Pharmacogenomics: Is This the FinalChapter in the Remarkable Storyof Warfarin?

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Jerry H. Gurwitz, MD

From the astute observations of a veterinary pathologistmore than 80 years ago, to cutting-edge applications ofwarfarin genome-wide association studies in the direct careof patients, this commonly prescribed oral anticoagulanthas provided one of the most remarkable stories in the historyof modernmedicine. In 1924, Schofield described a previouslyunrecognized bleeding disorder in cattle associated with theingestion of spoiled sweet clover silage.1 The hemorrhagicagent was identified as dicoumarol in 1939. In 1948, a syn-thetic cogener of dicoumarol was introduced and namedwarfarin for the Wisconsin Alumni Research Foundation,which sponsored the research and held the agent’s patent.Warfarin soon became a popular rat poison, and a youngU.S. Army inductee survived a suicide attempt in 1951 afteringesting large amounts of the rodenticide. That incident ledto increased acceptability of warfarin as an effective oralanticoagulant in the management of thromboembolic dis-ease, and today it is the most commonly prescribed oralanticoagulant in North America.Only a few years after Schofield’s discovery, the bleeding

disorder in cattle was determined to be caused by a reductionin prothrombin, yet it took another half century for themech-anism of action of warfarin to be more fully elucidated. In1978, warfarin was described as interfering with vitamin Kmetabolism by inhibiting vitamin K epoxide reductase.2 Aneven deeper understanding of the pharmacology of warfarinhas unfolded over recent years with the advent of pharmaco-genomics. Pharmacogenomics is the study of how geneticvariation explains individual differences in drug response.3

According to Wang and colleagues,4 ‘‘pharmacogenomicsfacilitates the identification of biomarkers that can help phy-sicians optimize drug selection, dose, and treatment duration,and avert adverse drug reactions.’’Variants in the gene encoding vitamin K epoxide reductase

complex subunit 1 (VKORC1), the target for warfarin, havebeen demonstrated to explain differences in warfarin doserequirements.5 Furthermore, the principal enzyme involved

rs Primary Care Institute, a joint endeavor of Fallon Community HealthFallon Clinic, and University of Massachusetts Medical School; and theon of Geriatric Medicine, Department of Medicine, University ofchusetts Medical School, Worcester, MA.

ss correspondence to Jerry H. Gurwitz, MD, Meyers Primary Carete, 630 Plantation Street, Worcester, MA 01605. E-mail: jerry.itz@umassmed.edu

shed by Elsevier Inc. on behalf of the American Medical Directorsiation, Inc.

0.1016/j.jamda.2011.04.011

ORIALS

in warfarin metabolism is CYP2C9, and 2 genetic variantshave been associated with the need for lower maintenancedosages of warfarin and an increased risk of overanticoagula-tion and bleeding events.6 It is now recognized that CYP2C9and VKORC1 genotypes together have a significant influenceon the required warfarin dosage.7 A study evaluating an algo-rithmbased on both clinical and pharmacogenetic data amongpatients of all ages indicated superior performance in predict-ing the appropriate warfarin dosage in comparison with eithera pure clinical algorithm or a fixed dosage approach.8 RevisedFood and Drug Administration labeling of warfarin in 2010emphasized that CYP2C9 and VKORC1 genotype informa-tion can assist in selecting the starting dosage and determiningthe expected therapeutic warfarin dosage.9

However, there remains controversy surrounding theclinical utility and practicality of applying warfarin pharma-cogenetic data to the direct care of patients, particularlythe very old. In this issue of the Journal of the AmericanMedical Directors Association, Schwartz and colleagues10

report the results of a small, cross-sectional study of69 warfarin-treated nursing home and senior care communityresidents, with an average age of 81 years. Warfarin dosageestimates with and without genotype information were com-pared with clinically established therapeutic dosages. Theaddition of genetic information to clinical informationincreased the percentage of the variability of the dosageexplained from 12% to 50%. The pharmacogenetic algorithmwas particularly accurate in predicting dosage requirementsfor patients requiring more than 2 mg per day. However, forpatients requiring a warfarin dosage of less than 2 mg perday, the pharmacogenetic algorithm consistently overesti-mated the dosage. As more than 20% of patients fell intothis category, previous enthusiasm regarding the benefits ofthe algorithm among ‘‘low warfarin dose’’ patients may needto be tempered.8 However, the use of CYP2C9 and VKORC1genetic information still provided dosage estimates that wereimproved over those without genotype data.

For all the promise and potential that pharmacogenetic-based dosing may provide in the care of patients, achievingboth safe and effective anticoagulation with warfarin willforever remain a challenge. The accurate prediction ofwarfarin dosage using clinical and pharmacogenetic data isjust one piece of the puzzle. Warfarin is among the leadingcauses of drug-related injury in the ambulatory and nursinghome settings.11–13 Optimal warfarin management requiressystems-level approaches to care to accommodate the com-plex interplay among dosing, monitoring, drug and dietary

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interactions, the changing clinical status of the patient,patient adherence, and communication and scheduling chal-lenges. Systems-based strategies have included specialized an-ticoagulation services managed by nurses and pharmacists,computerized provider order entry with clinical decision sup-port,14 structured communication protocols between nursingstaff and physicians around the use of warfarin therapy inthe nursing home setting,15 and interactive voice responsesystems for patients cared for in the ambulatory setting.16

Even under the most ideal circumstances of care, there arelarge numbers of patients at risk for thromboembolic diseasewho are not treated with warfarin or for whom therapy is dis-continued once it is started. Novel oral anticoagulants areshowing great promise, even among patients who are notfelt to be suitable for warfarin therapy.17 The opportunityto provide highly effective anticoagulant treatment, withequivalent or improved safety and with reduced dosing andmonitoring responsibilities, is an extremely attractive pros-pect for both providers and patients. Might we be witnessingthe final chapter in the remarkable story of warfarin? AsHylek has written,18 ‘‘if these novel, breakthrough, oral anti-coagulant drugs prove to be effective across a broad spectrumof patients in routine care and are conscientiously priced, theworld-wide impact will be huge.’’

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JAMDA – November 2011