Warfarin Pharmacogenetics
2012; Lippincott Williams & Wilkins; Volume: 125; Issue: 16 Linguagem: Inglês
10.1161/circulationaha.112.100628
ISSN1524-4539
Autores Tópico(s)Meta-analysis and systematic reviews
ResumoHomeCirculationVol. 125, No. 16Warfarin Pharmacogenetics Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWarfarin PharmacogeneticsA Rising Tide for Its Clinical Value Julie A. Johnson, PharmD Julie A. JohnsonJulie A. Johnson From the University of Florida, Gainesville, FL. Originally published19 Mar 2012https://doi.org/10.1161/CIRCULATIONAHA.112.100628Circulation. 2012;125:1964–1966Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 Warfarin has been in clinical use for nearly 60 years, and in 2010 there were >25 million prescriptions for warfarin in the United States. Although warfarin is highly efficacious, it has a narrow therapeutic window to achieve desired anticoagulation without excess risk of bleeding. Anticoagulation status is monitored with the International Normalized Ratio (INR), where the most common target INR is 2 to 3. Not only does warfarin exhibit a narrow therapeutic index, but there can be 10- to 20-fold differences in the warfarin dose required to achieve target INR. Thus, the early period after warfarin therapy initiation requires frequent INR monitoring to determine the proper dose for the patient, it is often associated with multiple dose adjustments, and many patients experience prolonged periods of over- or underanticoagulation while the appropriate dose is identified. These challenges lead to warfarin being a leading cause of emergency department visits and hospitalizations for an adverse drug reaction and to significant underuse of the drug in patients for whom it is strongly indicated, in particular, those with atrial fibrillation.1Article see p 1997The difficulties associated with warfarin use led to great enthusiasm for the new oral anticoagulants. Dabigatran and rivaroxaban were approved in the past 18 months, yet they have made only a small dent in the market share for oral anticoagulants, with warfarin remaining the predominant anticoagulant used clinically. For example, in the first year of use in the United States, ≈1.1 million dabigatran prescriptions were dispensed, in contrast to the 25 million prescriptions per year for warfarin.2 Reasons for the lack of uptake may include recent concerns about excess bleeding risk with dabigatran,2 lack of reversibility of the anticoagulation, twice daily dosing, challenges with dosing in renally impaired patients, bothersome adverse effects (in particular, gastrointestinal adverse effects with dabigatran), and cost, among others. Overall, these new agents have not been widely embraced in the manner anticipated, suggesting that warfarin will remain the mainstay of oral anticoagulant therapy for the foreseeable future. Thus, there remains a need to identify ways to more safely and effectively use warfarin.That genetic polymorphisms might influence the variability in warfarin dose requirements was first recognized in 1999, and since then a vast body of literature has documented the effects on warfarin dose of genetic variation in cytochrome P450 2C9 (CYP2C9), the major drug metabolizing enzyme of S-warfarin, and vitamin K epoxide reductase (VKORC1), the protein target of warfarin.3 Numerous studies have shown that polymorphisms in these genes explain up to 35% of the variability in warfarin dose requirements, and, through consideration of additional clinical factors (eg, body size, age, interacting drugs), >50% of interpatient dose variability can be explained.3–6That a better approach to identification of the therapeutic dose for a given patient is needed is highlighted by data from numerous studies suggesting that bleeding risk during the first 1 to 3 months of therapy is up to 10-fold higher than subsequent monthly risk.1 Use of genetic and clinical information to guide initial dose selection holds promise as such an approach. Indeed, numerous warfarin pharmacogenetic algorithms have been developed that incorporate both genetic and clinical factors, and the best validated among these come from the International Warfarin Pharmacogenetics Consortium5 and Gage et al.4 And, in 2010, the US Food and Drug Administration revised the warfarin product label to include dose recommendations based on CYP2C9 and VKORC1 genotype.7 The study by the International Warfarin Pharmacogenetics Consortium in >5000 patients from 4 continents clearly documented that its pharmacogenetic algorithm was superior to a clinical algorithm, or the usual 5 mg daily starting dose in estimating the stable warfarin dose.5 A later analysis by Finkelman et al8 confirmed this and documented that algorithm-based dosing was also superior to the US Food and Drug Administration dosing table. Based on these and numerous other studies, the Clinical Pharmacogenetics Implementation Consortium recently recommended use of the International Warfarin Pharmacogenetics Consortium or Gage algorithms as the preferred approach for genetic-guided initial warfarin dose selection.3Although there is little debate that genetic information allows for more precise initial dose selection, questions have remained about whether this leads to any real therapeutic advantage, such as fewer out-of-range INRs, greater time within the therapeutic range, or reduced incidence of adverse events, in particular, thromboembolic events and bleeds. Several small studies have attempted to address these issues, but none have been adequately powered, and thus there has continued to be a lack of clarity regarding the potential clinical benefits of pharmacogenetic-guided warfarin dosing. It is in this context that the article by Anderson et al9 represents an important advance.CoumaGen-II was a well-powered 2-part study of genotype-guided warfarin dosing.9 Part 1 was a randomized controlled trial testing a 1-step, modified version of the International Warfarin Pharmacogenetics Consortium warfarin pharmacogenetic algorithm versus a 3-step algorithm. In the 1-step algorithm, genetic information was incorporated no later than the second dose, but 84% had the genetic information incorporated for determination of the first dose. The 3-step algorithm incorporated VKORC1 but not CYP2C9 genotype for the first dose, with CYP2C9 genotype incorporated starting with dose 2 (step 2), with further incorporation of genetic information through a dose-revision algorithm based on the day 4/5 INR (step 3). Both patients and clinicians managing the warfarin therapy were blinded to the dosing algorithm used, and events were evaluated by a blinded events adjudication committee.The second component was a comparative effectiveness research study of genotype-guided dosing of patients from part 1 in comparison with a parallel standard dosing cohort of patients treated with warfarin in the same hospitals, in the same time frame, and managed by the same clinicians or anticoagulation service teams.The comparison of the 2 dosing algorithm approaches found that the 3-step algorithm approach was noninferior, but not superior to the 1-step algorithm, suggesting there is little reason to use the more complex 3-step approach. Based on similarity of the data from the 2 dosing algorithms, these data were combined to compare with the parallel standard care cohort.The findings from the pharmacogenetic versus standard care analysis were most impressive and suggest there is clinical benefit associated with the use of genetic information to guide warfarin dosing. Nearly all the end points tested showed significant benefits with the pharmacogenetic-guided dosing, including out-of-range INRs, percentage of time in the therapeutic range (PTTR), and serious adverse events. Specifically, the pharmacogenetic cohort had a 10.3% absolute (and 25% relative) reduction in the out-of-range INRs at 1 month, with similar differences at 3 months. This finding was primarily attributable to significantly fewer INR values 1 CYP2C9 or VKORC1 variant alleles (where 3 is the number possible). For example, those with standard dosing with no variant in either gene required average 10.5 mg/wk increases, and those with >1 variant required 11 mg/wk decreases, assuming a 35 mg/wk (5 mg/d) initial dose. In contrast, the mean dose changes in the pharmacogenetics cohort in the 0 and >1 variant groups were 0.31 and 0.25 mg/wk, respectively. Those with 1 variant allele have their dose similarly predicted by a standard 5-mg dose or by pharmacogenetic guidance.Some will argue that the parallel control group is not an appropriate comparator, because there might have been differences in the management of these patients, or specifically that the pharmacogenetic cohort was more aggressively managed because the clinicians knew those patients were in the pharmacogenetic study. Although it is not possible to rule this out, the fact that the average number of INRs measured was essentially identical between the 2 groups would not support differential management of the patients. Additionally, the standard care group spent 59% of time in therapeutic range, which is consistent with 2 recent analyses, suggesting that the average PTTR in the United States ranges from 55% to 58%.11 This suggests that the parallel standard care arm patients were treated similarly to the standard of care in the United States. There were also demographic differences in the 2 groups that might have contributed to differences in clinical outcomes, the most significant being the indication for warfarin therapy, where the pharmacogenetic cohort had a higher percentage of patients undergoing orthopedic surgery. However, stratified analyses of orthopedic and nonorthopedic patients found significant and nearly identical benefits of pharmacogenetic dosing in both groups for out-of-range INRs and PTTR.There are at least 4 large, randomized controlled trials ongoing to test the benefits of pharmacogenetic guidance of warfarin dosing, 2 in the United States, 1 in Europe, and 1 in Asia.3,8 These trials will provide important additional insights into the efficacy of pharmacogenetic dosing in a tightly controlled clinical trial setting. These trials will test hypotheses regarding warfarin pharmacogenetic dosing in a more robust manner than this comparative effectiveness study, and will answer some questions that were not addressed by the current study. However, the current study by Anderson et al provides us with excellent insight into the effectiveness of utilizing pharmacogenetics in a real-world setting. In fact, if this study approximates the potential benefit of pharmacogenetic dosing in patients managed in an anticoagulation clinic, one can imagine the benefits might be even greater for the vast majority of warfarin-treated patients who do not have access (geographically or otherwise) to an anticoagulation clinic, and therefore have their INR monitored less frequently, with poorer anticoagulation control.One limitation of the current study is that the participants were nearly all individuals of European ancestry, the group for whom the warfarin pharmacogenetic dosing algorithms are most predictive.5,6 It is therefore possible the benefits in blacks or Asians would be less than observed in the present study. The ongoing clinical trials have broader ethnic representation and therefore will provide insights for those ethnic groups.This study represents a landmark in the very large warfarin pharmacogenetics literature. For the first time, we have a vision of the potential clinical benefits associated with use of genetic information to guide warfarin dosing. It suggests that clinicians should more seriously consider adoption of warfarin pharmacogenetics into clinical practice and validates the recommendations from the Clinical Pharmacogenetics Implementation Consortium on warfarin pharmacogenetics.3 And, as we move toward a time when more and more patients will have their genetic information available, the current study data suggest that clinicians will be hard pressed to justify ignoring genetic information in selection of an initial warfarin dose, if the necessary genetic information is available. Anderson et al should be congratulated for this excellent contribution to the field.Sources of FundingDr Johnson is supported in part by National Institutes of Health grants U01 GM074492, R01NS073346, and UL1 RR029890.DisclosuresDr Johnson is a leader of the International Warfarin Pharmacogenetics Consortium and is a member of the Executive Committee and site principle investigator for the National Institutes of Health Clarification of Optimal Anticoagulation through Genetics (COAG) trial.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Julie A. Johnson, PharmD, Departments of Pharmacotherapy and Translational Research, and Medicine, Center for Pharmacogenomics, University of Florida, Box 100486, Gainesville, FL 32610-0486. E-mail [email protected]ufl.eduReferences1. Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: high risk periods and implications for new antithrombotic drugs. Thromb Haemost. 2010; 104:1099–1105.CrossrefMedlineGoogle Scholar2. FDA Drug Safety Communication: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate). December7, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm282724.htm. Accessed March 9, 2012.Google Scholar3. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB. Clinical pharmacogenetics implementation consortium guidelines for cyp2c9 and vkorc1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011; 90:625–629.CrossrefMedlineGoogle Scholar4. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL. 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Ren Y, Yang C, Chen H, Dai D, Wang Y, Zhu H and Wang F (2020) Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population, Frontiers in Pharmacology, 10.3389/fphar.2020.01014, 11 Ma Z, Wang P, Gao Z, Wang R, Khalighi K and Huk M (2018) Ensemble of machine learning algorithms using the stacked generalization approach to estimate the warfarin dose, PLOS ONE, 10.1371/journal.pone.0205872, 13:10, (e0205872) Ma Z, Wang P, Mahesh M, Elmi C, Atashpanjeh S, Khalighi B, Cheng G, Krishnamurthy M, Khalighi K and Huk M (2022) Warfarin sensitivity is associated with increased hospital mortality in critically Ill patients, PLOS ONE, 10.1371/journal.pone.0267966, 17:5, (e0267966) April 24, 2012Vol 125, Issue 16 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.100628PMID: 22431866 Originally publishedMarch 19, 2012 Keywordspharmacogeneticspolymorphism geneticswarfarinEditorialsPDF download Advertisement
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