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.

Impact of Dual Use of Department of Veterans Affairs and Medicare Part D Drug Benefits on Potentially Unsafe Opioid Use.

OBJECTIVES: To estimate the prevalence and consequences of receiving prescription opioids from both the Department of Veterans Affairs (VA) and Medicare Part D. METHODS: Among US veterans enrolled in both VA and Part D filling 1 or more opioid prescriptions in 2012 (n = 539 473), we calculated 3 opioid safety measures using morphine milligram equivalents (MME): (1) proportion receiving greater than 100 MME for 1 or more days, (2) mean days receiving greater than 100 MME, and (3) proportion receiving greater than 120 MME for 90 consecutive days. We compared these measures by opioid source. RESULTS: Overall, 135 643 (25.1%) veterans received opioids from VA only, 332 630 (61.7%) from Part D only, and 71 200 (13.2%) from both. The dual-use group was more likely than the VA-only group to receive greater than 100 MME for 1 or more days (34.3% vs 10.9%; adjusted risk ratio [ARR] = 3.0; 95% confidence interval [CI] = 2.9, 3.1), have more days with greater than 100 MME (42.5 vs 16.9 days; adjusted difference = 16.4 days; 95% CI = 15.7, 17.2), and to receive greater than 120 MME for 90 consecutive days (7.8% vs 3.1%; ARR = 2.2; 95% CI = 2.1, 2.3). CONCLUSIONS: Among veterans dually enrolled in VA and Medicare Part D, dual use of opioids was associated with more than 2 to 3 times the risk of high-dose opioid exposure.

Management of Bacteriuria in Veterans Affairs Hospitals.

BACKGROUND: Bacteriuria contributes to antibiotic overuse through treatment of asymptomatic bacteriuria (ASB) and long durations of therapy for symptomatic urinary tract infections (UTIs), yet large-scale evaluations of bacteriuria management among inpatients are lacking. METHODS: Inpatients with bacteriuria were classified as asymptomatic or symptomatic based on established criteria applied to data collected by manual chart review. We examined frequency of treatment of ASB, factors associated with treatment of ASB, durations of therapy, and frequency of complications including Clostridium difficile infection, readmission, and all-cause mortality within 28 days of discharge. RESULTS: Among 2225 episodes of bacteriuria, 64% were classified as ASB. After excluding patients with non-UTI indications for antibiotics, 72% of patients with ASB received antibiotics. When evaluating only patients not meeting SIRS criteria, 68% of patients with ASB received antibiotics. The mean (±SD) days of antibiotic therapy for ASB, cystitis, CA-UTI and pyelonephritis were 10.0 (4.5), 11.4 (4.7), 12.0 (6.1), and 13.6 (5.3), respectively. In sum, 14% of patients with ASB were treated for greater than 14 days, and fluoroquinolones were the most commonly used empiric antibiotic for ASB [245/691 (35%)]. Complications were rare but more common among patients with ASB treated with antibiotics. CONCLUSIONS: The majority of bacteriuria among inpatient veterans is due to ASB with high rates of treatment of ASB and prolonged durations of therapy for ASB and symptomatic UTIs.

Pharmacy Use in the First Year of the Veterans Choice Program: A Mixed-methods Evaluation.

BACKGROUND: The Veterans Choice Program (VCP) was created to ensure timely access to health care in the Department of Veterans Affairs (VA). Under this program, medications may be ordered by select non-VA clinicians to be dispensed by VA pharmacies, creating new challenges in ensuring medication safety. OBJECTIVES: To examine pharmaceutical use during the first year of the VCP and to understand barriers and facilitators for VA pharmacists to dispensing medications under the VCP. STUDY DESIGN: Mixed-methods evaluation. METHODS: We captured all prescriptions dispensed through the VCP and described the demographics of VCP users and their medications. We also conducted semistructured interviews of VA pharmacists, focusing on VA formulary management and experiences dispensing opioid and hepatitis C (HCV) medications. Codebook development and coding followed iterative qualitative methods. RESULTS: Overall, 17,346 Veterans received 56,426 VCP prescriptions from November 7, 2014 through November 7, 2015. The total medication cost was $27 million, 90% of which was for only 2772 HCV prescriptions. Topical eye drops and opioids represented the most commonly dispensed prescriptions (15.6% and 9.2% of all prescriptions, respectively). Pharmacists reported numerous challenges to dispensing VCP medications, including time required to contact non-VA clinicians about formulary issues, requiring controlled substance prescriptions to be hand delivered to VA pharmacies, and lack of access to laboratory data required to safely dispense medications. CONCLUSIONS: HCV-related medication costs predominated the first year of VCP, but this is likely to change going forward. The safe use of opioids, efficient management of nonformulary medications, and unintended new barriers to access created by the VCP must be addressed.

Who Gets Testosterone? Patient Characteristics Associated with Testosterone Prescribing in the Veteran Affairs System: a Cross-Sectional Study.

BACKGROUND: There has been concern about the growing off-label use of testosterone. Understanding the context within which testosterone is prescribed may contribute to interventions to improve prescribing. OBJECTIVE: To evaluate patient characteristics associated with receipt of testosterone. DESIGN: Cross-sectional. SETTING: A national cohort of male patients, who had received at least one outpatient prescription within the Veterans Affairs (VA) system during Fiscal Year 2008- Fiscal Year 2012. PARTICIPANTS: The study sample consisted of 682,915 non-HIV male patients, of whom 132,764 had received testosterone and a random 10% sample, 550,151, had not. MAIN MEASURES: Conditions and medications associated with testosterone prescription. KEY RESULTS: Only 6.3% of men who received testosterone from the VA during the study period had a disorder of the testis, pituitary or hypothalamus associated with male hypogonadism. Among patients without a diagnosed disorder of hypogonadism, the use of opioids and obesity were the strongest predictors of testosterone prescription. Patients receiving >100 mg/equivalents of oral morphine daily (adjusted odds ratio = 5.75, p < 0.001) and those with body mass index (BMI) >40 kg/m2 (adjusted odds ratio = 3.01, p < 0.001) were more likely to receive testosterone than non-opioid users and men with BMI <25 kg/m2. Certain demographics (age 40-54, White race), comorbid conditions (sleep apnea, depression, and diabetes), and medications (antidepressants, systemic corticosteroids) also predicted a higher likelihood of testosterone receipt, all with an adjusted odds ratio less than 2 (p < 0.001). CONCLUSIONS: In the VA, 93.7% of men receiving testosterone did not have a diagnosed condition of the testes, pituitary, or hypothalamus. The strongest predictors of testosterone receipt (e.g., obesity, receipt of opioids), which though are associated with unapproved, off-label use, may be valid reasons for therapy. Interventions should aim to increase the proportion of testosterone recipients who have a valid indication.

Adjuvant chemotherapy for stage III colon cancer: relative dose intensity and survival among veterans.

BACKGROUND: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS). METHODS: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations. RESULTS: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of ≤70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age ≥75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS. CONCLUSION: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.

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.

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.

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.

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.

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.

Impact of pharmacist-managed erythropoiesis-stimulating agents clinics for patients with non-dialysis-dependent CKD.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are associated with serious adverse events, and maintaining hemoglobin levels within a narrow range can be difficult. We examined the quality of ESA prescribing and monitoring in pharmacist-managed ESA clinics versus usual care in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). STUDY DESIGN: Historical cohort. SETTING & PARTICIPANTS: Outpatients receiving ESAs for NDD-CKD at 10 Veterans Affairs Medical Centers with both pharmacist-managed ESA clinics (n = 314) and physician-based care (ie, usual care; n = 91) and 6 sites with usual care only (n = 167) on January 1, 2009, were followed up for 6 months. PREDICTOR: Type/site of care (ie, pharmacist-managed ESA clinic, usual care at ESA clinic site, usual-care site). OUTCOMES: Primary outcomes were proportion of hemoglobin values in the target range of 10-12 g/dL, ESA dose, and frequency of hemoglobin monitoring. Factors associated with hemoglobin values out of target range were identified using multinomial logistic regression. RESULTS: More hemoglobin values were in the target range in pharmacist-managed ESA clinics (71.1% vs 56.9% for usual-care sites; P < 0.001). The average 30-day dose of darbepoetin was 163 µg in pharmacist-managed ESA clinic patients versus 240 µg in usual-care site patients and 258 µg in usual-care patients at ESA clinic sites. For epoetin, corresponding average 30-day doses were 44,890 versus 47,141 and 57,436 IU. Veterans in pharmacist-managed ESA clinics had more hemoglobin measurements on average (5.8 vs 3.6 in usual-care sites and 3.8 in usual care at ESA clinic sites; P = 0.007). In the multinomial model, usual care was associated with hemoglobin levels out of target range, whereas heart failure and diabetes were associated with values in range. LIMITATIONS: We could not assess whether different hemoglobin targets were used by usual-care providers. CONCLUSIONS: Relative to usual care, pharmacist-managed clinics provided improved quality of ESA dosing and monitoring for patients with NDD-CKD.

Active surveillance of postmarket medical product safety in the Federal Partners' Collaboration.

After half a century of monitoring voluntary reports of medical product adverse events, the Food and Drug Administration (FDA) has launched a long-term project to build an adverse events monitoring system, the Sentinel System, which can access and evaluate electronic health care data to help monitor the safety of regulated medical products once they are marketed. On the basis of experience gathered through a number of collaborative efforts, the Federal Partners' Collaboration pilot project, involving FDA, the Centers for Medicare & Medicaid Services, the Department of Veteran Affairs, and the Department of Defense, is already enabling FDA to leverage the power of large public health care databases to assess, in near real time, the utility of analytical tools and methodologies that are being developed for use in the Sentinel System. Active medical product safety surveillance is enhanced by use of these large public health databases because specific populations of exposed patients can be identified and analyzed, and can be further stratified by key variables such as age, sex, race, socioeconomic status, and basis for eligibility to examine important subgroups.

Incremental cost-effectiveness of various monthly doses of vardenafil.

OBJECTIVE: To compare the cost-effectiveness of four, six, and eight doses per month of vardenafil in the context of pharmacy benefit decision making. METHODS: A Markov model was used to estimate the incremental cost-effectiveness of zero, four, six, or eight doses of vardenafil per month in hypothetical cohorts of 60-year-old male veterans with erectile dysfunction. Efficacy values for vardenafil were obtained from the literature, and vardenafil costs were obtained from Veterans Affairs pharmacy data. The analysis was conducted from a third-party payer perspective with a lifetime horizon, and the effect of parameter uncertainty was explored in one-way and probabilistic sensitivity analyses. RESULTS: In the base case analysis, the cost per quality-adjusted life-year gained for four doses of vardenafil per month compared with no therapy was $576. Six doses per month compared with four cost $2585/quality-adjusted life-year gained, and eight doses per month compared with six cost $5169/quality-adjusted life-year gained. In one-way sensitivity analyses of six doses per month compared with four, variation of two parameters caused the incremental cost-effectiveness ratio to cross a willingness-to-pay threshold of $20,000: when the increased utility associated with giving two additional doses/month was less than 0.001 (baseline 0.01) and when the cost per dose increased to $15.00 (baseline $1.69). CONCLUSION: Although four doses per month of vardenafil was the most cost-effective strategy, the use of six or eight doses per month also compares favorably with other accepted medical treatments. The results were stable across a range of inputs and help to support the current Veterans Affairs policy on the number of vardenafil doses provided per month for erectile dysfunction.

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.

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.