title: Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation. A systematic review and meta-analysis.
abstract: 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 (primary 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 Χ(²)=4.46, p=0.35, I(²)=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 Χ(²)=43.31, p<0.001, I(²)=79%). Pre-specified exploratory analyses demonstrated that TTR was significantly higher when genotype-guided dosing was compared with fixed VKA dosing (6 trials, 997 patients: MD 8.41%; 95% CI 3.50,13.31; heterogeneity Χ(²)=15.18, p=0.01, I(²)=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 Χ(²)=1.53, p=0.68, I(²)=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.
authors.forename: Emilie P
authors.initials: EP
authors.lastname: Belley-Cote
authors.forename: Hasib
authors.initials: H
authors.lastname: Hanif
authors.forename: Frederick
authors.initials: F
authors.lastname: D'Aragon
authors.forename: John W
authors.initials: JW
authors.lastname: Eikelboom
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.forename: Mark
authors.initials: M
authors.lastname: Borgman
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Jonas
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kimmel
authors.forename: Vangelis G
authors.initials: VG
authors.lastname: Manolopoulos
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Baranova
authors.forename: Anke H
authors.initials: AH
authors.lastname: Maitland-van der Zee
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Richard Whitlock, David Braley Cardiac, Vascular and Stroke Research Institute, Room 1C1-5B, 237 Barton St. E., Hamilton, Ontario L8L 2X2, Canada, Tel.: +1 905 527 4322 ext. 44091, Fax: +1 905 577 8017, E-mail: Richard.Whitlock@phri.ca.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Whitlock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D016009:Chi-Square Distribution; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D014812:Vitamin K
keywords: Anticoagulants; genetics; meta-analysis; pharmacogenomics; warfarin