Dataset Information

Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users.

ABSTRACT: Importance:Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population. Objectives:To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions. Design, Setting, and Participants:This cross-sectional study included veterans who used national VHA pharmacy services from October 1, 2011, to September 30, 2017. Data analyses began April 26, 2018, and were completed February 6, 2019. Exposures:Receipt of level A drugs based on VHA pharmacy dispensing records. Main Outcomes and Measures:Projected prevalence of actionable pharmacogenetic variants among VHA pharmacy users based on variant frequencies from the 1000 Genomes Project and veteran demographic characteristics; incident number of level A prescriptions, and proportion of new level A drug recipients projected to carry an actionable pharmacogenetic variant. Results:During the study, 7?769?359 veterans (mean [SD] age, 58.1 [17.8] years; 7?021?504 [90.4%] men) used VHA pharmacy services. It was projected that 99% of VHA pharmacy users would carry at least 1 actionable pharmacogenetic variant. Among VHA pharmacy users, 4?259?153 (54.8%) received at least 1 level A drug with 1?188?124 (15.3%) receiving 2 drugs, and 912?189 (11.7%) receiving 3 or more drugs. The most common incident prescriptions during the study were tramadol (923?671 new recipients), simvastatin (533?928 new recipients), citalopram (266?952 new recipients), and warfarin (205?177 new recipients). Gene-drug interactions projected to have substantial clinical impacts in the VHA population include the interaction of SLCO1B1 with simvastatin (1?988?956 veterans [25.6%]), CYP2D6 with tramadol (318?544 veterans [4.1%]), and CYP2C9 or VKORC1 with warfarin (7?163?349 veterans [92.2%]). Conclusions and Relevance:Clinically important pharmacogenetic variants are highly prevalent in the VHA population. Almost all veterans would carry an actionable variant, and more than half of the population had been exposed to a drug affected by these variants. These results suggest that pharmacogenetic testing has the potential to affect pharmacotherapy decisions for commonly prescribed outpatient medications for many veterans.

SUBMITTER: Chanfreau-Coffinier C

PROVIDER: S-EPMC6563578 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users.

Chanfreau-Coffinier Catherine C Hull Leland E LE Lynch Julie A JA DuVall Scott L SL Damrauer Scott M SM Cunningham Francesca E FE Voight Benjamin F BF Matheny Michael E ME Oslin David W DW Icardi Michael S MS Tuteja Sony S

JAMA network open 20190605 6

<h4>Importance</h4>Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population.<h4>Objectives</h4>To project the proportion of veterans in the US Veterans Health Administration (VHA) with action ...[more]

PMID: 31173123

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Project description:Background: Genetic variability in some of the genes that affect absorption, distribution, metabolism, and elimination ("pharmacogenes") can significantly influence an individual's response to the drug and consequently the effectiveness of treatment and possible adverse drug events. The rapid development of sequencing methods in recent years and consequently the increased integration of next-generation sequencing technologies into the clinical settings has enabled extensive genotyping of pharmacogenes for personalized treatment. The aim of the present study was to investigate the frequency and variety of potentially actionable pharmacogenetic findings in the Slovenian population. Methods: De-identified data from diagnostic exome sequencing in 1904 cases submitted to our institution were analyzed for variants within 293 genes associated with drug response. Filtered variants were classified according to population frequency, variant type, the functional impact of the variant, pathogenicity predictions and characterization in the Pharmacogenomics Knowledgebase (PharmGKB) and ClinVar. Results: We observed a total of 24 known actionable pharmacogenetic variants (PharmGKB 1A or 1B level of evidence), comprising approximately 26 drugs, of which, 12 were rare, with the population frequency below 1%. Furthermore, we identified an additional 61 variants with PharmGKB 2A or 2B clinical annotations. We detected 308 novel/rare potentially actionable variants: 177 protein-truncating variants and 131 missense variants predicted to be pathogenic based on several pathogenicity predictions. Conclusion: In the present study, we estimated the burden of pharmacogenetic variants in nationally based exome sequencing data and investigated the potential clinical usefulness of detected findings for personalized treatment. We provide the first comprehensive overview of known pharmacogenetic variants in the Slovenian population, as well as reveal a great proportion of novel/rare variants with a potential to influence drug response.

Project description:ImportanceAndrogen deficiency is common among male opioid users, and opioid use has emerged as a common antecedent of testosterone treatment. The long-term health outcomes associated with testosterone therapy remain unknown, however.ObjectiveTo compare health outcomes between long-term opioid users with testosterone deficiency who filled testosterone prescriptions and those with the same condition but who did not receive testosterone treatment.Design, setting, and participantsThis cohort study focused on men in the care of the Veterans Health Administration (VHA) facilities throughout the United States from October 1, 2008, to September 30, 2014. It included male veterans who were long-term opioid users, had low testosterone levels (<300 ng/dL), and received either a testosterone prescription or any other prescription. It excluded male patients with HIV infection, gender dysphoria, or prostate cancer and those who received testosterone in fiscal year 2008. Data were analyzed from April 1, 2017, to April 30, 2019.ExposurePrescription for testosterone.Main outcomes and measuresAll-cause mortality and incidence of major adverse cardiovascular events (MACE), vertebral or femoral fractures, and anemia during the 6-year follow-up through September 30, 2015.ResultsAfter exclusions, 21 272 long-term opioid users (mean [SD] age, 53 [10] years; n = 16 689 [78.5%] white) with low total or free testosterone levels were included for analysis, of whom 14 121 (66.4%) received testosterone and 7151 (33.6%) did not. At baseline, compared with opioid users who did not receive testosterone, long-term opioid users who received testosterone treatment were more likely to have obesity (43.7% vs 49.0%; P < .001), hyperlipidemia (43.0% vs 48.8%; P < .001), and hypertension (53.9% vs 55.2%; P = .07) but had lower prevalence of coronary artery disease (15.9% vs 12.9%; P < .001) and stroke (2.4% vs 1.3%; P < .001). After adjusting for covariates, opioid users who received testosterone had significantly lower all-cause mortality (hazard ratio [HR] = 0.51; 95% CI, 0.42-0.61) and lower incidence of MACE (HR = 0.58; 95% CI, 0.51-0.67), femoral or hip fractures (HR = 0.68; 95% CI, 0.48-0.96), and anemia (HR = 0.73; 95% CI, 0.68-0.79) during the follow-up period of up to 6 years, compared with their counterparts without a testosterone prescription. In covariate-adjusted models, men who received opioids plus testosterone were more likely to have resolved anemia compared with those who received opioids only during the 6-year follow-up (HR = 1.16; 95% CI, 1.02-1.31). Similar results were obtained in propensity score-matched models and when analyses were restricted to opioid users with noncancer pain or those who did not receive glucocorticoids.Conclusions and relevanceThis study found that, in the VHA system, male long-term opioid users with testosterone deficiency who were treated with opioid and testosterone medications had significantly lower all-cause mortality and significantly lower incidence of MACE, femoral or hip fractures, and anemia after a multiyear follow-up. These results warrant confirmation through a randomized clinical trial to ascertain the efficacy of testosterone in improving health outcomes for opioid users with androgen deficiency.

Dataset Information

Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users.

Publications

Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users.

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