Warfarin Pharmacogenetic Trials: Is there a Future for Pharmacogenetic-Guided Dosing?

Scott, Stuart A.; Lubitz, Steven A.

doi:10.2217/pgs.14.18

Cited by 22 publications

(20 citation statements)

References 19 publications

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“…Our data help explain why African Americans fared worse with genotype-guided dosing in the COAG trial. While it had been suggested that the limited number of genotypes considered in the trial contributed to poor outcomes in African Americans,[10, 12] our data are the first to support this and to show the degree to which failure to account for variants important in African Americans affects dosing error. Another clinical trial of genotype-guided warfarin dosing is underway, and unlike previous trials, it will be powered to assess clinical outcomes.…”

Section: Discussionsupporting

confidence: 54%

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

Drozda

Wong

Patel

et al. 2015

Pharmacogenetics and Genomics

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Objectives Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine if omission of the CYP2C9*5, *6, *8, *11 alleles and rs12777823 G>A genotype affects performance of dosing algorithms in African Americans. Methods In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, *6, *8, *11 alleles and rs12777823 G>A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. Results The warfarindosing.org algorithm over-estimated doses by a median (IQR) of 1.2 (0.02 to 2.6) mg/day in rs12777823 heterozygotes (p<0.001 for predicted versus observed dose), 2.0 (0.6 to 2.8) mg/day in rs12777823 variant homozygotes (p=0.004), and 2.2 (0.5 to 2.9) mg/day in carriers of a CYP2C9 variant (p<0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm under-dosed warfarin by 0.8 (−2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (p<0.001) and over-dosed warfarin by 0.7 (−0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (p=0.04). Modifying the warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original warfarindosing.org (p<0.01) or IWPC (p<0.01) algorithm. Conclusions These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

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Section: Discussionsupporting

confidence: 54%

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

Drozda

Wong

Patel

et al. 2015

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

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“…Indeed, the African-American patients in COAG actually fared worse in the genotyped arm when compared with the control arm [34]. The contradictory findings from the two trials have led to much debate and confusion [35][36][37]. Comparison of the EU-PACT and COAG trials There are some similarities but also some fundamental differences between EU-PACT and COAG (Figure 2), which we believe led to the discordant findings.…”

Section: Warfarin-dosing Algorithmsmentioning

confidence: 97%

“…However, the frequency of INR Review Trends in Pharmacological Sciences March 2015, Vol. 36,No. 3 monitoring varies widely in different healthcare settings, and in different countries [29].…”

Section: Clinical Relevancementioning

confidence: 99%

Oral anticoagulation: a critique of recent advances and controversies

Pirmohamed

Kamali

Daly

et al. 2015

Trends in Pharmacological Sciences

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“…Although patients with rare genomic variants likely benefit from this approach, clinical outcomes remain equivalent to conventional prescribing when the testing is deployed across large groups [73, 74]. Conventional warfarin prescribing may therefore be cost-effective overall, but needlessly detrimental to a minority of patients in whom preventable bleeding or thrombotic complications may ensue.…”

Section: Costs and Opportunitiesmentioning

confidence: 99%

A path to precision in the ICU

et al. 2017

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Precision medicine is increasingly touted as a groundbreaking new paradigm in biomedicine. In the ICU, the complexity and ambiguity of critical illness syndromes have been identified as fundamental justifications for the adoption of a precision approach to research and practice. Inherently protean diseases states such as sepsis and acute respiratory distress syndrome have manifestations that are physiologically and anatomically diffuse, and that fluctuate over short periods of time. This leads to considerable heterogeneity among patients, and conditions in which a “one size fits all” approach to therapy can lead to widely divergent results. Current ICU therapy can thus be seen as imprecise, with the potential to realize substantial gains from the adoption of precision medicine approaches. A number of challenges still face the development and adoption of precision critical care, a transition that may occur incrementally rather than wholesale. This article describes a few concrete approaches to addressing these challenges.First, novel clinical trial designs, including registry randomized controlled trials and platform trials, suggest ways in which conventional trials can be adapted to better accommodate the physiologic heterogeneity of critical illness. Second, beyond the “omics” technologies already synonymous with precision medicine, the data-rich environment of the ICU can generate complex physiologic signatures that could fuel precision-minded research and practice. Third, the role of computing infrastructure and modern informatics methods will be central to the pursuit of precision medicine in the ICU, necessitating close collaboration with data scientists. As work toward precision critical care continues, small proof-of-concept studies may prove useful in highlighting the potential of this approach.

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Warfarin Pharmacogenetic Trials: Is there a Future for Pharmacogenetic-Guided Dosing?

Abstract: “In clinical practice, it is common for warfarin to be initiated at a fixed dose for the first several doses.”

Cited by 22 publications

References 19 publications

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

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

Oral anticoagulation: a critique of recent advances and controversies

A path to precision in the ICU

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