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Pharmacogenomic Dosing Strategies for Warfarin: Still Waiting for Evidence of Superior Health Outcomes

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Anticoagulation with warfarin is perilous. Inter-patient variability in the dose requirements and predilection for toxicity is largely explained by genetic variation in the expression of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1).1 Therefore, pharmacogenomic testing to predict warfarin responsiveness would appear to offer an improvement over traditional dosing approaches.

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Indeed, early research established that using genetic information is superior to non-genetic strategies in predicting warfarin maintenance doses and reducing the time needed to achieve stable levels of anticoagulation.2-5 Despite considerable effort, however, genomic-based approaches to warfarin dosing have not been associated with a reduction in adverse health outcomes (see Table 1).2-9 Moreover, two recent meta-analyses failed to detect a significant benefit from genetically guided dosing on the amount of time spent within the therapeutic range (a surrogate measure for quality of care),10,11 or on the likelihood of overshooting the INR target.10 Thus, despite the existence of validated algorithms that predict stable warfarin doses more efficiently than non-genetic based methods,12,13 pharmacogenomic testing prior to initiating therapy has not been established as the gold standard of patient care and debate persists between advocates and opponents.14-18

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Both sides are awaiting the results of two large randomized clinical trials (GIFT19 and WARFARIN20) that hope to end debate over the clinical utility of using a pharmacogenomic approach to guide the initiation of warfarin therapy.15,21 Specifically, both trials aim to determine the impact of genetic-based dosing on health outcomes in patients aged 65 or older. The Genetics InFormatics Trial (GIFT) will measure a composite endpoint of venous thromboemolism (VTE), major hemorrhage, INR>4, and death among 1,600 orthopedic surgery patients.19 The Warfarin Adverse Event Reduction For Adults Receiving Genetic Testing at Therapy INitiation (WARFARIN) trial will measure the incidence of major hemorrhage and thromboembolic events within 30 days of therapy initiation among 3,800 patients prescribed warfarin for any indication.20 Both trials chose the www.WarfarinDosing.org algorithms to initiate therapy and both trials are expected to be completed in 2015.20,22 Strategically, participation in either trial qualifies Medicare beneficiaries to receive genetic testing under the “Coverage with Evidence Development” provision of the US Social Security Act.21,23 Clearly, the future of Medicare and private third-party reimbursements for genetic testing to predict warfarin responsiveness hangs on the results from these two trials, as does widespread adoption of pharmacogenomic-based dosing of warfarin.

Reference(s) +
 1. Ghimire L, Stein C. Warfarin Pharmacogenetics. In: Brunton LL. eds. Goodman & Gilman Online Updates. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com./updatesContent.aspx?bookid=537&Sectionid=41706601. Accessed September 12, 2014.
 2. *Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008 Mar; 83(3): 460-70.   [PubMed: 17851566]
 3. *Burmester JK, Berg RL, Yale SH, et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med 2011 Jun; 13(6): 509-18.   [PubMed: 21423021]
 4. *Borgman MP, Pendleton RC, McMillin GA, et al. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. Thromb Haemost 2012 Sep; 108(3): 561-9. PMCID: PMC3434319. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMC3434319 
 5. *Wang M, Lang X, Cui S, et al. Clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality after rheumatic valve replacement: a randomized and controlled trial. Int J Med Sci 2012; 9(6): 472-9. PMCID: PMC3427951. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMC3427951
 6. *Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007 Nov 27; 116(22): 2563-70.   [PubMed: 17989110]
 7. *Jonas DE, Evans JP, McLeod HL, et al. Impact of genotype-guided dosing on anticoagulation visits for adults starting warfarin: a randomized controlled trial. Pharmacogenomics 2013 Oct; 14(13): 1593-603.   [PubMed: 24088130]
 8. *Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013 Dec 12; 369(24): 2283-93. PubMed Central PMCID: PMC3942158. http://www.ncbi.nlm.nih.gov/pubmed/?term=PMC3942158
 9. *Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013 Dec 12; 369(24): 2294-303.   [PubMed: 24251363]
10. Stergiopoulos K, Brown DL. Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues: Meta-analysis of Randomized Clinical Trials. JAMA Intern Med 2014 Aug 1; 174(8): 1330-8.   [PubMed: 24935087]
11. Liao Z, Feng S, Ling P, et al. Meta-analysis of randomized controlled trials reveals an improved clinical outcome of using genotype plus clinical algorithm for warfarin dosing. J Thromb Thrombolysis 2014 Jun 25. [Epub ahead of print].   [PubMed: 24962733]
12. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008 Sep; 84(3): 326-31. PubMed Central PMCID: PMC2683977. (Erratum in: Clin Pharmacol Ther. 2008 Sep;84(3):430.)  [PubMed: ] [[XSLOpenURL/]]
13. International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009 Feb 19; 360(8): 753-64. PMCID: PMC2722908. (Erratum in: N Engl J Med 2009 Oct 15; 361(16): 1613. Dosage error in article text.)  [PubMed: ] [[XSLOpenURL/]]
14. Kazi DS, Hlatky MA. Warfarin, genes, and the (health care) environment. JAMA Intern Med 2014 Aug 1; 174(8): 1338-9.   [PubMed: 24934523]
15. Scott SA, Lubitz SA. Warfarin pharmacogenetic trials: is there a future for pharmacogenetic-guided dosing? Pharmacogenomics 2014 Apr; 15(6): 719-22. PubMed Central PMCID: PMC4110075.  [PubMed: ] [[XSLOpenURL/]]
16. Cavallari LH, Nutescu EA. Warfarin pharmacogenetics: to genotype or not to genotype, that is the question. [Review] Clin Pharmacol Ther 2014 Jul; 96(1): 22-4.   [PubMed: 24942399]
17. Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and coumarin dosing--recalibrating expectations. N Engl J Med 2013 Dec 12; 369(24): 2273-5.   [PubMed: 24328463]
18. Boriani G. Predicting the quality of anticoagulation during warfarin therapy: the basis for an individualized approach. Chest 2013 Nov; 144(5): 1437-8.   [PubMed: 24189852]
19. Do EJ, Lenzini P, Eby CS, et al. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J 2012 Oct; 12(5): 417-24.PubMed Central PMCID: PMC3175019.  [PubMed: ] [[XSLOpenURL/]]
20. Iverson Genetic Diagnostics, Inc. Warfarin Adverse Event Reduction For Adults Receiving Genetic Testing at Therapy INitiation (WARFARIN). [ClinicalTrials.gov Identifier: NCT01305148]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: http://clinicaltrials.gov/show/NCT01305148. Last accessed 9/15/2014.  [PubMed: ] [[XSLOpenURL/]]
21. Jensen TS, Jacques LB, Ciccanti M, et al. Decision Memo for Pharmacogenomic Testing for Warfarin Response (CAG-00400N). Centers for Medicare and Medicaid Services. 8/3/2009. http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=224&IsPopup=y&NCDId=333&NcaName=Pharmacogenomic+Testing+for+Warfarin+Response&ncdver=1&bc=AAAAAAAAEAAA&. Last accessed 9/15/2014.  [PubMed: ] [[XSLOpenURL/]]
22. Washington University School of Medicine. Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT. [ClinicalTrials.gov Identifier: NCT01006733]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: http://clinicaltrials.gov/show/NCT01006733. Last accessed 9/15/2014.  [PubMed: ] [[XSLOpenURL/]]
23. Centers for Medicare and Medicaid Services. Pharmacogenomic Testing to Predict Warfarin Responsiveness [webpage]. Page last modified 4/03/2014 9:01 AM. http://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/Pharmacogenomic-Testing-to-Predict-Warfarin-Responsiveness.html. Last accessed 9/15/2014.  [PubMed: ] [[XSLOpenURL/]]
24. Ageno W, Johnson J, Nowacki B, et al. A computer generated induction system for hospitalized patients starting on oral anticoagulant therapy. Thromb Haemost 2000 Jun; 83(6): 849-52.   [PubMed: 10896237]

Table 1: Summary of Randomized Controlled Trials: Genotype-Guided Warfarin Dosing Initiation in Adults (BSA= Body surface area; PG= Pharmacogenetic-guided; NS= Not Significant; TTR= % of time spent within therapeutic range) +
Table Graphic Jump Location
Table 1: Summary of Randomized Controlled Trials: Genotype-Guided Warfarin Dosing Initiation in Adults (BSA= Body surface area; PG= Pharmacogenetic-guided; NS= Not Significant; TTR= % of time spent within therapeutic range)

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