key: cord-0686892-b7fvciay authors: Datta, Rupak; Barrett, Alexis; Burk, Muriel; Salone, Cedric; Au, Anthony; Cunningham, Francesca; Fisher, Ann; Dembry, Louise Marie; Akgün, Kathleen M. title: Surveillance of adverse drug events associated with tocilizumab in hospitalized veterans with coronavirus disease 2019 (COVID-19) to inform patient safety and pandemic preparedness date: 2021-05-14 journal: Infect Control Hosp Epidemiol DOI: 10.1017/ice.2021.227 sha: ef339a5cfdb1dad93904bb0f378acd39e65b3325 doc_id: 686892 cord_uid: b7fvciay We evaluated adverse drug events (ADEs) by chart review in a random national sample of 428 veterans with coronavirus disease 2019 (COVID-19) who received tocilizumab (n = 173 of 428). ADEs (median time, 5 days) occurred in 51 of 173 (29%) and included hepatoxicity (n = 29) and infection (n = 13). Concomitant medication discontinuation occurred in 22% of ADE patients; mortality was 39%. The rapid dissemination of practice patterns for coronavirus disease 2019 (COVID-19) underscores the need for ongoing critical safety and efficacy surveillance of off-label treatments. The Department of Veterans Affairs conducts a safety surveillance program to track the safe and appropriate use of off-label treatments for veterans with COVID-19, including those approved under emergency use authorization (EUA). Tocilizumab, a monoclonal antibody to the IL-6 receptor, has been used as an off-label treatment for hospitalized patients with moderate-severe COVID-19. 1, 2 Methods of posttreatment surveillance are needed to weigh the benefits and harms of off-label treatments such as tocilizumab, particularly while randomized controlled trials are ongoing. There are limited reports of adverse drug events (ADEs) and subsequent unfavorable outcomes associated with tocilizumab. 3 The Veterans Health Administration (VHA), with 170 medical centers across 22 geographic regions, offers an ideal setting to inform models of posttreatment surveillance. We characterized ADEs associated with tocilizumab using a random national sample of inpatients with COVID-19 across the VHA. We conducted a retrospective evaluation of patients ≥18 years of age with COVID-19 who were hospitalized between March 12, 2020, and August 31, 2020, in the VHA. We identified the subset of patients who received ≥1 dose of tocilizumab during hospitalization. Randomized controlled trials evaluating the safety and efficacy of tocilizumab in COVID-19 patients were not enrolling VHA patients during the evaluation; patients received tocilizumab at the discretion of their clinicians. Exposure to tocilizumab was ascertained through the electronic health record and confirmed on chart review. This project was approved under the Drug Use Evaluation project by the VHA Institutional Review Board. Among all inpatients prescribed tocilizumab for COVID-19associated diagnoses during the evaluation period, we selected a 40% sample of patients using simple random sampling. For all patients in the sample, we collected demographic, comorbidity, hospitalization, laboratory, and tocilizumab administration data by database extraction and confirmed these data via chart review. We ascertained whether patients were prescribed concomitant medications to manage COVID-19. We also obtained data related to the presence of symptoms associated with COVID-19, receipt of critical care, need for mechanical ventilation, and exposure to risk factors for COVID-19. The primary outcome was the proportion of patients with an ADE temporally associated with tocilizumab administration. ADEs included injection site reactions, neutropenia, thrombocytopenia, anaphylaxis, hepatotoxicity, gastrointestinal perforation, elevated triglycerides, and new infections (tuberculosis, candidemia, bacteremia, varicella zoster, and other infections). 4 Trained clinical pharmacist specialists used standardized definitions to evaluate ADEs (Supplementary Table 1 online) among equitable samples of patients. Among patients who developed ADEs, secondary outcomes of ADE severity were characterized as (1) discontinuation of concomitant medications associated with select ADEs (neutropenia, thrombocytopenia, anaphylaxis, or hepatotoxicity) during hospitalization and (2) death during hospitalization. Multiple measures (eg, verification by senior personnel, cross checking, standardized data collection instructions) were implemented to limit interreviewer variability. Descriptive characteristics were determined using frequencies and percentages for categorical variables or medians and interquartile ranges (IQRs) for continuous variables. To account for the geographic and temporal variation in prevalence and management of COVID-19 across the VHA, characteristics were stratified by the first wave (March 12, 2020-May 31, 2020) and the second wave (June 1, 2020-August 31, 2020) of COVID-19. The frequencies of ADEs were stratified by severity of COVID-19, defined by the need for mechanical ventilation. Bivariate tests were used to compare length-of-stay and all-cause mortality using the Wilcoxon rank-sum test and the χ 2 or Fisher exact test (as appropriate) among patients with versus without an ADE. Analyses were conducted using SAS version 9.4 software (SAS Institute, Cary, NC). All statistical tests were 2-tailed and P values < .05 were considered significant. We identified a random sample of 173 inpatients from 428 total inpatients with COVID-19 who received tocilizumab across 43 VHA medical centers. Table 1 shows descriptive characteristics. There appeared to be increased representation of women, adults aged ≥75 years, and concomitant treatments with corticosteroids and remdesivir in the second wave. Overall, 51 patients (29%) developed a total of 68 ADEs associated with tocilizumab per standardized criteria (Fig. 1) . Of these 51 patients, 11 (22%) had 1 or more concomitant medications discontinued due to an ADE. Median time to ADE from exposure to tocilizumab was 5 days (IQR=4). Among ADEs, there were 13 infections including 5 bacteremias, 1 candidemia, and 7 "other" severe infections. Of those with infection, 7 (54%) received concomitant steroids. There were no cases of tuberculosis or varicella zoster infection. One case of gastrointestinal perforation was observed. There was no difference in length-of-stay among patients with (median 19 days, IQR=19) versus without (median 15 days, IQR=18) an ADE (P = .60). Additionally, there was no difference in all-cause hospital mortality among patients with (n = 20 of 51, 39%) versus without (n = 49 of 122, 40%) an ADE (P = 1.0). Efficient and comprehensive surveillance of off-label treatments for COVID-19 is necessary to identify opportunities to improve patient safety among hospitalized patients. We evaluated ADEs associated with tocilizumab to inform a potential framework for the real-time assessment of the safety of off-label treatments used among VHA inpatients with COVID-19. Using a random national sample, nearly 30% developed ADEs, and ADEs often led to discontinuation of concomitant medications. Hospital mortality did not vary by the development of ADEs. Collectively, our findings support hospital epidemiology and antimicrobial stewardship programs that are charged with promoting patient safety, pandemic preparedness, and, increasingly, institutional treatment protocols for COVID-19. 5 The Sentinel Initiative led by the Food and Drug Administration includes the largest multicenter database in the world dedicated to medical product safety, 6 and collaborative efforts with VHA inform safety surveillance efforts in the largest integrated healthcare system in the United States. It is important to conduct surveillance in this population because VHA patients may be at increased risk of ADEs due to the prevalence of advanced age, multimorbidity, and disparities in COVID-19 burden. 7, 8 By conducting rigorous chart reviews using standardized definitions in a random sample of nationwide inpatients, our work offers 1 potential approach to evaluate the safety of off-label treatments for COVID-19 in close to real-time within VHA and general populations of older adults with multimorbidity. This approach presents opportunities to improve safety among hospitalized veterans with COVID-19 and helps capture real-world outcomes for patients exposed to off-label treatments, beyond what is typically reported from clinical trials. 9,10 An additional advantage of this approach using integrated VHA data is the potential to replicate this methodology over time for veteran and nonveteran populations, particularly during subsequent waves of COVID-19 and future pandemics. Developing mechanisms to monitor off-label treatments for emerging infectious diseases across healthcare systems may promote pandemic preparedness. Our work has limitations. This work was done within a national pharmacy safety surveillance program with the goal of tracking the safe and appropriate use of off-label medications in veterans. Consequently, we could not assess ADEs among all VHA inpatients exposed to tocilizumab. Nevertheless, inpatients were selected randomly, and the sample size is comparable to prior reports. 3 Second, our findings have limited representation of women. Finally, we were not powered to identify predictors of ADE in veterans. In summary, 29% of patients exposed to tocilizumab developed an ADE during hospitalization. ADEs often involved hepatotoxicity and secondary infections and frequently resulted in discontinuation of concomitant medications. This evaluation provides a potential framework for the real-time assessment of the safety of off-label treatments used for COVID-19 among VHA inpatients and may inform recommendations from hospital epidemiology and antimicrobial stewardship programs. reflect the views of the authors and do not represent the official positions of the United States Department of Veterans Affairs or other author affiliate organizations. Financial support. No financial support was provided relevant to this article. Conflicts of interest. All authors report no conflicts of interest relevant to this article. Tocilizumab in patients with severe COVID-19: a retrospective cohort study Tocilizumab for treatment of mechanically ventilated patients with COVID-19 Tocilizumab for severe COVID-19: a systematic review and meta-analysis Actemra (tocilizumab) prescribing information. Food and Drug Administration website Antimicrobial stewardship at the core of COVID-19 response efforts: implications for sustaining and building programs Food and Drug Administration Comparing the health status of VA and non-VA ambulatory patients: the veterans' health and medical outcomes studies Patterns of COVID-19 testing and mortality by race and ethnicity among US veterans: a nationwide cohort study Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial Acknowledgments. We thank the Hospital Epidemiology and Infection Prevention Program and the Pain Research, Informatics, Multimorbidities, and Education Center at the Veterans Affairs Connecticut Healthcare System for their support of this study. The statements contained in this article