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      Genetic Testing Before Anticoagulation? A Systematic Review of Pharmacogenetic Dosing of Warfarin

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          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.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s11606-009-0949-1) contains supplementary material, which is available to authorized users.

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          Most cited references49

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          Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.

          P Kesteven, Guruprasad P Aithal, Rebecca A. Daly … (1999)
          The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups. The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls. We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.
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            Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

            Mitchell Higashi (2002)
            Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.
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              Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice.

              Julian PT Higgins, Simon Thompson, Jonathan Deeks … (2002)
              Heterogeneity between study results can be a problem in any systematic review or meta-analysis of clinical trials. Identifying its presence, investigating its cause and correctly accounting for it in analyses all involve difficult decisions for the researcher. Our objectives were: to collate recommendations on the subject of dealing with heterogeneity in systematic reviews of clinical trials; to investigate current practice in addressing heterogeneity in Cochrane reviews; and to compare current practice with recommendations. We review guidelines for those undertaking systematic reviews and examine how heterogeneity is addressed in practice in a sample of systematic reviews, and their protocols, from the Cochrane Database of Systematic Reviews. Advice to reviewers is on the whole consistent and sensible. However, examination of a sample of Cochrane protocols and reviews demonstrates that the advice is difficult to follow given the small numbers of studies identified in many systematic reviews, the difficulty of pre-specifying important effect modifiers for subgroup analysis or meta-regression and the unresolved debate concerning fixed versus random effects meta-analyses. There was disagreement between protocols and reviews, often either regarding choice of important potential effect modifiers or due to the review identifying too few studies to perform planned analyses. Guidelines that address practical issues are required to reduce the risk of spurious findings from investigations of heterogeneity. This may involve discouraging statistical investigations such as subgroup analyses and meta-regression, rather than simply adopting a cautious approach to their interpretation, unless a large number of studies is available. The notion of a priori specification of potential effect modifiers for a retrospective review of studies is ill-defined, and the appropriateness of using a statistical test for heterogeneity to decide between analysis strategies is suspect.
              Article 0 comments Cited 129 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : +1-415-5027105 , +1-415-5142094 , kkangelaris@medicine.ucsf.edu
                Journal
                Journal ID (nlm-ta): J Gen Intern Med
                Title: Journal of General Internal Medicine
                Publisher: Springer-Verlag (New York )
                ISSN (Print): 0884-8734
                ISSN (Electronic): 1525-1497
                Publication date (Electronic): 21 March 2009
                Publication date (Print): May 2009
                Volume: 24
                Issue: 5
                Pages: 656-664
                Affiliations
                [1 ]Division of General Internal Medicine, University of California, Box 0131, 533 Parnassus Ave, San Francisco, CA 94143-0131 USA
                [2 ]Division of Hospital Medicine, University of California, Box 0131, 533 Parnassus Ave, San Francisco, CA 94143-0131 USA
                [3 ]Division of Medical Genetics, University of California, San Francisco, CA USA
                [4 ]Division of General Internal Medicine, Veterans Affairs Medical Center, San Francisco, CA USA
                [5 ]Department of Medicine, University of New Mexico, Albuquerque, NM USA
                Article
                Publisher ID: 949
                DOI: 10.1007/s11606-009-0949-1
                PMC ID: 2669873
                PubMed ID: 19306050
                SO-VID: 05e447e1-c8e7-40c2-b2c6-5a44d4dfc8ce
                Copyright © © The Author(s) 2009
                History
                Date received : 25 November 2008
                Date revision received : 25 February 2009
                Date accepted : 27 February 2009
                Categories
                Subject: Clinical Review
                Custom metadata
                issue-copyright-statement © Society of General Internal Medicine 2009

                ScienceOpen disciplines: Internal medicine
                Keywords: systematic review,pharmacogenetics,cyp2c9,warfarin,vkorc1
                Data availability:
                ScienceOpen disciplines: Internal medicine
                Keywords: systematic review, pharmacogenetics, cyp2c9, warfarin, vkorc1

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