Antibiotic stewardship in the emergency department setting: Focus on oral antibiotic selection for adults with skin and soft tissue infections.

PURPOSE: An advisory panel of experts was convened by the ASHP Foundation as a part of its Medication-Use Evaluation Resources initiative to provide commentary on an approach to antibiotic stewardship in the treatment of skin and soft tissue infections (SSTIs), with a focus on oral antibiotics in the emergency department (ED) setting for patients who will be treated as outpatients. Considerations include a need to update existing guidelines to reflect new antibiotics and susceptibility patterns, patient-specific criteria impacting antibiotic selection, and logistics unique to the ED setting. SUMMARY: While national guidelines serve as the gold standard on which to base SSTI treatment decisions, our advisory panel stressed that institutional guidelines must be regularly updated and grounded in local antimicrobial resistance patterns, patient-specific factors, and logistical considerations. Convening a team of experts locally to establish institution-specific guidelines as part of a comprehensive antibiotic stewardship program can ensure patients receive the most appropriate oral therapy for the outpatient treatment of SSTIs in patients visiting the ED. CONCLUSION: SSTI treatment considerations for antibiotic selection in the ED supported by current, evidence-based guidelines, including guidance on optimal oral antibiotic selection for patients discharged for outpatient treatment, are a useful tool to improve the quality and efficiency of care, enhance patient-centric outcomes and satisfaction, decrease healthcare costs, and reduce overuse of antibiotics.

Pharmacogenetic testing and monitoring of complete blood counts among Veterans newly prescribed thiopurine treatments: a retrospective cohort study.

Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA's efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021. Aggregate monthly counts of thiopurine prescriptions and associated lab tests were tabulated, and the trend in the proportion of patients tested was analyzed using the Mann-Kendall test. The proportion of patients undergoing PGx testing rose from 30.0% in 2010 to 47.5% in late 2014 (July-December). However, PGx testing and overall testing only increased slightly after the sentinel event, and orders levelled off over time at slightly lower levels than before the sentinel event. Very little change was seen in the overall proportion of individuals receiving any testing across all patients with new prescriptions from the time of the sentinel event in 2014 to the end of 2021. A large portion of patients prescribed thiopurine drugs did not receive testing that could help prevent the development of potential adverse events, leading to a predominantly reactive approach. Increased PGx testing may result in a more proactive approach to the prevention of adverse events due to genetic interaction.

Buprenorphine use and courses of care for opioid use disorder treatment within the Veterans Health Administration.

BACKGROUND: Retention of patients in buprenorphine medication treatment for opioid use disorder (B-MOUD) reduces harms associated with opioid use disorder (OUD). We sought to characterize the patients receiving B-MOUD and courses of B-MOUD in a large healthcare system. METHODS: We conducted a retrospective, open cohort study of patients with OUD who either did or did not receive B-MOUD courses within the Veterans Health Administration (VHA) from January 2006 through July 2019, using VHA clinical data. We compared patients receiving or not receiving B-MOUD, characterized B-MOUD courses (e.g., length and doses), and examined persistence, across patient characteristics, over time. We used analyses for normally or non-normally distributed continuous variables, categorical data, and persistence over time (Kaplan-Meier persistence curves). RESULTS: We identified 255,726 Veterans with OUD; 40,431 (15.8%) had received 63,929 B-MOUD courses. Compared to patients with OUD without B-MOUD, patients with B-MOUD were younger, more often of white race, and had more co-morbidities. The frequency of new B-MOUD starts and prevalent B-MOUD patients ranged from 1550 and 1989 in 2007 to 8146 and 16,505 in 2018, respectively. The median duration of B-MOUD was 157 (IQR: 37-537) days for all courses and 33.8% patients had more than one course. The average proportion days covered was 90% (SD: 0.15), and the average prescribed daily dose was 13.44 (SD: 6.5). CONCLUSIONS: Within a VHA B-MOUD cohort, courses increased more than 10-fold from 2006 to 2016 with nearly half of patients experiencing multiple courses. Patient demographics seem to dictate the length of courses.

Veterans Health Administration: Implementation of pharmacogenomic clinical decision support with statin medications and the SLCO1B1 gene as an exemplar.

PURPOSE: To describe the implementation of clinical decision support tools for alerting prescribers of actionable drug-gene interactions in the Veterans Health Administration (VHA). SUMMARY: Drug-gene interactions have been the focus of clinicians for years. Interactions between SCLO1B1 genotype and statin medications are of particular interest as these can inform risk for statin-associated muscle symptoms (SAMS). VHA identified approximately 500,000 new users of statin medications prescribed in VHA in fiscal year 2021, some of whom could benefit from pharmacogenomic testing for the SCLO1B1 gene. In 2019, VHA implemented the Pharmacogenomic Testing for Veterans (PHASER) program to offer panel-based, preemptive pharmacogenomic testing and interpretation. The PHASER panel includes SLCO1B1, and VHA utilized Clinical Pharmacogenomics Implementation Consortium statin guidelines to build its clinical decision support tools. The program's overarching goal is to reduce the risk of adverse drug reactions such as SAMS and improve medication efficacy by alerting practitioners of actionable drug-gene interactions. We describe the development and implementation of decision support for the SLCO1B1 gene as an example of the approach being used for the nearly 40 drug-gene interactions screened for by the panel. CONCLUSION: The VHA PHASER program identifies and addresses drug-gene interactions as an application of precision medicine to reduce veterans' risks for adverse events. The PHASER program's implementation of statin pharmacogenomics utilizes a patient's SCLO1B1 phenotype to alert providers of the risk for SAMS with the statin being prescribed and how to lower that risk through a lower dose or alternative statin selection. The PHASER program may help reduce the number of veterans who experience SAMS and may improve their adherence to statin medications.

Comparison of hospitalization costs for the same adverse reaction associated with different medications.

PURPOSE: Costs of hospitalization due to severe adverse drug reactions (ADRs) were previously estimated within the Veterans Health Administration (VHA), but additional analyses are needed to infer potential interventions to mitigate these negative outcomes. The objective of this study was to compare specific adverse reaction-related hospitalization costs between medications with similar indications. METHODS: Mean hospitalization costs associated with the same ADR symptom were compared for different drugs with similar indications using adjusted generalized linear models with a Bonferroni correction for multiple comparisons as well as a gamma distribution. RESULTS: Overall, hospitalization costs between medications with similar indications were not significantly different for specific adverse reactions. However, gastrointestinal hemorrhage-associated costs were higher for warfarin versus nonsteroidal anti-inflammatory drugs (model estimate of mean cost, $18,114 [range of lower and upper model estimates, $12,522-$26,202] vs $14,255 [estimate range, $9,710-$20,929]). Similarly, the estimated mean hospitalization cost associated with angioedema was higher for losartan versus lisinopril or lisinopril/hydrochlorothiazide: $14,591 (range, $9467-$22,488) versus $8,935 (range, $6,301-$12,669) and $8,022 (range, $5,424-$11,865), respectively. CONCLUSION: Although we found few differences in the cost of hospitalization when comparing drugs with similar indications and the same adverse reaction, there were specific drug-ADR pairs that merit attention and consideration of interventions to improve safe and appropriate medication use. Evaluation of the effect of those interventions on the incidence of ADRs is an area for future study.

PCSK9 Inhibitor Use and Outcomes Using Concomitant Lipid-Lowering Therapies in the Veterans Health Administration.

Background: Real-world data on use of PCSK9 inhibitors (PCSK9-Is), with or without statins and/or ezetimibe, and associated outcomes, can inform more effective prescribing. The objective was to evaluate clinical effectiveness and safety of PCSK9-Is within the Veterans Health Administration (VHA). Methods: In this retrospective cohort study, we included Veterans who had at least one outpatient prescription for alirocumab and/or evolocumab filled within VHA between August 21, 2015, and September 30, 2020. Analyses included 4 mutually exclusive subgroups: PCSK9-I alone, PCSK9-I+statin, PCSK9-I+ezetimibe, and PCSK9-I+statin+ezetimibe subgroups. Primary outcomes included medication possession ratio, persistence, and low-density lipoprotein (LDL). Results: Among Veterans in the analytical cohort (n = 2428), 36.2% were on PCSK9-I monotherapy; 24.0% received a PCSK9-I+statin; 27.4% were on a PCSK9-I+ezetimibe; and 12.4% received triple therapy, that is, PCSK9-I+statin+ezetimibe. The mean medication possession ratio (standard deviation [SD]) for PCSK9-I monotherapy was 83.8% (13.3) compared to 84.3% (11.2) with PCSK9-I+statin therapy, 87.1% (10.1) with PCSK9-I+ezetimibe therapy, and 85.8% (11.7) with triple therapy. The percentage of patients who discontinued PCSK9-I in the monotherapy subgroup was 12.3% vs 9.5%, 6.6%, and 7.4% in the concomitant statin, ezetimibe, and triple-therapy subgroups, respectively (p = .002 among the groups). Mean LDL level was greater in the PCSK9-I monotherapy subgroup (85.6 mg/dL) compared with the concomitant statin (66.5 mg/dL), ezetimibe (65.7 mg/dL), and triple-therapy subgroups (68.1 mg/dL). Conclusions: Veterans showed good adherence and/or persistence with PCSK9-I regimens. On average, those receiving concomitant therapy with a statin and/or ezetimibe achieved significantly lower LDL levels.

VA Big Data Science: A Model for Improved National Pandemic Response Present and Future.

Background: The US Department of Veterans Affairs (VA) enterprise approach to research (VA Research) has built a data-sharing framework available to all research teams within VA. Combined with robust analytic systems and tools available for investigators, VA Research has produced actionable results during the COVID-19 pandemic. Big data science techniques applied to VA's health care data demonstrate that medical research can be performed quickly and judiciously during nationwide health care emergencies. Observations: We envision a common framework of data collection, management, and surveillance implemented in partnership with other health care agencies that would capture even broader, actionable, and timely observational data on populations, while providing opportunities for enhanced collaborative research across agencies. This model should be continued and expanded through the current COVID-19 and future pandemics. Conclusions: Extending the achievements of VA Research in the COVID-19 pandemic to date, we advocate national goals of open science by working toward a synergistic national framework of anonymized, synchronized, shared health data that would provide researchers with potent tools to combat future public health crises.

Medication Use Evaluation of High-Dose Long-Term Opioid De-prescribing in Multiple Veterans Affairs Medical Centers.

BACKGROUND: The Opioid Safety Initiative (OSI) was implemented in 2013 to enhance the safe and appropriate use of opioids in the Veterans Health Administration (VA). Opioid use decreased nationally in subsequent years, but characterization of opioid de-prescribing practices has not been well established. OBJECTIVES: To describe changes in patient characteristics and patterns of de-prescribing since OSI implementation for opioid users at > 90 morphine equivalent daily dose for at least 90 days for those that discontinued opioids within the VA. DESIGN: Retrospective observational pre-post intervention medication use evaluation using VA data and electronic health records to identify differences in opioid de-prescribing between fiscal year 2013 (FY13; early OSI) and FY17 (late OSI). Reviewers' insights for local opioid management and de-prescribing practices collected through web-based post-data collection survey. PARTICIPANTS: Veterans prescribed high-dose long-term opioid therapy in FY13 and FY17 who subsequently discontinued opioids at 27 VA medical centers. MAIN MEASURES: Chart review data from local facility reviewers identified socioeconomic characteristics, opioid de-prescribing rationale (e.g., risk-benefit, diversion) and practices (e.g., rate of opioid discontinuation, taper monitoring activities, withdrawal monitoring), and outcomes following discontinuation. KEY RESULTS: Among 315 patients in FY13 and 322 patients in FY17 with opioid discontinuation, discontinuation rationale focused on diversion in FY13 and risk-benefit in FY17. Clinical pharmacists and pain management specialists had increased involvement in FY17 opioid discontinuations (36% versus 16%). Of all discontinuations, 56% of patients were tapered in FY13 versus 70% of patients in FY17. Tapering plans were longer in FY17 than in FY13 (163 days versus 65 days). Transitions to non-opioid pain therapy following opioid discontinuation were higher in FY17 compared to FY13 (70% versus 60%). CONCLUSIONS: Veterans discontinued from high-dose long-term opioids in FY17 were more optimally managed compared to those in FY13. Findings suggest improvements in opioid de-prescribing following OSI implementation, but interpretation is limited by study design.

Interventions to Increase Leukocyte Testing during Treatment with Dimethyl Fumarate.

Dimethyl fumarate (DMF), a treatment for multiple sclerosis, may cause leukopenia and infection. Accordingly, periodic white blood cell (WBC) monitoring is recommended. We sought to evaluate the US Department of Veteran Affairs' safety program which provides facilities with a list of patients prescribed DMF therapy without a documented white blood cell count (WBC). We identified 118 sites with patients treated with DMF from 1 January 2016 through 30 September 2016. Each site was asked if any of seven interventions were used to improve WBC monitoring (academic detailing, provider education without academic detailing, electronic clinical reminders, request for provider action plan, draft orders for WBC monitoring, patient mailings, and patient calls). The survey response rate was 78%. For the 92 responding sites (78%) included sites (1115 patients) the mean rate of WBC monitoring was 54%. In multivariate analysis, academic detailing increased the rate by 17% (95% CI 4 to 30%, p = 0.011) and provider education increased the rate by 9% (95% CI 0.6 to 18%, p = 0.037). The WBC monitoring rate increased by 3.8% for each additional intervention used (95% CI 1.2-6.4%, p = 0.005). Interventions focused on the physician, including academic detailing, were associated with improved WBC monitoring for patients at risk for leukopenia from DMF treatment.

Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System.

Importance: Using real-world data, the US Department of Veterans Affairs (VA) initiated a surveillance evaluation of edaravone after its approval for amyotrophic lateral sclerosis (ALS) in 2017. The use and safety of edaravone for patients with ALS in the VA health care system remain to be assessed. Objective: To describe a pharmacovigilance surveillance initiative with edaravone to monitor patient characteristics, utilization (edaravone cycles and riluzole use), and safety and to evaluate safety/effectiveness. Design, Setting, and Participants: This propensity score-matched cohort study used data on 369 patients with documented definite or probable ALS in the Veterans Health Administration (VHA) with at least 1 prescription for edaravone between August 1, 2017, and September 30, 2019. The analysis compared edaravone (alone or with riluzole) with riluzole only. For chronic users (≥6 months of drug), a time-to-event model evaluated ALS-related outcomes, with censoring at outcome, death, or end of evaluation. Patients with Parkinson disease, dementia, schizophrenia, or significant respiratory insufficiency per diagnosis codes within 2 years before prescription initiation were excluded. In overall matched cohorts, 223 patients treated with edaravone were 1:3 propensity score matched based on predefined confounders. For the chronic user subgroup analysis, 96 patients receiving edaravone and 424 patients receiving riluzole only were included. Exposures: Edaravone (alone or with riluzole) vs riluzole only. Main Outcomes and Measures: Patient characteristics, ALS drug use, and mortality. Acute outcomes (within 6 months of index) included proportion and mean time to event for death, discontinuation, or all-cause hospitalization, and outcomes for chronic users (receiving >6 months of treatment) included hazard ratios of outcomes related to disease-state progression. Results: Of 369 patients who received edaravone, most were older (mean [SD] age, 64.6 [11.3] years), male (346 [93.8%]), and White (261 [70.7%]). As of September 2019, 59.9% of edaravone patients had discontinued treatment; of those, 49.5% (108 of 218) received only 1 to 3 treatment cycles. Approximately 30% (110 patients) died. In a matched evaluation, significantly more acute all-cause hospitalization events occurred with edaravone (35.4% vs 22.0% for riluzole only); 72.6% of the edaravone cohort received edaravone with riluzole. Among chronic users, edaravone patients (70.8% edaravone with riluzole) had an increased hazard ratio of ALS-associated hospitalization (2.51; 95% CI, 1.18-8.16). The death rate was lower with edaravone but the difference was not statistically significant. Conclusions and Relevance: Early edaravone discontinuation was common in the VA. Although outcomes favored use of riluzole only in the matched analysis, results should be interpreted with caution, as unmeasured bias in observational data is likely.

Serious cardiovascular adverse events with fluoroquinolones versus other antibiotics: A self-controlled case series analysis.

The objective of this study was to evaluate the association between fluoroquinolone (FQ) use and the occurrence of aortic aneurysm/dissection (AA/AD), acute myocardial infarction (AMI), ventricular arrhythmias (VenA), and all-cause mortality vs other commonly used antibiotics. We conducted a self-controlled case series analysis of patients who experienced the outcomes of AA/AD, AMI, and VenA, based on diagnosis codes from emergency department visits and hospitalizations within Veterans Health Administration, and death in FY2014-FY2018. These Veterans also received outpatient prescriptions for FQs. Conditional Poisson regression models were used to estimate the association between FQs and each of the outcomes vs antibiotics of interest (ie amoxicillin or amoxicillin/clavulanate, azithromycin, doxycycline, cefuroxime or cephalexin, or sulfamethoxazole-trimethoprim), adjusted for time-varying covariates. Using a 30-day risk period after each antibiotic prescription, adjusted incidence rate ratios (aIRRs) for FQs vs each comparator antibiotic were not statistically different for outcomes of VenA or AMI. For AA/AD, incidence was higher during FQ risk periods vs amoxicillin [aIRR 1.50 (95% CI 1.01, 2.25)] and azithromycin [aIRR 2.15 (95% CI 1.27, 3.64)] risk periods. A significantly increased risk of mortality was observed with FQs vs each antibiotic of interest. FQs were associated with an increased risk of AA/AD vs amoxicillin and azithromycin and an increased risk of all-cause mortality vs multiple antibiotics commonly used for outpatient infections. Although the differences in event rates are small, FQ use should be limited to serious infections without appropriate alternatives.

Inpatient Management of Uncomplicated Skin and Soft Tissue Infections in 34 Veterans Affairs Medical Centers: A Medication Use Evaluation.

BACKGROUND: Skin and soft tissue infections (SSTIs) are a key antimicrobial stewardship target because they are a common infection in hospitalized patients, and non-guideline-concordant antibiotic use is frequent. To inform antimicrobial stewardship interventions, we evaluated the proportion of veterans hospitalized with SSTIs who received guideline-concordant empiric antibiotics or an appropriate total duration of antibiotics. METHODS: A retrospective medication use evaluation was performed in 34 Veterans Affairs Medical Centers between 2016 and 2017. Hospitalized patients who received antibiotics for uncomplicated SSTI were included. Exclusion criteria were complicated SSTI, severe immunosuppression, and antibiotics for any non-SSTI indication. Data were collected by manual chart review. The primary outcome was the proportion of patients receiving both guideline-concordant empiric antibiotics and appropriate treatment duration, defined as 5-10 days of antibiotics. Data were analyzed and reported using descriptive statistics. RESULTS: Of the 3890 patients manually evaluated for inclusion, 1828 patients met inclusion criteria. There were 1299 nonpurulent (71%) and 529 purulent SSTIs (29%). Overall, 250 patients (14%) received guideline-concordant empiric therapy and an appropriate duration. The most common reason for non-guideline-concordance was receipt of antibiotics targeting methicillin-resistant Staphylococcus aureus (MRSA) in 906 patients (70%) with a nonpurulent SSTI. Additionally, 819 patients (45%) received broad-spectrum Gram-negative coverage, and 860 patients (48%) received an antibiotic duration >10 days. CONCLUSIONS: We identified 3 common opportunities to improve antibiotic use for patients hospitalized with uncomplicated SSTIs: use of anti-MRSA antibiotics in patients with nonpurulent SSTIs, use of broad-spectrum Gram-negative antibiotics, and prolonged durations of therapy.

Reporting of adverse drug events in the Veterans Health Administration for patients whose treatment with empagliflozin or apixaban was discontinued.

PURPOSE: To examine the reporting rates of adverse drug events (ADEs) with apixaban and empagliflozin as reports move up to the next level of spontaneous reporting. METHODS: This was a retrospective cohort study of outpatients who discontinued apixaban or empagliflozin within 3 years of Food and Drug Administration (FDA) approval. We enriched the sample using an active surveillance strategy to identify subsets of patients with International Classification of Diseases (ICD) codes possibly associated with an ADE. Stratified random samples of charts were reviewed to determine if patients discontinued the medication due to an ADE. If so, we ascertained whether these were uploaded into the Veterans Administration (VA) electronic health record reporting system (Adverse Reaction Tracking System [ARTS]), VA national Web-based system (VA Adverse Drug Event Reporting System [VA ADERS]), and FDA MedWatch. RESULTS: From the cohort of 2,973 patients who discontinued apixaban, 321 patients (10.8%) were randomly sampled for chart review (including 61 patients with relevant ICD codes). During chart review, 88 ADEs were identified, with 40/61 (65.6%) from the subset with ICD codes. Of the total of 88 ADEs, 18.2%, 10.2%, and 6.8% were reported in ARTS, VA ADERS, and MedWatch, respectively. Of the 1,555 patients who discontinued empagliflozin, 179 patients (11.5%) were randomly sampled for chart review (40 patients with relevant ICD codes). During chart review, 78 ADEs were identified, with 19/40 (47.5%) from the subset with ICD codes. Of the 78 ADEs, 28.2%, 19.2%, and 7.7% were reported in ARTS, VA ADERS, and MedWatch, respectively. CONCLUSION: We found substantial underreporting of apixaban and empagliflozin ADEs that became worse at each higher level of spontaneous reporting.

Use of targeted therapies for advanced renal cell carcinoma in the Veterans Health Administration.

BACKGROUND: The objective of this study is to describe the use of targeted therapies for the treatment of advanced renal cell carcinoma (RCC) and overall survival (OS) among patients in clinical practice in the Veterans Health Administration (VHA). METHODS: A retrospective cohort of 286 patients from 24 VHA Medical Centers diagnosed with advanced clear cell RCC between Fiscal Year (FY) 2010 and FY2014 was followed through September 30, 2016. Among patients who received targeted therapy, we described the medications taken, duration of therapy, and overall survival. We also assessed the effect of the first therapy received on overall survival using Cox Proportional Hazards models. RESULTS: There were 66 patients who did not receive therapy for their advanced RCC. Of the 220 treated patients, the mean (sd) number of medications received was 1.9 (1.1). The medications most commonly used first were sunitinib (61.8%), pazopanib (17.3%), and temsirolimus (10.9%). The median duration of first-line therapy was 86 days (interquartile range [IQR] 42, 210). Median total duration of therapy was 159 days (IQR 58, 397). 62.3% of patients had ≥ 1 dose of therapy held or reduced, mainly due to an adverse drug event (ADE). Median survival from the start of treatment to death was 1.08 years (IQR 0.80, 1.31). Finally, receipt of temsirolimus vs sunitinib (HR 1.95 [95%CI 1.09,3.47]) as the first targeted therapy was independently associated with an increased hazard of death. CONCLUSION: Our analysis of targeted therapies for advanced RCC in VHA suggests duration of treatment is shorter in a real-world setting than in clinical trials, and dose reductions and ADEs are more common.

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

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.

Adverse drug reactions in the Veterans Affairs healthcare system: Frequency, severity, and causative medications analyzed by patient age.

PURPOSE: Adverse drug events (ADEs) in the U.S. Department of Veterans Affairs (VA) were evaluated, and differences in age group report rates and reported medications in different age groups were assessed. METHODS: We utilized the VA Adverse Drug Event Reporting System (ADERS) to assess 10-year age groups regarding ADE reporting rates, event severity, and associated reported medications. Data were derived from 484,351 ADE reports from 395,703 patients included in VA ADERS from 2009 through 2016. RESULTS: Reported rates of ADEs per 10,000 unique users demonstrated a nonlinear relationship with age, peaking in the group aged 60-69 years (148.6 reports/10,000 unique users) and declining thereafter. However, the percentage of adverse events reported as severe consistently rose with age group (3% in patients age 20-29 years versus 6% in patients older than 90 years). The types of medications reported as causative agents shifted over time from predominantly mental health and pain medications in younger veterans (e.g., age 20-29 years) to medications for chronic diseases in older cohorts (e.g., age 60-69 years). CONCLUSION: An analysis of VA ADE reports revealed a nonlinear relationship between age and events, with events peaking at age 60-69 years. Rates of severe ADEs increased in older age groups. Drugs commonly associated with ADEs tended to be those primarily used for mental health and pain treatment in younger patients and those used to address chronic disease states in older patients.

Central Nervous System Medication Burden and Risk of Recurrent Serious Falls and Hip Fractures in Veterans Affairs Nursing Home Residents.

OBJECTIVES: To examine the association between central nervous system (CNS) medication dosage burden and risk of serious falls, including hip fractures, in individuals with a history of a recent fall. DESIGN: Nested case-control study. SETTING: Veterans Health Administration (VHA) Community Living Centers (CLCs). PARTICIPANTS: CLC residents aged 65 and older with a history of a fall or hip fracture in the year before a CLC admission between July 1, 2005, and June 30, 2009. Each case (n = 316) was matched to four controls (n = 1264) on age, sex, and length of stay. MEASUREMENTS: Outcomes were serious falls identified using International Classification of Diseases, Ninth Revision (ACD-9) or Current Procedural Terminology (CPT) E codes, diagnosis codes, or procedure codes associated with a VHA emergency department visit or hospitalization during the CLC stay. Bar code medication administration data were used to calculate CNS standardized daily doses (SDDs) for opioid and benzodiazepine receptor agonists, some antidepressants, antiepileptics, and antipsychotics received in the 6 days before the outcome date by dividing residents' actual CNS daily doses by the minimum effective geriatric daily doses and adding the results. Multivariable conditional logistic regression models were used to evaluate the association between total CNS medication dosage burden, categorized as 0, 1 to 2, and 3 or more SDDs, and the outcome of recurrent serious falls. RESULTS: More cases (44.3%) than controls (35.8%) received 3.0 or more CNS SDDs (p = .02). Risk of serious falls was greater in residents with 3.0 or more SDDs than in those with 0 (adjusted odds ratio (aOR)=1.49, 95% confidence interval (CI)=1.03-2.14). Those with 1.0 to 2.9 SDDs had a risk similar to that of those with 0 SDDs (aOR=1.03, 95%CI=0.72-1.48). CONCLUSION: Nursing home residents with a history of a fall or hip fracture receiving 3.0 or more CNS SDDs were more likely to have a recurrent serious fall than those taking no CNS medications. Interventions targeting this vulnerable population may help reduce serious falls. J Am Geriatr Soc 67:74-80, 2019.

Preventing Hepatitis B Reactivation During Anti-CD20 Antibody Treatment in the Veterans Health Administration.

Hepatitis B virus (HBV) reactivation may occur with high risk immunosuppression, such as anti-cluster of differentiation (CD)20 antibodies (Abs). Appropriate HBV prophylaxis during anti-CD20 Ab therapy averts hepatitis, chemotherapy disruption, and death. Serologic evidence of prior HBV exposure is present in one in nine veterans in the Veterans Health Administration (VHA). In 2014, most (61%-73%) patients in the VHA who were receiving anti-CD20 Ab treatment underwent HBV testing, yet <20% of eligible patients received HBV antiviral prophylaxis. We aimed to prevent HBV reactivation by increasing HBV testing and antiviral treatment rates among anti-CD20 Ab recipients through prospective interventions. A multidisciplinary team of clinicians, pharmacists, and public health professionals developed comprehensive prevention systems, including national seminars/newsletters/websites; pharmacy criteria for HBV screening/treatment prior to anti-CD20 Ab use; changes to national formulary restrictions to expand HBV prophylaxis prescribing authority; Medication Use Evaluation Tracker to identify omissions; national e-mail alert to all VHA oncology providers detailing specific testing and HBV antiviral treatment needs; and a voluntary electronic medical record "order check" used at interested facilities (n = 11) to automatically assess pretreatment HBV testing and antiviral treatment and only generate a reminder to address deficiencies. Analysis of monthly data from June 2016 through September 2017 among anti-CD20 Ab recipients revealed pre-anti-CD20 Ab treatment HBV testing increased to 91%-96% and appropriate HBV antiviral prophylaxis to 76%-85% nationally following implementation of the intervention. Medical centers using the voluntary electronic medical record order check increased HBV testing rates to 93%-98% and HBV antiviral prophylaxis rates to 99%. Conclusion: Multimodal intervention systems to prevent HBV reactivation among VHA patients receiving anti-CD20 Ab therapies increased national rates of HBV testing to >90% and antiviral prophylaxis to >80%.