased monitoring costs, increased physician time and a possibly greater incidence of adverse events. If a generic warfarin product is started and then used exclusively in a patient, it is likely to be as safe as the brand drug.
The prothrombin time PT is the primary assay used in monitoring warfarin therapy. Changes in the PT noted in the first few days of warfarin therapy are primarily due to reductions in factors VII and IX, which have the shortest half-lives six and 24 hours, respectively.
The early changes in PT vary based on the responsiveness of the particular thromboplastin that a laboratory uses to perform the PT test. Because of the variations in thromboplastin sensitivity and the different ways of reporting PT, information about patients treated with oral anticoagulants was not interchangeable among laboratories until , when the World Health Organization Expert Committee on Biologic Standardization developed the INR. When a patient is started on an oral anticoagulant, INR monitoring should be performed on a daily basis until the INR is within the therapeutic range for at least two consecutive days.
Then INR monitoring should be performed two to three times a week for one to two weeks. If the patient remains stable, this interval can be widened to a monitoring frequency of once every four to six weeks. If dosage adjustments are necessary, INR monitoring should be performed more often until a new state of stability is achieved. Unexpected fluctuations of the INR in an otherwise stable patient should be investigated.
If none of these causes can be identified, laboratory error should be considered. When no cause for INR fluctuations can be determined, weekly dosage adjustment should be tried. The reduction or withholding of a single dose or an increase in that day's dose is often sufficient to restore a therapeutic INR in a patient who is otherwise medically stable. The most common complication of warfarin therapy is bleeding, which occurs in 6 to 39 percent of recipients annually.
With the reductions in anticoagulation intensity that have evolved over the past 20 years, the incidence of hemorrhagic complications has decreased dramatically. In patients receiving warfarin therapy, the median annual rate of major bleeding ranges from 0.
The incidence of complications varies within the ranges, depending on the clinical indication and the intensity of anticoagulation. Intracranial hemorrhage accounts for approximately 2 percent of the reported hemorrhagic complications of warfarin therapy and is associated with a mortality rate of 10 to 68 percent. Patient characteristics associated with a major risk of hemorrhage have been identified in a number of randomized studies Table 2.
Age greater than 65 years Age greater than 75 years with concomitant atrial fibrillation intracranial hemorrhage 24 , History of gastrointestinal bleeding Comorbid disease states Hypertension 20 , Cerebrovascular disease Serious heart disease 4 , Renal insufficiency Information from references 4 , 20 , and 23 through If bleeding occurs during warfarin therapy, the physician should immediately consider the severity of bleeding, the intensity of anticoagulation at the time of the bleeding episode and whether the patient has completed most of the prescribed course of therapy.
Recommendations for the reversal of high INR values in patients with or without bleeding are summarized in Figure 4. Algorithm for the management of an elevated INR in adult patients with or without bleeding. Warfarin resistance is common after the administration of large doses of vitamin K. If anticoagulation therapy must be continued, heparin therapy should be initiated until the effects of vitamin K have been reversed and the patient is again responsive to warfarin.
One of the physician's most difficult tasks is to decide whether the risk of anticoagulation outweighs the potential benefit of warfarin therapy in an elderly patient. One study 28 found that the risk of intracranial hemorrhage among the elderly is highest in patients with poor control large variations in INR , patients receiving high-intensity therapy INR greater than 4 and patients older than 80 years.
Another recent study 30 investigated the incidence of ischemic stroke in elderly patients with atrial fibrillation who were receiving anticoagulant therapy. This study found that subtherapeutic INRs i. For example, the relative risk of ischemic stroke is 3. The study findings suggest that tighter control of therapy at an INR range of 2 to 3 is superior to the use of lower levels of anticoagulation.
The study was discontinued after a mean follow-up period of 1. This reduction in events was associated with similar major bleeding rates 2. Interestingly, in the adjusted-dose group, the INR was greater than 3 in seven of the 12 major bleeding events. In determining whether to treat a patient with warfarin, one of the major concerns is the risk of potential drug interactions Table 3. In most instances, the interacting drugs either inhibit or induce warfarin metabolism.
These types of interactions are easily managed when the medications are for the treatment of chronic diseases. In such circumstances, close INR monitoring is required during the initiation or discontinuation of the medications.
Advise patient to limit total acetaminophen dosage to less than 2 g per day; if higher dosages are used, increased monitoring may be necessary. Decreases warfarin metabolism within a week of coadministration; effect may persist for 1 to 3 months after discontinuation of amiodarone May induce hypothyroidism or hyperthyroidism.
A 25 percent reduction in the warfarin dosage is recommended when amiodarone is initiated. Monitor INR closely when amiodarone is added or withdrawn.
Fluconazole Diflucan , ketoconazole Nizoral and miconazole Monistat decrease warfarin metabolism. Hyperthyroidism results in metabolism of vitamin K clotting factors and increased sensitivity to oral anticoagulants. Increase warfarin metabolism and frequently reduce hypoprothrombinemic effect of warfarin. Monitor INR when barbiturates are added or withdrawn; the addition of warfarin in patients stabilized on a chronic barbiturate regimen is of less significance.
Use colestipol Colestid , which has a lower potential for interaction, instead of cholestyramine Questran in patients who need a bile sequestrant. Increase warfarin doses when carbamazepine is added, and reduce doses when carbamazepine is discontinued stabilization occurs after 4 to 6 weeks.
Methylthiotetrazole ring in cefoperazone Cefobid , cefamandole Mandol , cefotetan Cefotan and cefmetazole Zefazone inhibits production of vitamin K—dependent clotting factors. Avoid concomitant use of warfarin and cefoperazone, cefamandole, cefotetan or cefmetazole. May increase clotting factor synthesis May inhibit oxidative metabolism. If possible, avoid oral contraceptives because of increased risk of thromboembolism Monitor INR frequently when oral contraceptives are used concurrently with warfarin.
Displaces warfarin from protein binding, inhibits platelet aggregation, causes gastric erosions. Acute ethanol use may inhibit anticoagulant metabolism. Chronic ethanol use induces liver enzymes. Cirrhosis is associated with reduced warfarin metabolism. Caution patients to drink in moderation and to avoid binge drinking. Because liver damage results in greater sensitivity to warfarin, use lower starting doses.
Note that lovastatin Mevacor is more commonly associated with hypoprothrombinemia. Displaces warfarin from protein-binding sites Inhibits warfarin metabolism. Avoid concomitant administration of warfarin and nalidixic acid. Monitor INR if concomitant use is necessary. Inhibit platelet aggregation Cause gastric erosions.
Consider having patients take misoprostol Cytotec to reduce risk of gastric erosions. Dicloxacillin Pathocil and nafcillin Unipen may enhance warfarin metabolism. Inhibit platelet aggregation Cause gastric erosions In large doses, result in hypoprothrombinemic effect.
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