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

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

› Author Affiliations

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

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