Tixagevimab/cilgavimab for preventing COVID-19 during the Omicron surge: retrospective analysis of National Veterans Health Administration electronic data.

Little is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection in vaccinated immunocompromised patients, particularly after the emergence of the Omicron variant. In this retrospective cohort study with exact matching and propensity score adjustment within the U.S. Department of Veterans Affairs (VA) healthcare system, we selected immunocompromised veterans age ≥18 years as of 1 January 2022, receiving VA healthcare. We compared a cohort of 1,878 patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to 7,014 matched controls selected from patients who met study criteria but were not treated. Patients were followed through 15 June 2022, or until death, whichever occurred earlier. The primary outcome was a composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and all-cause mortality. We used Cox proportional hazards modeling to estimate the hazard ratios (HRs) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes. Most (73%) tixagevimab/cilgavimab recipients were ≥65 years old, and 80% had ≥3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to matched controls, recipients had a lower incidence of the composite COVID-19 outcome (49/1,878 [2.6%] versus 312/7,014 [4.4%]; HR 0.35; 95% CI, 0.24-0.52), and individually SARS-CoV-2 infection (HR 0.44; 95% CI, 0.22-0.88), COVID-19 hospitalization (HR 0.24; 95% CI, 0.10-0.59), and all-cause mortality (HR 0.32; 95% CI, 0.19-0.55). In conclusion, tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection and severe COVID-19 during the Omicron BA.1, BA.2, and BA.2.12.1 surge. IMPORTANCE SARS-CoV-2 remains an ongoing global health crisis that justifies continued efforts to validate and expand, when possible, knowledge on the efficacy of available vaccines and treatments. Clinical trials have been limited due to fast tracking of medications for mitigation of the COVID-19 pandemic for the general population. We present a real-world analysis, using electronic health record data, of the effectiveness of tixagevimab/cilgavimab for the prevention of COVID-19 infection in the unique population of U.S. veterans. Unlike those in the PROVENT clinical trial from which the emergency use authorization for tixagevimab/cilgavimab as a preventative treatment arose, the veterans population is highly immunocompromised and nearly 96% totally vaccinated. These demographics allowed us to analyze the effectiveness of tixagevimab/cilgavimab in preventing COVID-19 under different conditions in a more fragile population than that of the initial clinical trial.

Opioid Prescribing by Dentists in the Veterans Health Administration.

INTRODUCTION: Nonopioid analgesics are more effective for most oral pain, but data suggest that dental prescribing of opioids is excessive. This study evaluates the extent to which opioids exceed recommendations and the characteristics associated with opioid overprescribing by Veterans Health Administration dentists. METHODS: This was a national cross-sectional study of Veterans' dental visits from 2015 to 2018. Overprescribing was defined per national guidelines as >120 morphine milligram equivalents (primary outcome). The association of dental visit and patient demographic and medical characteristics was modeled with overprescribing (defined as >120 morphine milligram equivalents) using Poisson regression with clustering by facility and patient. A secondary analysis assessed opioid prescriptions >3 days' supply. The dates of analysis were January 2020‒May 2021. RESULTS: Of the 196,595 visits, 28.7% exceeded 120 morphine milligram equivalents. Friday visits and people with chronic oral pain or substance misuse were associated with a higher prevalence of overprescribing. Women, older Veterans, and Black and Latinx Veterans were less likely to be overprescribed than men, younger Veterans, and White Veterans, respectively. Routine dental visits had a higher prevalence of opioid overprescribing than invasive visits. Opioid overprescribing decreased over time. White Veterans were more likely to receive oxycodone and hydrocodone, whereas people of Black race and Latinx ethnicity were more likely to receive codeine and tramadol. In the secondary analysis, 68.5% of opioid prescriptions exceeded a 3-day supply. CONCLUSIONS: Nearly 1 in 3 opioids prescribed by Veterans Health Administration dentists exceed guidelines. Prescribing higher potency and quantities of opioids, especially on Fridays and to certain demographic groups, should be addressed as part of dental opioid stewardship programs.

Outpatient Prescribing of Antibiotics and Opioids by Veterans Health Administration Providers, 2015-2017.

INTRODUCTION: Antibiotics and opioids are targeted by public health and stewardship communities for reductions in prescribing across the country. This study evaluates trends and factors associated with outpatient prescribing by dental and medical providers in a large integrated health system. METHODS: This was a cross-sectional study of national dental and medical outpatient visits from Department of Veterans Affairs facilities in 2015-2017; analyzed in 2019-2020. Antibiotic and opioid prescribing rates were assessed by provider and facility characteristics. Multivariable Poisson regression adjusted for repeated measures by the provider was used to assess the independent association between facility and provider characteristics and rate of prescribing. RESULTS: Over the study period, 4,625,840 antibiotic and 10,380,809 opioid prescriptions were identified for 115,625,890 visits. Physicians prescribed most antibiotics (67%). Dentists prescribed 6% of the antibiotics but had the highest per-visit antibiotic prescribing rate compared to medical providers (6.75 vs 3.90 prescriptions per 100 visits, p<0.0001), which was largely driven by dental specialists. By contrast, dentists had lower opioid prescribing than medical providers (3.02 vs 9.20 prescriptions per 100 visits, p<0.0001). Overall, antibiotic and opioid prescribing decreased over time, with opioids having the greatest decreases (-28.0%). In multivariable analyses, U.S. geographic region, rurality, and complexity were associated with prescribing for both drug classes. Opioid and antibiotic prescribing were positively correlated. CONCLUSIONS: Although antibiotic and opioid prescribing has decreased, there are still important target areas for improvement. Interventions need to be tailored to community characteristics such as rurality and provider type.

Learning to detect and understand drug discontinuation events from clinical narratives.

OBJECTIVE: Identifying drug discontinuation (DDC) events and understanding their reasons are important for medication management and drug safety surveillance. Structured data resources are often incomplete and lack reason information. In this article, we assessed the ability of natural language processing (NLP) systems to unlock DDC information from clinical narratives automatically. MATERIALS AND METHODS: We collected 1867 de-identified providers' notes from the University of Massachusetts Medical School hospital electronic health record system. Then 2 human experts chart reviewed those clinical notes to annotate DDC events and their reasons. Using the annotated data, we developed and evaluated NLP systems to automatically identify drug discontinuations and reasons at the sentence level using a novel semantic enrichment-based vector representation (SEVR) method for enhanced feature representation. RESULTS: Our SEVR-based NLP system achieved the best performance of 0.785 (AUC-ROC) for detecting discontinuation events and 0.745 (AUC-ROC) for identifying reasons when testing this highly imbalanced data, outperforming 2 state-of-the-art non-SEVR-based models. Compared with a rule-based baseline system for discontinuation detection, our system improved the sensitivity significantly (57.75% vs 18.31%, absolute value) while retaining a high specificity of 99.25%, leading to a significant improvement in AUC-ROC by 32.83% (absolute value). CONCLUSION: Experiments have shown that a high-performance NLP system can be developed to automatically identify DDCs and their reasons from providers' notes. The SEVR model effectively improved the system performance showing better generalization and robustness on unseen test data. Our work is an important step toward identifying reasons for drug discontinuation that will inform drug safety surveillance and pharmacovigilance.

Site-level variation in and practices associated with dabigatran adherence.

IMPORTANCE: Unlike warfarin, which requires routine laboratory testing and dose adjustment, target-specific oral anticoagulants like dabigatran do not. However, optimal follow-up infrastructure and modifiable site-level factors associated with improved adherence to dabigatran are unknown. OBJECTIVES: To assess site-level variation in dabigatran adherence and to identify site-level practices associated with higher dabigatran adherence. DESIGN, SETTING, AND PARTICIPANTS: Mixed-methods study involving retrospective quantitative and cross-sectional qualitative data. A total of 67 Veterans Health Administration sites with 20 or more patients filling dabigatran prescriptions between 2010 and 2012 for nonvalvular atrial fibrillation were sampled (4863 total patients; median, 51 patients per site). Forty-seven pharmacists from 41 eligible sites participated in the qualitative inquiry. EXPOSURE: Site-level practices identified included appropriate patient selection, pharmacist-driven patient education, and pharmacist-led adverse event and adherence monitoring. MAIN OUTCOMES AND MEASURES: Dabigatran adherence (intensity of drug use during therapy) defined by proportion of days covered (ratio of days supplied by prescription to follow-up duration) of 80% or more. RESULTS: The median proportion of patients adherent to dabigatran was 74% (interquartile range [IQR], 66%-80%). After multivariable adjustment, dabigatran adherence across sites varied by a median odds ratio of 1.57. Review of practices across participating sites showed that appropriate patient selection was performed at 31 sites, pharmacist-led education was provided at 30 sites, and pharmacist-led monitoring at 28 sites. The proportion of adherent patients was higher at sites performing appropriate selection (75% vs 69%), education (76% vs 66%), and monitoring (77% vs 65%). Following multivariable adjustment, association between pharmacist-led education and dabigatran adherence was not statistically significant (relative risk [RR], 0.94; 95% CI, 0.83-1.06). Appropriate patient selection (RR, 1.14; 95% CI, 1.05-1.25), and provision of pharmacist-led monitoring (RR, 1.25; 95% CI, 1.11-1.41) were associated with better patient adherence. Additionally, longer duration of monitoring and providing more intensive care to nonadherent patients in collaboration with the clinician improved adherence. CONCLUSIONS AND RELEVANCE: Among nonvalvular atrial fibrillation patients treated with dabigatran, there was variability in patient medication adherence across Veterans Health Administration sites. Specific pharmacist-based activities were associated with greater patient adherence to dabigatran.

Adherence to dabigatran therapy and longitudinal patient outcomes: insights from the veterans health administration.

BACKGROUND: Dabigatran is a novel oral anti-coagulant (NOAC) that reduces risk of stroke in patients with non-valvular atrial fibrillation (NVAF). It does not require routine monitoring with laboratory testing which may have an adverse impact on adherence. We aimed to describe adherence to dabigatran in the first year after initiation and assess the association between non-adherence to dabigatran and clinical outcomes in a large integrated healthcare system. METHODS: We studied a national cohort of 5,376 patients with NVAF, initiated on dabigatran between October-2010 and September-2012 at all Veterans Affairs hospitals. Adherence to dabigatran was calculated as proportion of days covered (PDC) and association between PDC and outcomes was assessed using standard regression techniques. RESULTS: Mean age of the study cohort was 71.3 ± 9.7 years; 98.3% were men and mean CHADS2 score was 2.4 ± 1.2 (mean CHA2DS2VASc score 3.2 ± 1.4). Median PDC was 94% (IQR 76%-100%; mean PDC 84% ± 22%) over a median follow-up of 244 days (IQR 140-351). A total of 1,494 (27.8%) patients had a PDC <80% and were classified as non-adherent. After multivariable adjustment, lower adherence was associated with increased risk for combined all-cause mortality and stroke (HR 1.13, 95% CI 1.07-1.19 per 10% decrease in PDC). Adherence to dabigatran was not associated with non-fatal bleeding or myocardial infarction. CONCLUSIONS: In the year after initiation, adherence to dabigatran for a majority of patients is very good. However, 28% of patients in our cohort had poor adherence. Furthermore, lower adherence to dabigatran was associated with increased adverse outcomes. Concerted efforts are needed to optimize adherence to NOACs.

Retreatment of hepatitis C with consensus interferon and ribavirin after nonresponse or relapse to pegylated interferon and ribavirin: a national VA clinical practice study.

BACKGROUND: Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV) of hepatitis C virus (HCV)-infected patients who failed prior pegylated interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical practice were evaluated within the Department of Veterans Affairs (VA), the largest national, integrated system for HCV care. AIMS: The purpose of this study was to determine rates of sustained virologic response (SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective review of national VA data in HCV-infected patients who had previously failed≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006. RESULTS: A total of 597 patients met the study criteria. CIFN was primarily dosed as 15 mcg subcutaneously daily combined with standard doses of RBV. Mean treatment duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%. Hematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders (31% vs. 6%, respectively; P<0.0001). A 2-log10 or greater drop in HCV RNA after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV. CONCLUSIONS: CIFN/RBV was used frequently in clinical practice for retreatment of PEG-IFN/RBV. In this setting, early treatment discontinuation was common. Overall SVR was low, although response was significantly better in prior PEG-IFN/RBV relapsers and those who had a 2-log(10) or greater decline than in nonresponders.

Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis.

BACKGROUND: Herpes zoster occurs more commonly in patients taking immunosuppressive medications, although the risk associated with different medications is poorly understood. METHODS: We conducted a retrospective cohort study involving 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster and herpes zoster-free survival. Chart review was performed to validate the diagnosis of herpes zoster. RESULTS: The incidence of herpes zoster was 9.96 episodes per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (P < .001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor-alpha antagonists, etanercept (hazard ratio, 0.62) and adalimumab (hazard ratio, 0.53) were associated with a lower risk of herpes zoster. There was excellent agreement between the International Classification of Diseases, Version 9, Clinical Modification diagnosis of herpes zoster and diagnosis by chart review (kappa = 0.92). CONCLUSIONS: Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs' national administrative databases can be used to study rare adverse drug events.

Insulin temperature and stability under simulated transit conditions.

PURPOSE: The transit temperature profiles, mean kinetic temperatures (MKTs), and stability of insulin samples in both insulated and noninsulated containers exposed to summer and winter temperatures were evaluated. METHODS: Regular insulin, isophane insulin human (NPH) insulin, and 70% isophane-30% regular (70/30) insulin were packaged in the most commonly dispensed quantity of four vials in noninsulated mailers and insulated containers with frozen gel packs. After packaging, sealed containers and mailers were placed in an environmental chamber for 24-120 hours and exposed to summer and winter transit conditions. Temperatures inside the environmental chamber were recorded every 15 minutes and maintained within 3 degrees C of the specified transit temperature. After exposure to the transit conditions, insulin cartons were removed from their packaging, visually inspected for changes in physical appearance, and stored at 4 degrees C until analysis. The MKT of each package was calculated. High-performance liquid chromatography was performed to determine sample stability, and size-exclusion chromatography was conducted to detect aggregate products of insulin. RESULTS: Regardless of shipping conditions or packaging, all samples met the United States Pharmacopeia's ( USP's) specified limits and retained product stability. Visual inspection of the physical appearance of insulin samples before and after temperature exposure revealed results similar to those described in the product inserts. Microscopic analysis of the injectable suspensions confirmed similar crystal morphologies before and after temperature exposure. CONCLUSION: Regular, NPH, and 70/30 insulin maintained potency within USP limits when stored in programmable environmental chambers simulating summer and winter overnight or three- to five-day ground delivery conditions, regardless of packaging material.

Differential associations of beta-blockers with hemorrhagic events for chronic heart failure patients on warfarin.

PURPOSE: Beta-blockers have many different physiologic effects that could potentially influence the risk of hemorrhagic events in chronic heart failure patients (CHF) on warfarin. We examined how different beta-blockers vary in their associated risk of a hemorrhagic event. METHODS: We used databases from the Department of Veterans Affairs (VA) that contain information on medications prescribed, diagnoses, and hospitalizations. We identified patients with CHF on warfarin and either metoprolol, carvedilol, atenolol, or no beta-blocker during 1999-2001. We modeled time to first hemorrhagic event using a Cox proportional hazards model, adjusting for age, ethnicity, comorbidities, and other factors. INR levels were examined in a subsample of 3546 patients. RESULTS: We identified 66,988 CHF patients on warfarin. Hemorrhagic events occurred in 15.3% of the sample and, in 3.8% of the sample, the hemorrhage was considered severe. Compared to patients on carvedilol, the hazards ratio for a new hemorrhagic event was 1.25 (1.17, 1.34) for no beta-blocker, 1.27 (1.18, 1.38) for atenolol, and 1.38 (1.28, 1.48) for metoprolol. No differences in INR levels were evident among the four groups. CONCLUSIONS: The risk for a hemorrhagic event among CHF patients on warfarin may be affected by beta-blocker use and varies depending on which beta-blocker is prescribed.

Antihypertensive medication use in the Department of Veterans Affairs: a national analysis of prescribing patterns from 2000 to 2002.

BACKGROUND: Studies describe differences between recommendations for hypertension treatment and actual drug use. Antihypertensive use data from the Department of Veterans Affairs (VA) for 1995 to 1999 showed a downward trend for calcium antagonist (CA) use and increased use of beta-blockers (BB) and thiazide diuretics (TD). This study evaluates national VA antihypertensive treatment for 2000 to 2002 and compares these data to treatment data for 1995 to 1999. METHODS: National VA pharmacy data were used to determine use of BB, TD, CA, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and combinations of antihypertensive drugs for 2000 to 2002. Dispensing data were converted to treatment days. In addition to national trends, data were analyzed regionally to examine geographic differences. Pharmacoeconomic analysis estimated the financial impact of medication changes. RESULTS: Antihypertensive drug use in the VA represented more than 1 billion days in 2002. The ACEI were most commonly used, representing 33.4% and 33.5% of treatment days in 2000 and 2002, respectively. Changes from 2000 to 2002 were 21.9% to 24.2% for BB, 29.3% to 24.4% for CA, and 13.2% to 14.2% for TD. Use of ARB increased from 2.1% to 3.7% of treatment days. Analysis of the 21 VA regions showed geographic variation. For example, the proportion of BB treatment days is highest in a northeast VA region (28.6%) and lowest in a southeast region (19.9%). In 2002 the VA has saved an estimated US 8.5 million dollars because of changes in medication use. CONCLUSIONS: As a proportion of antihypertensive agent use, CA continues to fall in the VA, whereas BB, TD, and ARB use have increased. However, TD use remains low, despite national guidelines that promote use of this class of agent.

Monitoring depression care: in search of an accurate quality indicator.

BACKGROUND: Linking process and outcomes is critical to accurately estimating healthcare quality and quantifying its benefits. OBJECTIVES: The objective of this study was to explore the relationship of guideline-based depression process measures with subsequent overall and psychiatric hospitalizations. RESEARCH DESIGN: This is a retrospective cohort study during which we used administrative and centralized pharmacy records for sample identification, derivation of guideline-based process measures (antidepressant dosage and duration adequacy), and subsequent hospitalization ascertainment. Depression care was measured from June 1, 1999, through August 31, 1999. We used multivariable regression to evaluate the link between depression care and subsequent overall and psychiatric hospitalization, adjusting for patient age, race, sex, socioeconomic status, comorbid illness, and hospitalization in the prior 12 months. SUBJECTS: We studied a total of 12,678 patients from 14 Northeastern VHA hospitals. RESULTS: We identified adequate antidepressant dosage in 90% and adequate duration in 45%. Those with adequate duration of antidepressants were less likely to be hospitalized in the subsequent 12 months than those with inadequate duration (odds ratio [OR],.90; 95% confidence interval [CI], .81-1.00). Those with adequate duration of antidepressants were less likely to have a psychiatric hospitalization in the subsequent 12 months than those with inadequate duration (OR, .82; 95% CI, .69-.96). We did not demonstrate a significant link between dosage adequacy and subsequent overall or psychiatric hospitalization. CONCLUSIONS: Guideline-based depression process measures derived from centralized data sources offer an important method of depression care surveillance. Their accuracy in capturing depression care quality is supported by their link to healthcare utilization. Further work is needed to assess the effect of implementing these quality indicators on depression care.

Use of antidepressant medications: are there differences in psychiatric visits among patient treatments in the Veterans Administration?

BACKGROUND: Information on the effectiveness of newer antidepressants like serotonin-norepinephrine reuptake inhibitors in terms of healthcare utilization is limited. Treatment guidelines affect evaluation. Second-line medications are usually prescribed to patients with higher utilization. OBJECTIVES: The objective of this study was to compare antidepressants within the Veterans Affairs (VA) healthcare system on the basis of the number of outpatient psychiatric visits for each class of antidepressants. RESEARCH DESIGN AND SUBJECTS: We conducted a retrospective cohort design using precollected information from VA national databases from 1999 and 2000. The study identified 92,537 patients on serotonin specific reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs). MEASURES: We stratified individual patients by the number of visits in the baseline year for each medication class. For each stratum, we created a dichotomized variable YK: Yk = 1 if there is a reduction of K visits or more and 0 if there is no reduction. We calculated the odds of reduction of psychiatric visits among the 3 classes of antidepressants. RESULTS: TCAs and SSRIs were associated with greater odds of reduction compared with SNRIs at the level of 1 through 10 or 11 visits, respectively. SNRIs were associated with greater odds of reduction in visits at the level of 14, 16, or more visits compared with SSRIs and TCAs, respectively (P <0.05). SSRIs were associated with greater odds of reduction compared with TCAs at the level of 1 to 11 visits (P <0.05); there were no significant differences between the 2 classes above 11 visits. CONCLUSION: Effectiveness research using databases should consider how medications are prescribed within systems. Treatment guidelines result in differences in severity and utilization among users of different medications.