Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans

Drozda, Katarzyna; Wong, Shan S.; Patel, SR; Bress, Adam P.; Nutescu, Edith A.; Kittles, Rick A.; Cavallari, Larisa H.

doi:10.1097/fpc.0000000000000108

Cited by 84 publications

(72 citation statements)

References 37 publications

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“…This could explain the overdosing observed among African Americans receiving genotype-guided dosing in COAG. This has been highlighted by a recent study by Drozda et al, 35 which showed that the algorithm used in COAG overestimates warfarin doses in African Americans possessing CYP2C9 (*5, *6, *8, and *11) variants. Our findings are consistent with this.…”

Section: 14mentioning

confidence: 86%

Race influences warfarin dose changes associated with genetic factors

Limdi¹,

Brown

Yan

et al. 2015

Blood

102

111

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• The influence of known genetic variants on warfarin dose differs by race.• Race-specific pharmacogenetic algorithms, rather than race-adjusted algorithms, should be used to guide warfarin dosing.Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P 5 .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P 5 .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. (Blood. 2015;126(4):539-545)

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Section: 14mentioning

confidence: 86%

Race influences warfarin dose changes associated with genetic factors

Limdi¹,

Brown

Yan

et al. 2015

Blood

102

111

View full text Add to dashboard Cite

show abstract

“…Genetic variants that influence drug response may occur exclusively or at different frequencies between population groups. 28, 29 However, in a recent review of the pharmacogenomics of ICS response, 30 none of the existing genome-wide association studies included substantial numbers of African American individuals. Therefore, it is not known whether the risk variants that have been identified to date are generalizable to multiple population groups.…”

Section: Discussionmentioning

confidence: 99%

Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects

Wells

Cajigal

Peterson

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Inhaled corticosteroids (ICS) are the preferred treatment for achieving asthma control. However, little is known regarding the factors contributing to treatment response and whether treatment response differs by population group. Objective To assess behavioral, socio-demographic, and genetic factors related to ICS response among African American and European American individuals with asthma. Methods Study participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). The analytic sample included individuals with asthma aged 12–56 years, >12% bronchodilator reversibility, and a percent of predicted forced expiratory volume at one second (FEV1) between 40–90%. Participants received 6 weeks of inhaled beclomethasone dipropionate. The primary measure of ICS response was a change in Asthma Control Test (ACT) score; the secondary measure was the change in pre-bronchodilator FEV1. Adherence was measured with electronic monitors. Genetic ancestry was estimated for African American participants using genome-wide genotype data. Results There were 339 study participants; 242 self-identified as African American and 97 as European American. Baseline ACT score, percent of predicted FEV1, degree of bronchodilator response, and ICS adherence were significantly associated with ICS response. A baseline ACT score ≤19 was useful in identifying those who would respond as evidenced by the significant dose-response relationship with ICS adherence. Neither self-reported race-ethnicity among all participants nor proportion of African ancestry among African American participants was associated with ICS responsiveness. Conclusions Our findings suggest that baseline lung function measures and self-reported asthma control predict ICS response, whereas self-reported race-ethnicity and genetic ancestry do not.

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“…We were unable to make meaningful comparisons among Asian participants due to an inadequate sample size (n=18). Sixth, the COAG trial did not include genetic variants that might uniquely improve dose prediction in black populations [18,20,21]. …”

Section: Discussionmentioning

confidence: 99%

A systematic analysis and comparison of warfarin initiation strategies

French

Wang

Gage

et al. 2016

Pharmacogenetics and Genomics

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Objective Randomized trials have reported inconsistent evidence regarding the effectiveness of algorithms that use genotypes to initiate warfarin therapy. The Clarification of Optimal Anticoagulation through Genetics (COAG) trial initiated therapy based on predicted maintenance doses, with a pharmacogenetic-guided algorithm in one study group and a clinically guided algorithm in the other. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) consortium initiated therapy based on loading doses, with an algorithm-based prediction in one study group and a fixed-dose regimen in the other. To understand the differences between these trials, we compared the initial doses between alternative dosing algorithms (the pharmacogenetic-guided and clinically guided algorithms developed by Gage and colleagues and those developed by the International Warfarin Pharmacogenetics Consortium), and between the COAG and EU-PACT dose-initiation strategies. Methods Secondary analysis of the COAG trial—a double-blind, randomized controlled trial (2009–2013)—conducted at 18 clinical centers in the United States, which included 1,010 adults initiating warfarin therapy, of whom 719 achieved maintenance dose. Results Among COAG participants, the distribution of initial doses differed between algorithms, but exhibited similar prediction accuracy for maintenance dose. However, had the COAG trial implemented the EU-PACT strategy, the 3-day initial dose would have been 4.8 mg greater among participants randomized to pharmacogenetic-guided dosing, but only 2.5 mg greater among participants randomized to clinically guided dosing (P<0.001). Conclusions Compared to the COAG trial, the EU-PACT trial used systematically larger loading doses in the pharmacogenetic-guided group and might have inadequately adjusted for clinical variability in warfarin dose requirements in the fixed-dose group.

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Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans

Cited by 84 publications

References 37 publications

Race influences warfarin dose changes associated with genetic factors

Race influences warfarin dose changes associated with genetic factors

Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects

A systematic analysis and comparison of warfarin initiation strategies

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