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NEON WARFARIN ANTICOAGULATION CLINICAL GUIDELINES: 7/08
Overview
Warfarin is taken by mouth to inhibit vitamin K. This vitamin is essential for effective production ofclotting factors II, VII, IX, X, and anticoagulant proteins C&S. Warfarin is given once daily. It is monitoredby the prothrombin time and the international normalized ratio (INR). Warfarin is a narrow therapeuticindex drug (NTI). When the INR falls below 2.0 thrombosis risk increases and when the INR rises above4.0 serious bleeding risk increases.
General Therapeutic recommendations for warfarin
INR Range
Duration of Action
Warfarin takes 4-7 days to have its optimum effect. Large loading doses do not markedly shorten thetime to achieve a full therapeutic effect but cause rapid falls in the level of protein C, which mayprecipitate paradoxical thrombosis in the first few days of warfarin therapy. The following generalrecommendations for warfarin use are made:  Initiate therapy with the estimated daily maintenance dose (2-5 mg.).
 Elderly or debilitated patients often require low daily doses of warfarin (2-4 mg.).
 Patients are confused by alternating daily doses (e.g. 7.5 and 5.0 mg).
 Significant changes in INR can usually be achieved by small changes in dose (15% or less).
 4-5 days are required after any dose change or any new diet or drug interaction to reach the new Frequency of Dosing
Monitoring
 Warfarin is monitored by the one stage prothrombin time. Prothrombin times are reported in seconds, as a ratio of the prothrombin time in seconds to the mean normal prothrombin time ofthe laboratory, and as the international normalized ratio (INR). The INR is the most reliable way tomonitor the prothrombin time.
Goals of Anticoagulation
The goal of anticoagulant therapy is to administer the lowest possible dose of anticoagulant to preventclot formation or expansion. The required degree of anticoagulation continues to evolve as studiesprovide more information about the efficacy and safety of lower doses. Current therapeutic goals forvarious disease states are summarized in Table 1.4-9 By using the lowest possible required dose ofwarfarin, the physician can minimize the risk of bleeding while providing the benefits of anticoagulation.
To achieve this goal, the physician must have a working knowledge of the pharmacologic,pharmacokinetic and pharmacodynamic properties of warfarin.
NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Pharmacology
Warfarin is an antagonist of vitamin K, a necessary element in the synthesis of clotting factors II, VII, IXand X, as well as the naturally occurring endogenous anticoagulant proteins C and S. These factors andproteins are biologically inactive without the carboxylation of certain glutamic acid residues. Thiscarboxylation process requires a reduced vitamin K as a cofactor. Antagonism of vitamin K or adeficiency of this vitamin reduces the rate at which these factors and proteins are produced, therebycreating a state of anticoagulation.
Therapeutic doses of warfarin reduce the production of functional vitamin Kdependent clotting factors byapproximately 30 to 50 percent. A concomitant reduction in the carboxylation of secreted clotting factorsyields a 10 to 40 percent decrease in the biologic activity of the clotting factors. As a result, thecoagulation system becomes functionally deficient.10 Pharmacokinetics
A knowledge of the pharmacokinetics of warfarin is helpful in understanding the initial response totherapy. Warfarin can be detected in the plasma one hour after oral administration, and peakconcentrations occur in two to eight hours.10 Warfarin is a racemic mixture of stereo isomers, which are99 percent bound to albumin.11 The drug is metabolized in the liver and kidneys, with the subsequentproduction of inactive metabolites that are excreted in the urine and stool.10 The half-life of racemic warfarin ranges from 20 to 60 hours. The mean plasma half-life is approximately40 hours, and the duration of effect is two to five days.10 Thus, the maximum effect of a dose occurs up to48 hours after administration, and the effect lingers for the next five days.
Pharmacodynamics and Dosing Considerations
Anticoagulant Activity. The anticoagulant activity of warfarin depends on the clearance of functionalclotting factors from the systemic circulation after administration of the dose. The clearance of theseclotting factors is determined by their half-lives. The earliest changes in the International NormalizedRatio (INR) are typically noted 24 to 36 hours after a dose of warfarin is administered. These changesare due to the clearance of functional factor VII, which is the vitamin Kdependent clotting factor with theshortest half-life (six hours). However, the early changes in the INR are deceptive because they do notactually affect the body's physiologic ability to halt clot expansion or form new thromboses.4 Antithrombotic Effect. The antithrombotic effect of warfarin, or the inability to expand or form clots, is notpresent until approximately the fifth day of therapy. This effect depends on the clearance of functionalfactor II (prothrombin), which has a half-life of approximately 50 hours in patients with normal hepaticfunction.
The difference between the antithrombotic and anticoagulant effects of warfarin need to be understoodand 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.4,12 Because warfarin has along half-life, increases in the INR may not be noted for 24 to 36 hours after administration of the firstdose, and maximum anticoagulant effect may not be achieved for 72 to 96 hours.4 Loading doses of warfarin (i.e., 10 mg or more per day) may increase the patient's risk of bleedingepisodes early in therapy by eliminating or severely reducing the production of functional factor VII. Theadministration of loading doses is a possible source of prolonged hospitalization secondary to dramaticrises in INR that necessitate increased monitoring. Administration of loading doses has also beenhypothesized to potentiate a hypercoagulable state because of severe depletion of protein C. Thepractice of using loading doses should be abandoned because it has no effect on the inhibition ofthrombosis.4[corrected] NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
A potential paradoxic consequence of loading doses is the development of a hypercoagulable statebecause of a precipitous reduction in the concentration of protein C (approximate half-life of eight hours)during the first 36 hours of warfarin therapy.12 Thus, loading doses theoretically may cause clot formationand/or expansion by limiting the production of proteins C and S, which have shorter half-lives thanprothrombin. Consequently, the concurrent use of heparin is extremely important.
The initial dose of warfarin should approximate the chronic maintenance dose that is anticipated. In mostpatients, the average maintenance dose is 4 to 6 mg per day. Dose has an inverse relation with age. Inpatients 50 years old, the average daily dose is 6.3 mg; in patients 70 years old, the average daily doseis 3.6 mg.13 Drug interactions (discussed in detail in another section) need to be considered when warfarin therapy isinitiated. Other factors include the patient's nutritional status and gender. Patients who are malnourishedshould receive lower doses of warfarin because they probably have low vitamin K intake and decreasedserum 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 perday). This dose is then titrated to the lower end of a given therapeutic range, depending on theindication. For example, the goal may be an INR of 2 to 2.5 in a patient with a history of bleeding, chronicatrial fibrillation and no additional risk factors for thrombosis.
Current recommendations for the initiation of warfarin therapy differ based on the urgency for achievingan anticoagulant effect. While warfarin is being initiated, patients who require rapid anticoagulationshould also be given unfractionated heparin or low-molecular-weight heparin intravenously orsubcutaneously in doses appropriate for the given indication.4 Heparin and warfarin therapies should overlap for approximately four to five days. The presence of atherapeutic INR does not confer protection from clot formation and expansion during the first few days ofwarfarin 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 requirelower maintenance doses. The opposite holds for patients who tend to respond slowly to warfarin. 13 A small decrease in the INR is expected to occur with the discontinuation of unfractionated heparintherapy.14 (A drop of 0.3 to 0.8 in the INR has been noted by the authors of this article.) Patients who require non-urgent anticoagulation, such as those with stable chronic atrial fibrillation, canbe started on warfarin as outpatients, without the concomitant administration of heparin.4 NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Recommended Therapeutic Goals for Oral Anticoagulation Indication
Duration
Prophylaxis of venous thrombosis for high-risk surgery Thrombosis associated with antiphospholipid antibody Acute myocardial infarction (to prevent systemic Valvular heart disease (after thrombotic event or if the 3 weeks before and 4 weeks after atrialfibrillation if normal sinus rhythm ismaintained *--One study6 suggested that 4 weeks may be an adequate duration of oral anticoagulant therapy in patients withoutcontinuing risk factors.
†--If oral anticoagulant therapy is elected to prevent recurrent myocardial infarction, an INR of 2.5 to 3.5 isrecommended.
‡--Depending on the type of mechanical valve (i.e., caged ball or caged disk) and the valve position (mitral), somepatients may benefit from INRs in the upper end of the range.
Information derived from references 4 through 9.
Risk Factors for Hemorrhagic Complications of Anticoagulation Therapy • Age greater than 65 years23• Age greater than 75 years with concomitant atrial fibrillation (intracranial hemorrhage)24,25• History of gastrointestinal bleeding20• Comorbid disease states26 --Hypertension20,27--Cerebrovascular disease20--Serious heart disease4,20--Renal insufficiency20 NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Warfarin-Treated Patient with Elevated INR
NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Characteristics of interaction
Severity
Evidence
Mechanism
Management of interaction
acetaminophen dosage to lessthan 2 g per day; if higherdosages are used, increasedmonitoring may be necessary.
• May inducehypothyroidism orhyperthyroidism increased sensitivity tooral anticoagulants on a chronic barbiturateregimen is of less significance.
cholestyramine (Questran) inpatients who need a bilesequestrant.
carbamazepine is added ordiscontinued.
• Increase warfarin doses whencarbamazepine is added, andreduce doses whencarbamazepine is discontinued(stabilization occurs after 4 to 6weeks).
NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Severity
Evidence
Mechanism
Management of interaction
(Cefotan) andcefmetazole (Zefazone)inhibits production ofvitamin Kdependentclotting factors concomitant use of warfarinand cimetidine is necessary.
thromboembolism• Monitor INR frequently whenoral contraceptives are usedconcurrently with warfarin.
hypercoagulability• May have ulcerogeniceffects use of warfarin and disulfiram.
• Monitor INR if concomitantuse is necessary.
1 to 2 weeks after fluvoxamineis started.
NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Severity
Evidence Mechanism
Management of interaction
warfarin may prolong partialthrombin time.
• Be aware of small risk ofbleeding events.
warfarin and metronidazole.
• Monitor INR if concomitantuse is necessary.
• Monitor INR if concomitantuse is necessary.
intermittently.
• Instruct patients to takeNSAIDs with food or antacids.
• Consider having patients takemisoprostol (Cytotec) to reducerisk of gastric erosions.
metabolism.
• Penicillin may reducegastrointestinal florasynthesis of vitamin K.
protein-binding sites• Enhances metabolismof clotting factors propafenone is added ordiscontinued.
NEON WARFARIN ANTICOAGULATION GUIDELINES July 2008
Severity
Evidence
Mechanism
Management of interaction
patients to use a small dosage (325mg or less per day).
• Consider having patients takemisoprostol to reduce the risk ofNSAID-induced ulceration.
of warfarin and sulfinpyrazone.
• Monitor for bleeding whenconcomitant use is necessary.
warfarin• Inhibits platelet aggregation sulfamethoxazole.
• Monitor INR when concomitantuse is necessary.
related and more likely to occurwith vitamin E dosages greaterthan 800 U per day; monitor INR iflarger dosages are taken.
or dietary supplementscontaining vitamin K.
INR=International normalized ratio; HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A; NSAIDs=nonsteroidalanti-inflammatory drugs.
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Retail perspective and provider perspective audit. Plymouth Meeting, Pa.: IMS America, 1998.
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Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeuticrange. Chest 1995;108(4 Suppl):231S-46S.
Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AG. Antithrombotic therapy in patients with mechanical and biologicprosthetic heart valves. Chest 1995;108(4 Suppl):371S-9S [Published erratum in Chest 1996;109:592].
Levine HJ, Pauker SG, Eckman MH. Antithrombotic therapy in valvular heart disease. Chest 1995; 108(4 Suppl):360S -70S.
Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, et al. The duration of oral anticoagulant therapy after a secondepisode of venous thromboembolism. N Engl J Med 1997; 336:393-8.
Laupacis A, Albers G, Dalen J, Dunn M, Feinberg W, Jacobson A. Antithrombotic therapy in atrial fibrillation. Chest 1995;108( 4Suppl):352S-9S.
Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J, et al. Optimal duration of oral anticoagulant therapy: a randomized trialcomparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995;74:606-11.
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Goodman and Gilman's The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:1347-51.
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15. Ansell JE. Oral anticoagulant therapy--50 years later. Arch Intern Med 1993;153:586-96.
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