Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation

Emilie P. Belley-Cote; Hasib Hanif; Frederick D’Aragon; John W. Eikelboom; Jeffrey L. Anderson; Mark Borgman; Daniel E. Jonas; Stephen E. Kimmel; Vangelis G. Manolopoulos; Ekaterina Baranova; Anke H. Maitland-van der Zee; Munir Pirmohamed; Richard P. Whitlock

doi:10.1160/TH15-01-0071

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 114(04): 768-777
DOI: 10.1160/TH15-01-0071

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation

A systematic review and meta-analysis

Authors

Emilie P. Belley-Cote

¹Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
Hasib Hanif

²Division of Cardiac Surgery, McMaster University, Hamilton, Ontario, Canada
Frederick D’Aragon

¹Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

³Anaesthesiology Department, Sherbrooke University, Quebec, Canada
John W. Eikelboom

⁴Department of Medicine, McMaster University, Hamilton, Ontario, Canada

⁵Population Health Research Institute, Hamilton, Ontario, Canada
Jeffrey L. Anderson

⁶Intermountain Medical Center, Murray, Utah, USA
Mark Borgman

⁷PGXL Labs, Louisville, Kentucky, USA
Daniel E. Jonas

⁸University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA
Stephen E. Kimmel

⁹University of Pennsylvania, Philadelphia, Pennsylvania, USA
Vangelis G. Manolopoulos

¹⁰Laboratory of Pharmacology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
Ekaterina Baranova

¹¹Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
Anke H. Maitland-van der Zee

¹¹Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
Munir Pirmohamed

¹²University of Liverpool, Liverpool, UK
Richard P. Whitlock

¹Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

²Division of Cardiac Surgery, McMaster University, Hamilton, Ontario, Canada

⁵Population Health Research Institute, Hamilton, Ontario, Canada

Abstract

Summary

Variability in vitamin K antagonist (VKA) dosing is partially explained by genetic polymorphisms. We performed a meta-analysis to determine whether genotype-guided VKA dosing algorithms decrease a composite of death, thromboembolic events and major bleeding (pri-mary outcome) and improve time in therapeutic range (TTR). We searched MEDLINE, EMBASE, CENTRAL, trial registries and conference proceedings for randomised trials comparing genotype-guided and standard (non genotype-guided) VKA dosing algorithms in adults initiating anticoagulation. Data were pooled using a random effects model. Of the 12 included studies (3,217 patients), six reported all components of the primary outcome of mortality, thromboembolic events and major bleeding (2,223 patients, 87 events). Our meta-analysis found no significant difference between groups for the primary outcome (relative risk 0.85, 95 % confidence interval [CI] 0.54–1.34; heterogeneity X²=4.46, p=0.35, I²=10 %). Based on 10 studies (2,767 patients), TTR was significantly higher in the genotype-guided group (mean difference (MD) 4.31 %; 95 % CI 0.35, 8.26; heterogeneity X²=43.31, p< 0.001, I²=79 %). Pre-specified exploratory analyses demonstrated that TTR was significantly higher when geno-type-guided dosing was compared with fixed VKA dosing (6 trials, 997 patients: MD 8.41 %; 95 % CI 3.50,13.31; heterogeneity X²=15.18, p=0.01, I²=67 %) but not when compared with clinical algorithm-guided dosing (4 trials, 1,770 patients: MD –0.29 %; 95 % CI –2.48,1.90; heterogeneity X²=1.53, p=0.68, I²=0 %; p for interaction=0.002). In conclusion, genotype-guided compared with standard VKA dosing algorithms were not found to decrease a composite of death, thromboembolism and major bleeding, but did result in improved TTR. An improvement in TTR was observed in comparison with fixed VKA dosing algorithms, but not with clinical algorithms.

Keywords

Anticoagulants - genetics - meta-analysis - pharmacogenomics - warfarin

Full Text

References

References
1 Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
2 Connolly SJ, Pogue J, Eikelboom J. et al. Benefit of oral anticoagulant over anti-platelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118: 2029-2037.
3 Veeger NJ, Piersma-Wichers M, Tijssen JG. et al. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 2005; 128: 513-519.
4 Gallego P, Roldan V, Marin F. et al. Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost 2013; 110: 1189-1198.
5 De Caterina R, Husted S, Wallentin L. et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 110: 1087-1107.
6 Guyatt GH, Akl EA, Crowther M. et al. American College of Chest Physicians Antithrombotic T et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) 7S-47S.
7 Epstein RS, Moyer TP, Aubert RE. et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010; 55: 2804-2812.
8 Anderson JL, Horne BD, Stevens SM. et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012; 125: 1997-2005.
9 Wadelius M, Chen LY, Lindh JD. et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113: 784-792.
10 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; 108: 561-569.
11 Pirmohamed M, Burnside G, Eriksson N. et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013; 369: 2294-2303.
12 Kimmel SE, French B, Kasner SE. et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013; 369: 2283-2293.
13 Verhoef TI, Ragia G, de Boer A. et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013; 369: 2304-2312.
14 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; 14: 1593-1603.
15 Hillman MA, Wilke RA, Yale SH. et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005; 3: 137-145.
16 Stergiopoulos K, Brown DL. Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues: Meta-analysis of Randomized Clinical Trials. J Am Med Assoc Intern Med 2014; 174: 1330-1338.
17 Li X, Yang J, Wang X. et al. Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials. Thromb Res. 2015 Epub ahead of print.
18 Franchini M, Mengoli C, Cruciani M. et al. Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 1480-1487.
19 Higgins JP, Altman DG, Gotzsche PC. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Br Med J 2011; 343: d5928.
20 Balshem H, Helfand M, Schunemann HJ. et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401-406.
21 Wu C, Alotaibi GS, Alsaleh K. et al. Case fatality of bleeding and recurrent venous thromboembolism during, initial therapy with direct oral anticoagulants: A systematic review. Thromb Res. 2014 Epub ahead of print.
22 Huang SW, Chen HS, Wang XQ. et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics 2009; 19: 226-234.
23 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. Intern J Med Sci 2012; 9: 472-479.
24 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
25 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics Med 2002; 21: 1539-1558.
26 Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000; 53: 1119-1129.
27 Akl EA, Briel M, You JJ. et al. Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review. Br Med J 2012; 344: e2809.
28 Burmester JK, Berg RL, Yale SH. et al. A randomized controlled trial of geno-type-based Coumadin initiation. Genetics Med 2011; 13: 509-518.
29 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 Therap 2008; 83: 460-470.
30 Anderson JL, Horne BD, Stevens SM. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116: 2563-2570.
31 Radhakrishnan A, Vido D, Tayur S. et al. Genotype Guided Therapeutic Dosing of Warfarin in Geriatric Patients. J Am Coll Cardiol 2012; 59: E1696.
32 McMillin GA, Melis R, Wilson A. et al. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Therap Drug Monitor 2010; 32: 338-345.
33 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
34 Investigators E, Bauersachs R, Berkowitz SD. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
35 Man-Son-Hing M, Laupacis A, O’Connor A. et al. Warfarin for atrial fibrillation. The patient’s perspective. Arch Intern Med 1996; 156: 1841-1848.
36 Jones M, McEwan P, Morgan CL. et al. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 472-477.
37 Matchar DB, Jacobson A, Dolor R. et al. Effect of home testing of international normalized ratio on clinical events. N Engl J Med 2010; 363: 1608-1620.
38 van Walraven C, Oake N, Coyle D. et al. Changes in surrogate outcomes can be translated into clinical outcomes using a Monte Carlo model. J Clin Epidemiol 2009; 62: 1306-1315.
39 Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. Br Med J 2010; 340: c117.
40 Kovacs MJ, Rodger M, Anderson DR. et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003; 138: 714-719.
41 Ageno W, Johnson J, Nowacki B. et al. A computer generated induction system for hospitalized patients starting on oral anticoagulant therapy. Thromb Hae-most 2000; 83: 849-852.
42 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011 Available from www.cochrane-handbook.org

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