Charles H. Brown

News in the world of anticoagulation is presented, including insights on the new guidelines for warfarin.

Warfarin Update: Understanding the Guidelines

You may be hearing discussion about the very important matter of whether patients receiving warfarin should get higher loading doses and/or have less frequent international normalized ratio (INR) test monitoring. New 2012 Chest antithrombosis guidelines

 suggest that some patients may need 10-mg (previous guidelines recommended 5 mg) loading doses of warfarin for 2 or more days, and that some patients may be able to have their INRs monitored every 12 weeks.

These new guidelines may be misinterpreted by some clinicians, who may mistakenly think that they apply to everyone. Although an INR may quickly appear in the therapeutic range after a couple of days of high-dose therapy, this value may falsely indicate that a therapeutic value has been achieved. This practice may be due to a lack of understanding about warfarin’s pharmacokinetics and mechanism of action.

Understanding the Pharmacokinetics of Warfarin Therapy

Warfarin (4-hydroxycoumarin), a vitamin K antagonist (VKA), produces its anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the carboxylation of glutamate residues on the N-terminal regions of vitamin K—dependent proteins. Vitamin K–dependent coagulation factors II, VII, IX, and X require carboxylation for their procoagulant activity, and treatment with VKAs results in the hepatic production of partially carboxylated and decarboxylated proteins with reduced coagulant activity.

Racemic warfarin has a half-life of 36 to 42 hours (R-warfarin 45 hours, S-warfarin 29 hours), circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where the 2 enantiomers are metabolized by different pathways. The S enantiomer of warfarin (2.7-3.8 times more potent than the R enantiomer) undergoes approximately 90% oxidative metabolism, primarily by the cytochrome P450 (CYP) 2C9 enzyme, and to a lesser extent by CYP3A4. The less potent R enantiomer undergoes approximately 60% oxidative metabolism, primarily by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19.

Initial antithrombotic effect of warfarin generally requires 5 to 7 days of treatment and the reduction of prothrombin (factor II), which has a half-life of 60 to 72 hours. Researchers believe that an early rise in the INR value is related to the rapid reduction of VKA factors VII and IX (half-lives of 6 and 24 hours, respectively), but factor II levels are not depleted.

Monitoring INRs every 12 weeks may be possible for patients who are “stable” (no warfarin dosage changes month after month; INRs consistently in the therapeutic range; no medication, diet, or disease changes; and no noncompliance issues).

However, a number of factors could increase/decrease INR values during this time period, and the patient would likely be unaware of any INR changes. Thus, monitoring INRs every 4 weeks may provide a safer approach for most patients.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.

1. Agneo W, Gallus A, Wittkowsky A, Crowther M, et al. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST, 2012 (141): no. 2 suppl; e44S-e88S.

2. FDA Once Again Delays Approval Of Apixaban (Eliquis). http://www.forbes.com/sites/larryhusten/2012/06/25/fda-once-again-delays-approval-of-apixaban-eliquis/ Accessed July 2, 2012.

3. Boehringer Ingelheim updates U.S. prescribing information for Pradaxa for Stroke http://www.thepharmaletter.com/file/113934/boehringer-ingelheim-updates-us-labelling-of-pradaxa-for-stroke.html Accessed July 2, 2012

4. Prescribers Letter; June 2012; Vol. 28 Geriatrics http://prescribersletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PRL&cat=6083&dd=280619 Accessed July 2, 2012

5. Price MJ, Walder JS, Baker BA, et al. Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease. The RECOVERY trial. J Am Coll Cardiol 2012l DOI:10.1016/j.jacc.2012.02.042 June 19/26 2012:2338-2343. 

Charles H. Brown

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