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. 2009 May;24(5):656-64.
doi: 10.1007/s11606-009-0949-1. Epub 2009 Mar 21.

Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin

Kirsten Neudoerffer Kangelaris  1 , Stephen Bent, Robert L Nussbaum, David A Garcia, Jeffrey A Tice
Affiliations

Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin

Kirsten Neudoerffer Kangelaris et al. J Gen Intern Med. 2009 May.

Erratum in

  • J Gen Intern Med. 2009 Dec;24(12):1358

Abstract

Background: Genotype-guided initial warfarin dosing may reduce over-anticoagulation and serious bleeding compared to a one-dose-fits-all dosing method.

Objective: The objective of this review was to investigate the safety and efficacy of genotype-guided dosing of warfarin in reducing the occurrence of serious bleeding events and over-anticoagulation.

Data sources: The authors searched PubMed, EMBASE and International Pharmaceutical Abstracts through January 23, 2009, without language restrictions. Selected articles were randomized trials comparing pharmacogenetic dosing of warfarin versus a "standard" dose control algorithm in adult patients taking warfarin for the first time.

Review methods: Two reviewers independently extracted data and assessed study quality using a validated instrument. The primary outcomes were major bleeding and time spent within the therapeutic range International Normalized Ratio (INR). Secondary outcomes included minor bleeding, thrombotic events and other measures of anticoagulation quality.

Results: Three of 2,014 studies (423 patients) met the inclusion and exclusion criteria. Differences in study quality, dosing algorithms, length of follow-up and outcome measures limited meta-analysis. Summary estimates revealed no statistically significant difference in bleeding rates or time within the therapeutic range INR. The highest quality study found no significant difference in primary or secondary outcomes, although there was a trend towards more rapid achievement of a stable dose (14.1 vs. 19.6 days, p = 0.07) in the pharmocogenetic arm.

Conclusions: We did not find sufficient evidence to support the use of pharmacogenetics to guide warfarin therapy. Additional clinical trials are needed to define the optimal approach to use warfarin pharmacogenetics in clinical practice.

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Figures

Figure 1
Figure 1
Flow diagram of process to select studies for inclusion: search January 23, 2009. *General pharmacogenetic reviews, warfarin drug interactions, other drugs metabolized by cytochrome P450 enzymes. †Case report N = 39, case control N = 15, cohort studies N = 171. ‡References.,,
Figure 2
Figure 2
Forest plot. Meta-analysis of the risk ratio of major bleeding between pharmacogenetic dosing and the control group. This shows a pooled risk ratio of 0.69 favoring pharmacogenetics dosing, though it does not meet statistical significance (95% CI 0.16 to 2.9).
Figure 3
Figure 3
Forest plot. Meta-analysis of average percentage time spent in the therapeutic range. The SMD is the difference in time spent in therapeutic range as a proportion of the standard deviation around the average value for the entire group. Here, no summary estimate is shown due to significant heterogeneity (chi-squared p = 0.03, I2 = 72.5%).
See this image and copyright information in PMC

Comment in

  • Systematic review of pharmacogenetic warfarin dosing.
    van Schie RM, Jorgensen AL, de Boer A, Maitland-van der Zee AH; EU-PACT study group. van Schie RM, et al. J Gen Intern Med. 2009 Oct;24(10):1171. doi: 10.1007/s11606-009-1083-9. J Gen Intern Med. 2009. PMID: 19693633 Free PMC article. No abstract available.

References

    1. FDA Approves Updated Warfarin (Coumadin) Prescribing Information: New Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed February 19, 2009.
    1. Verigene Warfarin Test. http://www.nanosphere.us/VerigeneWarfarinMetabolismNucleicAcidTest_4472..... Accessed February 19, 2009.
    1. Kimball Warfarin Test. http://www.kimballgenetics.com/pdf/WarfarinEdusheetv7.pdf. Accessed February 19, 2009.
    1. Genelex Warfarin Test. http://www.healthanddna.com/drug-safety/warfarin.html. Accessed February 19, 2009.
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '14726811', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/14726811/'}]}
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