Early Mortality After the First Dose of COVID-19 Vaccination: A Target Trial Emulation.

BACKGROUND: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans. METHODS: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up. The study cohort included individuals aged ≥18 years enrolled in the Veterans Health Administration system and eligible to receive a COVID-19 vaccination according to guideline recommendations from 1 March 2021 through 1 July 2021. The outcomes of interest included deaths from any cause and excluding a COVID-19 diagnosis. Observations were cloned to both treatment strategies, censored, and weighted to estimate per-protocol effects. RESULTS: We included 3 158 507 veterans. Under the vaccination strategy, 364 993 received vaccine within 7 days. At 60 days, there were 156 deaths per 100 000 veterans under the vaccination strategy versus 185 deaths under the no vaccination strategy, corresponding to an absolute risk difference of -25.9 (95% confidence limit [CL], -59.5 to 2.7) and relative risk of 0.86 (95% CL, .7 to 1.0). When those with a COVID-19 infection in the first 60 days were censored, the absolute risk difference was -20.6 (95% CL, -53.4 to 16.0) with a relative risk of 0.88 (95% CL, .7 to 1.1). CONCLUSIONS: Vaccination against COVID-19 was associated with a lower but not statistically significantly different risk of death in the first 60 days. These results agree with prior scientific knowledge suggesting vaccination is safe with the potential for substantial health benefits.

Identifying Veterans Who Benefit From Nirmatrelvir-Ritonavir: A Target Trial Emulation.

BACKGROUND: Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed. METHODS: We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir-ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model. RESULTS: Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], -0.50% points [95% confidence interval {CI}: -.69 to -.35]) and death (0.11% vs 0.30%; RD, -0.20 [95% CI: -.24 to -.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD -2.85 [95% CI: -3.94 to -1.76]), immunocompromised persons (RD -1.91 [95% CI: -3.09 to -.74]), and persons aged ≥75 years (RD -1.16 [95% CI: -1.73 to -.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years. CONCLUSIONS: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death.

Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes.

BACKGROUND: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited. OBJECTIVE: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19. DESIGN: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy. MEASUREMENTS: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. RESULTS: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. LIMITATION: The date of COVID-19 symptom onset for most veterans was unknown. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans : A Target Trial Emulation.

BACKGROUND: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. OBJECTIVE: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs. DESIGN: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir treatment for acute COVID-19. MEASUREMENTS: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. RESULTS: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points]). LIMITATIONS: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. CONCLUSION: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

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.

Opioid Prescribing and Opioid Risk Mitigation Strategies in the Veterans Health Administration.

INTRODUCTION: The Veterans Health Administration (VHA) has taken a multifaceted approach to addressing opioid safety and promoting system-wide opioid stewardship. AIM: To provide a comprehensive evaluation of current opioid prescribing practices and implementation of risk mitigation strategies in VHA. SETTING: VHA is the largest integrated health care system in the United States. PROGRAM DESCRIPTION: VHA prescribing data in conjunction with implementation of opioid risk mitigation strategies are routinely tracked and reviewed by VHA's Pharmacy Benefits Management Services (including Academic Detailing Service) and the Pain Management Program Office. Additional data are derived from the Partnered Evidence-Based Policy Resource Center (PEPReC) and from a 2019 survey of interdisciplinary pain management teams at VHA facilities. Prescribing data are reported quarterly until first quarter fiscal year 2020 (Q1FY2020), ending December 31, 2019. PROGRAM EVALUATION: VHA opioid dispensing peaked in 2012 with 679,376 Veterans receiving an opioid prescription, and when including tramadol, in 2013 with 869,956 Veterans. Since 2012, the number of Veterans dispensed an opioid decreased 56% and co-prescribed opioid/benzodiazepine decreased 83%. Veterans with high-dose opioids (≥ 100 mg morphine equivalent daily dose) decreased 77%. In Q1FY2020, among Veterans on long-term opioid therapy (LTOT), 91.1% had written informed consent, 90.8% had a urine drug screen, and 89.0% had a prescription drug monitoring program query. Naloxone was issued to 217,469 Veterans and resulted in > 1,000 documented overdose reversals. In 2019, interdisciplinary pain management teams were fully designated at 68%, partially designated at 28%, and not available at 4% of 140 VA parent facilities. Fifty percent of Veterans on opioids at very high risk for overdose/suicide received interdisciplinary team reviews. IMPLICATIONS: VHA clinicians have greatly reduced their volume of opioid prescribing for pain management and expanded implementation of opioid risk mitigation strategies. IMPACTS: VHA's integrated health care system provides a model for opioid stewardship and interdisciplinary pain care.

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.

Opioid dispensing and overlap in veterans with non-cancer pain eligible for Medicare Part D.

OBJECTIVES: Pain is the most prevalent problem among veterans, who receive pain diagnoses 5 times more frequently than the general population. Opioids are commonly prescribed for pain, but they have potential for misuse and serious adverse events. The study objective was to evaluate opioid dispensing patterns and predictors for overlap in veterans who are eligible for Medicare Part D benefits. METHODS: A sample of male and all female veterans aged 66 years and older without cancer in 2005-2009 was included. Overlapping days' supply of opioids were evaluated within the U.S. Department of Veterans Affairs (VA), within Part D, and in cross-system users of VA and Part D-reimbursed pharmacies during 2007-2009. Dispensing patterns were analyzed with t tests and chi-square tests. Predictors of overlap were identified with general estimating equations. RESULTS: At least 1 opioid was dispensed to 88.5% of the sample. In 2006 after Part D implementation, 55.2% of opioids were dispensed by VA, decreasing to 44.3% in 2009 (P <0.0001). Opioids dispensed from Part D-reimbursed pharmacies had a higher frequency of overlap compared to those filled at a VA facility (P <0.0001). While overlapping days' supply for opioids filled at VA decreased, overlap increased for prescriptions filled at Part D-reimbursed pharmacies (P <0.0001). There was minimal overlap in opioids between systems, but cross-system use increased over the study period. Predictors for overlap include females, Part D enrollment, no VA medication copay, sleep disorders, psychiatric diagnoses, and substance or alcohol abuse (all P <0.01). Veterans who were Hispanic, older, and had higher incomes had lower overlap odds (all P <0.0001). CONCLUSIONS: Opioids dispensed from Part D-reimbursed pharmacies had a higher frequency of overlapping days' supply as compared to those filled by the VA, but there was minimal overlap between systems. While overlapping opioid prescriptions filled by the VA decreased from 2007 to 2009, overlap increased for prescriptions filled at Part D-reimbursed pharmacies. Tools, such as drug monitoring programs, should be used by VA and non-VA providers to decrease opioid-related harms and misuse.

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.

Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis.

BACKGROUND: The influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barré syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barré syndrome is a rare but serious health disorder in which a person's own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barré syndrome. METHODS: Data were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barré syndrome per million vaccinations. We used a self-controlled risk-interval design. FINDINGS: Influenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2·35, 95% CI 1·42-4·01, p=0·0003). This finding translated to about 1·6 excess cases of Guillain-Barré syndrome per million people vaccinated. INTERPRETATION: The modest risk of Guillain-Barré syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks. FUNDING: US Federal Government.

Overview of U.S. COVID-19 vaccine safety surveillance systems.

The U.S. COVID-19 vaccination program, which commenced in December 2020, has been instrumental in preventing morbidity and mortality from COVID-19 disease. Safety monitoring has been an essential component of the program. The federal government undertook a comprehensive and coordinated approach to implement complementary safety monitoring systems and to communicate findings in a timely and transparent way to healthcare providers, policymakers, and the public. Monitoring involved both well-established and newly developed systems that relied on both spontaneous (passive) and active surveillance methods. Clinical consultation for individual cases of adverse events following vaccination was performed, and monitoring of special populations, such as pregnant persons, was conducted. This report describes the U.S. government's COVID-19 vaccine safety monitoring systems and programs used by the Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, the Department of Defense, the Department of Veterans Affairs, and the Indian Health Service. Using the adverse event of myocarditis following mRNA COVID-19 vaccination as a model, we demonstrate how the multiple, complementary monitoring systems worked to rapidly detect, assess, and verify a vaccine safety signal. In addition, longer-term follow-up was conducted to evaluate the recovery status of myocarditis cases following vaccination. Finally, the process for timely and transparent communication and dissemination of COVID-19 vaccine safety data is described, highlighting the responsiveness and robustness of the U.S. vaccine safety monitoring infrastructure during the national COVID-19 vaccination program.

COVID-19 Vaccine Safety Technical (VaST) Work Group: Enhancing vaccine safety monitoring during the pandemic.

During the COVID-19 pandemic, candidate COVID-19 vaccines were being developed for potential use in the United States on an unprecedented, accelerated schedule. It was anticipated that once available, under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) or FDA approval, COVID-19 vaccines would be broadly used and potentially administered to millions of individuals in a short period of time. Intensive monitoring in the post-EUA/licensure period would be necessary for timely detection and assessment of potential safety concerns. To address this, the Centers for Disease Control and Prevention (CDC) convened an Advisory Committee on Immunization Practices (ACIP) work group focused solely on COVID-19 vaccine safety, consisting of independent vaccine safety experts and representatives from federal agencies - the ACIP COVID-19 Vaccine Safety Technical Work Group (VaST). This report provides an overview of the organization and activities of VaST, summarizes data reviewed as part of the comprehensive effort to monitor vaccine safety during the COVID-19 pandemic, and highlights selected actions taken by CDC, ACIP, and FDA in response to accumulating post-authorization safety data. VaST convened regular meetings over the course of 29 months, from November 2020 through April 2023; through March 2023 FDA issued EUAs for six COVID-19 vaccines from four different manufacturers and subsequently licensed two of these COVID-19 vaccines. The independent vaccine safety experts collaborated with federal agencies to ensure timely assessment of vaccine safety data during this time. VaST worked closely with the ACIP COVID-19 Vaccines Work Group; that work group used safety data and VaST's assessments for benefit-risk assessments and guidance for COVID-19 vaccination policy. Safety topics reviewed by VaST included those identified in safety monitoring systems and other topics of scientific or public interest. VaST provided guidance to CDC's COVID-19 vaccine safety monitoring efforts, provided a forum for review of data from several U.S. government vaccine safety systems, and assured that a diverse group of scientists and clinicians, external to the federal government, promptly reviewed vaccine safety data. In the event of a future pandemic or other biological public health emergency, the VaST model could be used to strengthen vaccine safety monitoring, enhance public confidence, and increase transparency through incorporation of independent, non-government safety experts into the monitoring process, and through strong collaboration among federal and other partners.

Emergency use authorization medication distribution, utilization, and monitoring in a national integrated healthcare system.

PURPOSE: The purpose of this project was to develop and optimize a dashboard and registry to manage the distribution, utilization, and monitoring of coronavirus disease 2019 (COVID-19) emergency use-authorized medications (CEUAMs). SUMMARY: CEUAMs have specific requirements that must be met for prescribing, monitoring, and compliance. When remdesivir, the first COVID-19 medication with emergency use authorization (EUA), was approved, it immediately became necessary for the Veterans Health Administration, a national integrated health system, to describe the requirements for EUA, to distribute the medication in a fair and equitable manner, and to ensure compliance with all EUA requirements. A dashboard was developed and iteratively updated as additional CEUAMs were approved. The dashboard tracked CEUAM distribution and monitoring at the national, regional, facility, and patient level. Par stock levels were initially determined at the national level. Facilities were also able to request an additional allotment of medication based on demand and allocated supplies from the Department of Health and Human Services. Providers completed a questionnaire for the CEUAM for each patient to ensure all requirements for the medication were met. If there were data integrity concerns, the entry was flagged for review at the facility level and, upon evaluation, corrections were made. CONCLUSION: Development of the dashboard was resource intensive but provided an excellent mechanism to share information among facilities and national offices. Other healthcare systems can develop similar dashboards to ensure appropriate use of CEUAMs for their patients while meeting all CEUAM requirements.

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.

Incidence Rates and Clinical Characteristics of Patients With Confirmed Myocarditis or Pericarditis Following COVID-19 mRNA Vaccination: Experience of the Veterans Health Administration Through 9 October 2022.

Background: Although the benefits outweigh the risks, COVID-19 vaccines have been associated with an increased risk of myocarditis and pericarditis. This report is based on a national US veteran population with confirmed myocarditis/pericarditis following mRNA COVID-19 vaccines according to the near real-time active surveillance program of Veterans Affairs. Methods: This study is based on a cohort evaluation of all adults administered ≥1 mRNA COVID-19 vaccine, including boosters, in the Veterans Health Administration between 14 December 2020 and 9 October 2022. ICD-10-CM diagnosis codes were used to identify potential safety signals in near real time through a database analysis. All potential cases of myocarditis/pericarditis identified in the database analysis underwent in-depth chart review and case validation by a team of pharmacists and expert clinicians. Our main outcome was the incidence rate of confirmed myocarditis/pericarditis among vaccine recipients (overall and those aged 18-39 years) within 21 days of a first, second, or booster dose of a mRNA COVID-19 vaccine. We calculated the ratio of observed events among COVID-19 vaccine recipients over expected events from historical vaccine recipient controls (2015-2020) in the Veterans Health Administration. We used confirmed cases to calculate incidence rates and 95% CIs. Results: Through 9 October 2022, 3 877 453 doses of BNT162b2 (Pfizer-BioNTech) and 4 221 397 doses of mRNA-1273 (Moderna) were administered as first or second dose across Veterans Affairs, and 1 012 561 BNT162b2 and 1 156 160 mRNA-1273 booster doses were administered. Among all doses, the rapid cycle analysis identified 178 potential cases of myocarditis/pericarditis among vaccinees of any age and 22 potential cases among those aged 18-39 years. Of these, 33 cases, including 6 among those 18-39 years old, were confirmed after in-depth chart review and validation, corresponding with an overall incidence rate per million ranging from 0.46 (95% CI, .01-2.55) for Moderna dose 1 to 6.91 (95% CI, 2.78-14.24) for Pfizer booster. Among those aged 18-39, incidence rates ranged from 7.1 (95% CI, .18-39.56) for Moderna dose 2 to 19.76 (95% CI, 5.38-50.58) for Pfizer dose 2. Patients with confirmed cases were hospitalized for a mean 4.1 days (range, 1-15). The final disposition for 32 (97%) of 33 cases was discharge to home. Conclusions: This report is a real-world demonstration of the Veterans Affairs' active surveillance system for vaccines. Although the rapid cycle analysis initially identified 178 potential cases of myocarditis/pericarditis, only 1 of 5 cases was confirmed to be related to a COVID-19 vaccine after chart review. These findings highlight the paramount importance of active surveillance and chart validation for rare but serious adverse events related to COVID-19 vaccines.