Curators' Favorite Papers

For this month's edition of "Curators' Favorite Papers" we present two articles discussing how the recommendations from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines have been used at two different healthcare settings.

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services by Sissung et al. discusses the experience of the Cleveland Clinic with pharmacogenetic (PGx) implementation as well as how a collaboration between pharmacists and physician-geneticists established an ambulatory PGx clinic to provide testing, interpretation, prescribing recommendations, and patient education. The authors go on to discuss how the implementation of three CPIC guidelines (HLA-B*57:01 and abacavir and HLA-B*15:02 and carbamazepine and TPMT and thiopurines) was managed by pharmacists that incorporated patient data into electronic health records (EHR) who developed clinical decision support tools (CDS) based on CPIC guidelines and included custom pre- and post-test alerts. The selection of which guidelines to implement was based on third-party payment reimbursement for genetic tests, the life-threatening nature of potential adverse events as recognized by the Food and Drug Administration (FDA) in drug labels and physician support.

Pharmacogenomics Implementation at the National Institutes of Health Clinical Center also by Sissung et al. reviews the PGx implementation process at the National Institutes of Health Clinical Center (NIH CC), which uses the recommendations of CPIC guidelines to inform the selection of gene-drug pairs to be implemented.  The NIH CC has already implemented PGx testing and prescribing recommendations for HLA-B alleles with allopurinol, abacavir, and carbamazepine, and it is currently in the process of PGx implementation for genes involved in the absorption, distribution, metabolism, or excretion (ADME) of drugs using the DMET genotyping platform.  The NIH CC model makes PGx testing, results and recommendations available to all NIH clinicians and also makes test results available to patients and their personal care physicians. The NIH CC expects to cover all CPIC gene-drug pairs within the next five years.

Additional guidelines can be found on the CPIC and PharmGKB and additional information about drugs and genes can also be found on PharmGKB.

Genotype-Guided Warfarin Dosing Lowers Rate of Composite Adverse Events vs. Clinical Dosing

Warfarin is a widely prescribed blood-thinning agent to prevent strokes, heart attacks, and blood blots. Despite the extensive literature documenting the significant association between CYP2C9/VKORC1 genotypes and warfarin dose, there's still debate surrounding the clinical utility of the genotype-guided warfarin dosing. A few large randomized clinical trials have been published with mixed results. Using the percentage of time that a patient is within the therapeutic range (PTTR) as the primary endpoint, two studies (Kimmel et al 2013, Verhoef et al 2013) showed no significant difference between the genotype-guided group vs. control, while one study (Pirmohamed et al 2013) suggested improvement with added genetic information. Additionally, these trials were not powered to examine clinical outcomes such as bleeding and thrombotic complications. The long-awaited Genetic Informatics Trial (GIFT) of warfarin is the first warfarin pharmacogenetics trial powered for these safety outcomes. The result of GIFT trial has just been published this month in JAMA and demonstrated genotype-guided warfarin dosing lowered the combined risk of adverse events compared to clinical dosing.

In this multicenter randomized controlled trial, 1650 patients 65 years or older initiating warfarin for elective hip or knee arthroplasty were randomized to receive either genotype-guided or clinically-guided warfarin dosing on day 1 through day 11 of therapy. 1597 patients completed the trial. The primary endpoint was the composite of major bleeding, venous thromboembolism, international normalized ratio (INR) of 4 or greater, and death. The GIFT trial included genotyping for CYP2C9*2, *3, VKORC1 -1639G>A and CYP4F2 V433M, but did not include the African American specific CYP2C9 alleles or CYP2C variant rs12777823 (6.4% of the 1597 patients were black). The rate of composite adverse events was 10.8% in the genotype-guided group, versus 14.7% in the clinically guided group, corresponding to 3.9% absolute risk reduction ([95%CI, 0.7%-7.2%], p=0.02) and 27% relative risk reduction (RR=0.73, [95% CI, 0.56-0.95]). The absolute reduction in risk appears to be primarily due to improved INR control in the genotype-guided group. This is the first randomized controlled trial confirming the clinical benefit of genotype-guided warfarin dosing with a lower rate of adverse events, exemplifying the use of genetic information to improve patient outcomes.

Read the articles:

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty The GIFT Randomized Clinical Trial. JAMA. 2017;318(12):1115–1124. 
Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Li J, Rodríguez T, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple BD, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Anderson JL, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Dávila-Román V, Eby CS

Editorial:
Pharmacogenomic Testing and Warfarin What Evidence Has the GIFT Trial Provided?. JAMA.2017;318(12):1110–1112
Emery JD

Interview about the GIFT trial, Pharmacogenetics and Warfarin.  Pharmacogenomics 2017 Oct; 18(15) 1379-1380
Gage BF

More information on warfarin dosing:

CPIC Guideline for Pharmacogenetics-Guided Warfarin Dosing

PharmVar Launches Website

The Cytochrome P450 (CYP) Allele Nomenclature Database has transitioned to the Pharmacogene Variation Consortium at www.PharmVar.org.  Please check out the PharmVar website!

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