The Use and Safety Risk of Repurposed Drugs for COVID-19 patients: Lessons Learned Utilizing the Food and Drug Administrations Adverse Event Reporting System

ObjectivesThis study was designed to assess the disproportionality analyses of adverse drug reactions (ADRs) related to hydroxychloroquine and remdesivir and how ADR reporting fluctuated during the COVID-19 pandemic. MethodsA retrospective observational study was conducted utilizing the Food and Drug Administrations Adverse Event Reporting System (FAERS) data between 2019 and 2021. The study was conducted in two phases. In the first phase, all reports associated with the drugs of interest were evaluated to assess all related adverse drug reactions. In the second phase, specific outcomes of interest (i.e., QT prolongation and renal and hepatic events) were determined to study their association with the drugs of interest. A descriptive analysis was conducted for all adverse reactions related to the drugs being studied. In addition, disproportionality analyses were conducted to compute the reporting odds ratio, the proportional reporting ratio, the information component, and the empirical Bayes geometric mean. All analyses were conducted using RStudio. ResultsA total of 9,443 ADR reports related to hydroxychloroquine; 6,160 (71.49) patients were female, and higher percentage of patients of both sexes were over the age of 65 years. QT prolongation (1.48%), pain (1.38%), and arthralgia (1.25%) were most frequently reported ADRs during the COVID-19 pandemic. The association of QT prolongation with use of hydroxychloroquine was statistically significant (ROR 47.28 [95% CI 35.95-62.18]; PRR 42.41 [95% CI 32.25-55.78]; EBGM 16.08; IC 4.95) compared with fluoroquinolone. The outcome was serious medical events in 48.01% of ADR reports; 27.42% required hospitalization and 8.61% resulted in death. Of 6,673 ADR reports related to remdesivir, 3,928 (61.13%) patients were male. During 2020, the top three ADR reports were elevated liver function tests (17.26%), acute kidney injury (5.95%) and death (2.84%). Additionally, 42.71% of ADR reports indicated serious medical events; 19.69% resulted in death and 11.71% indicated hospitalization. The ROR and PRR of hepatic and renal events associated with remdesivir were statistically significant, (4.81 [95% CI 4.46-5.19] and 2.96 [95% CI 2.66-3.29], respectively. ConclusionOur study showed that several serious ADRs were reported with the use of hydroxychloroquine, which resulted in hospitalization and death. Trends with the use of remdesivir were similar, but to a lesser extent. Therefore, this study showed us that off-label use should be based on thorough evidence-based evaluation.

Health Economic Burden of COVID-19 in Saudi Arabia

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has placed a massive economic burden on health care systems worldwide. Saudi Arabia is one of the numerous countries that have been economically affected by this pandemic. The objective of this study was to provide real-world data on the health economic burden of COVID-19 on the Saudi health sector and assess the direct medical costs associated with the management of COVID-19. MethodsA retrospective cohort study was conducted based on data collected from patients hospitalized with COVID-19 across ten institutions in eight different regions in Saudi Arabia. The study calculated the estimated costs of all cases during the study period by using direct medical costs. These costs included costs directly related to medical services, such as the health care treatment, hospital stays, laboratory investigations, treatment, outcome, and other related care. ResultsA total of 5,286 adult patients admitted with COVID-19 during the study period were included in the study. The average age of the patients was 54 years, and the majority were male. Among the COVID-19 patients hospitalized in a general ward, the median hospital length of stay was 5.5 days (mean: 9.18 days), while the ICU stay was 4.26 days (mean: 7.94 days). The total medical costs for general ward and ICU patients were 14,585,640 SAR and 90,776,250 SAR, respectively. The total laboratory investigations ranked as the highest-cost services (22,086,296 SAR), followed by treatment (14,574,233.1 SAR). Overall, the total cost of all medical services for patients hospitalized with COVID-19 was 193,394,103.1 SAR. ConclusionThis national study found that COVID-19 was not only a serious concern for patients but also a serious economic burden on the health care system in Saudi Arabia. Key pointsO_LIThe nursing costs and length of stay were lower in the ICU than in the general ward. C_LIO_LIThe costs of hospitalization in general medical wards were less than those of admission to the ICU. C_LIO_LIThese cost data will be valuable for future researchers evaluating the COVID-19 pandemics increasing health care economic burden in Saudi Arabia and the implementation of cost-effective models to assess the possible implications of COVID-19 prevention and treatment initiatives. C_LI

Vaccine Adverse Event Reporting System (VAERS): Evaluation of 31 Years of Reports and Pandemics' Impact

BackgroundVaccine adverse event reporting system (VAERS) was established in the United States (U.S.) as an early warning system with a main purpose of collecting postmarketing adverse events following immunizations (AEFIs) reports to monitor the vaccine safety and to mitigate the risks from vaccines. During the coronavirus diseases 2019 (COVID-19) pandemic, VAERS got more attention as its important role in monitoring the safety of the vaccines. Thus, the aim of this study was to investigate VAERS patterns, reported AEFIs, adverse events of special interest (AESIs), impact of different pandemics since its inception, and surveillance rate of serious vs nonserious AEFIs. MethodsThis was an observational study using VARES data from 2/7/1990 to 12/11/2021. Patterns of reports over years were first described, followed by a comparison of reports statistics per year. Furthermore, a comparison of incidents (death, ER visits, etc.) statistics over years, in addition to statistics of each vaccine were calculated. Moreover, each incidents statistics for each vaccine were calculated and top vaccines were reported. Finally, survival analysis utilizing cox regression was done, in addition to AESIs distribution stratified by age groups and gender. All analyses were conducted using R (Version 1.4.1717) and Excel for Microsoft 365. ResultsThere were 1,396,280 domestic and 346,210 non-domestic reports during 1990-2021, including 228 vaccines. For both domestic and non-domestic reports, year of 2021 had the highest reporting rate (48.52% and 70.33%), in addition a notable changes in AEFIs patterns were recorded during 1991, 1998, 2000, 2006, 2009, 2011, and 2017. AEFIs were as follow: deaths (1.00% and 4.08%), ER or doctor visits (13.37% and 2.27%), hospitalizations (5.84% and 27.78%), lethal threat (1.42% and 4.38%), and disabilities (1.4% and 7.96%). Pyrexia was the top reported symptom during the past 31 years, except for 2021 where headache was the top one. COVID-19 vaccines namely Moderna, Pfizer-Biontech, and Janssen were the top 3 reported vaccines with headache, pyrexia, and fatigue as the top associated AEFIs. Followed by Zoster, Seasonal Influenza, Pneumococcal, and Human papillomavirus vaccines. Myocarditis or Pericarditis were the top reported AESIs (26.95% and 25.84%). Male (HR:1.15, 1.14 - 1.16) for domestic (HR:1.23, 1.22 -1.25) for nondomestic have a higher probability of having serious AEFIs. In addition, age group [≤] 5 years old in domestic and >84 years old in nondomestic have a higher probability of having AEFIs compared to other age groups. ConclusionsThe large data available in VARES make it a useful tool for detecting and monitoring vaccine AEFIs. However, its usability relies on understating the limitations of this surveillance system, the impact of governmental regulations, availability of vaccines, and public health recommendations on the reporting rate.

Analyzing the U.S. Post-marketing safety surveillance of COVID-19 vaccines

BackgroundSince December 2020, three COVID-19 vaccines have been authorized in the United States (U.S.) and were proceeded by large immunization programs. The aim of this study was to characterize the U.S. post-marketing safety (PMS) profiles of these vaccines with an in-depth analysis of mortality data. MethodsThis was a retrospective database analysis study. Details of the U.S. PMS reports (15 December 2020 to 19 March 2021) of the three vaccines (Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S) were retrieved from the U.S. Vaccine Adverse Event Reporting System (VAERS). A descriptive analysis was conducted to characterize the reported adverse events (AEs). A comparative (Pfizer-BioNTech vs. Moderna) analysis of mortality was conducted. The mean count ratio of death between the two vaccines was estimated using a negative binomial regression model adjusting for the measured confounders. ResultsA total of 44,451 AE reports were retrieved (corresponding to 0.05% of the U.S. population who received at least one dose). The most commonly reported AEs were injection site reactions (30.4% of the reports), pain (reported in 26.7% of the reports), and headache (18.6% of the reports). Serious AEs were reported in only 14.6% of the reports with 4,108 hospitalizations. The total number of deaths was 1,919 with a mean count ratio of Moderna (n=997) vs. Pfizer-BioNTech (n=899) of 1.07 (95% confidence interval 0.86 to 1.33). ConclusionsThe vast majority of PMS AEs in the U.S. were non-serious, and the number of serious AEs is very low given the total number of vaccinated U.S. population.

Characteristics and outcomes of 118,155 COVID-19 individuals with a history of cancer in the United States and Spain

PurposeWe aimed to describe the demographics, cancer subtypes, comorbidities and outcomes of patients with a history of cancer with COVID-19 from March to June 2020. Secondly, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. MethodsWe conducted a cohort study using eight routinely-collected healthcare databases from Spain and the US, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: i) diagnosed with COVID-19, ii) hospitalized with COVID-19, and iii) hospitalized with influenza in 2017-2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes. ResultsWe included 118,155 patients with a cancer history in the COVID-19 diagnosed and 41,939 in the COVID-19 hospitalized cohorts. The most frequent cancer subtypes were prostate and breast cancer (range: 5-19% and 1-14% in the diagnosed cohort, respectively). Hematological malignancies were also frequent, with non-Hodgkins lymphoma being among the 5 most common cancer subtypes in the diagnosed cohort. Overall, patients were more frequently aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 8% to 14% and from 18% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n=242,960) had a similar distribution of cancer subtypes, sex, age and comorbidities but lower occurrence of adverse events. ConclusionPatients with a history of cancer and COVID-19 have advanced age, multiple comorbidities, and a high occurence of COVID-19-related events. Additionaly, hematological malignancies were frequent in these patients.This observational study provides epidemiologic characteristics that can inform clinical care and future etiological studies.

Characteristics, outcomes, and mortality amongst 133,589 patients with prevalent autoimmune diseases diagnosed with, and 48,418 hospitalised for COVID-19: a multinational distributed network cohort analysis

ObjectivePatients with autoimmune diseases were advised to shield to avoid COVID-19, but information on their prognosis is lacking. We characterised 30-day outcomes and mortality after hospitalisation with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza. DesignMultinational network cohort study SettingElectronic health records data from Columbia University Irving Medical Center (CUIMC) (NYC, United States [US]), Optum [US], Department of Veterans Affairs (VA) (US), Information System for Research in Primary Care-Hospitalisation Linked Data (SIDIAP-H) (Spain), and claims data from IQVIA Open Claims (US) and Health Insurance and Review Assessment (HIRA) (South Korea). ParticipantsAll patients with prevalent autoimmune diseases, diagnosed and/or hospitalised between January and June 2020 with COVID-19, and similar patients hospitalised with influenza in 2017-2018 were included. Main outcome measures30-day complications during hospitalisation and death ResultsWe studied 133,589 patients diagnosed and 48,418 hospitalised with COVID-19 with prevalent autoimmune diseases. The majority of participants were female (60.5% to 65.9%) and aged [≥]50 years. The most prevalent autoimmune conditions were psoriasis (3.5 to 32.5%), rheumatoid arthritis (3.9 to 18.9%), and vasculitis (3.3 to 17.6%). Amongst hospitalised patients, Type 1 diabetes was the most common autoimmune condition (4.8% to 7.5%) in US databases, rheumatoid arthritis in HIRA (18.9%), and psoriasis in SIDIAP-H (26.4%). Compared to 70,660 hospitalised with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2% to 4.3% versus 6.3% to 24.6%). ConclusionsPatients with autoimmune diseases had high rates of respiratory complications and 30-day mortality following a hospitalization with COVID-19. Compared to influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality. Future studies should investigate predictors of poor outcomes in COVID-19 patients with autoimmune diseases. What is already known about this topicO_LIPatients with autoimmune conditions may be at increased risk of COVID-19 infection andcomplications. C_LIO_LIThere is a paucity of evidence characterising the outcomes of hospitalised COVID-19 patients with prevalent autoimmune conditions. C_LI What this study addsO_LIMost people with autoimmune diseases who required hospitalisation for COVID-19 were women, aged 50 years or older, and had substantial previous comorbidities. C_LIO_LIPatients who were hospitalised with COVID-19 and had prevalent autoimmune diseases had higher prevalence of hypertension, chronic kidney disease, heart disease, and Type 2 diabetes as compared to those with prevalent autoimmune diseases who were diagnosed with COVID-19. C_LIO_LIA variable proportion of 6% to 25% across data sources died within one month of hospitalisation with COVID-19 and prevalent autoimmune diseases. C_LIO_LIFor people with autoimmune diseases, COVID-19 hospitalisation was associated with worse outcomes and 30-day mortality compared to admission with influenza in the 2017-2018 season. C_LI

Baseline characteristics, management, and outcomes of 55,270 children and adolescents diagnosed with COVID-19 and 1,952,693 with influenza in France, Germany, Spain, South Korea and the United States: an international network cohort study

ObjectivesTo characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children/adolescents diagnosed or hospitalized with COVID-19. Secondly, to describe health outcomes amongst children/adolescents diagnosed with previous seasonal influenza. DesignInternational network cohort. SettingReal-world data from European primary care records (France/Germany/Spain), South Korean claims and US claims and hospital databases. ParticipantsDiagnosed and/or hospitalized children/adolescents with COVID-19 at age <18 between January and June 2020; diagnosed with influenza in 2017-2018. Main outcome measuresBaseline demographics and comorbidities, symptoms, 30-day in-hospital treatments and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome (ARDS), multi-system inflammatory syndrome (MIS-C), and death. ResultsA total of 55,270 children/adolescents diagnosed and 3,693 hospitalized with COVID-19 and 1,952,693 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were all more common among those hospitalized vs diagnosed with COVID-19. The most common COVID-19 symptom was fever. Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital treatments for COVID-19 included repurposed medications (<10%), and adjunctive therapies: systemic corticosteroids (6.8% to 37.6%), famotidine (9.0% to 28.1%), and antithrombotics such as aspirin (2.0% to 21.4%), heparin (2.2% to 18.1%), and enoxaparin (2.8% to 14.8%). Hospitalization was observed in 0.3% to 1.3% of the COVID-19 diagnosed cohort, with undetectable (N<5 per database) 30-day fatality. Thirty-day outcomes including pneumonia, ARDS, and MIS-C were more frequent in COVID-19 than influenza. ConclusionsDespite negligible fatality, complications including pneumonia, ARDS and MIS-C were more frequent in children/adolescents with COVID-19 than with influenza. Dyspnea, anosmia and gastrointestinal symptoms could help differential diagnosis. A wide range of medications were used for the inpatient management of pediatric COVID-19. What is already known on this topic?O_LIMost of the early COVID-19 studies were targeted at adult patients, and data concerning children and adolescents are limited. C_LIO_LIClinical manifestations of COVID-19 are generally milder in the pediatric population compared with adults. C_LIO_LIHospitalization for COVID-19 affects mostly infants, toddlers, and children with pre-existing comorbidities. C_LI What this study adds This study comprehensively characterizes a large international cohort of pediatric COVID-19 patients, and almost 2 million with previous seasonal influenza across 5 countries. Although uncommon, pneumonia, acute respiratory distress syndrome (ARDS) and multi-system inflammatory syndrome (MIS-C) were more frequent in children and adolescents diagnosed with COVID-19 than in those with seasonal influenza. Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more frequent in COVID-19, and could help to differentiate pediatric COVID-19 from influenza. A plethora of medications were used during the management of COVID-19 in children and adolescents, with great heterogeneity in the use of antiviral therapies as well as of adjunctive therapies.

Baseline phenotype and 30-day outcomes of people tested for COVID-19: an international network cohort including >3.32 million people tested with real-time PCR and >219,000 tested positive for SARS-CoV-2 in South Korea, Spain and the United States

Early identification of symptoms and comorbidities most predictive of COVID-19 is critical to identify infection, guide policies to effectively contain the pandemic, and improve health systems response. Here, we characterised socio-demographics and comorbidity in 3,316,107persons tested and 219,072 persons tested positive for SARS-CoV-2 since January 2020, and their key health outcomes in the month following the first positive test. Routine care data from primary care electronic health records (EHR) from Spain, hospital EHR from the United States (US), and claims data from South Korea and the US were used. The majority of study participants were women aged 18-65 years old. Positive/tested ratio varied greatly geographically (2.2:100 to 31.2:100) and over time (from 50:100 in February-April to 6.8:100 in May-June). Fever, cough and dyspnoea were the most common symptoms at presentation. Between 4%-38% required admission and 1-10.5% died within a month from their first positive test. Observed disparity in testing practices led to variable baseline characteristics and outcomes, both nationally (US) and internationally. Our findings highlight the importance of large scale characterization of COVID-19 international cohorts to inform planning and resource allocation including testing as countries face a second wave.

Clinical characteristics, symptoms, management and health outcomes in 8,598 pregnant women diagnosed with COVID-19 compared to 27,510 with seasonal influenza in France, Spain and the US: a network cohort analysis

OBJECTIVESTo describe comorbidities, symptoms at presentation, medication use, and 30-day outcomes after a diagnosis of COVID-19 in pregnant women, in comparison to pregnant women with influenza. DESIGNMultinational network cohort SETTINGA total of 6 databases consisting of electronic medical records and claims data from France, Spain, and the United States. PARTICIPANTSPregnant women with [≥] 1 year in contributing databases, diagnosed and/or tested positive, or hospitalized with COVID-19. The influenza cohort was derived from the 2017-2018 influenza season. OUTCOMESBaseline patient characteristics, comorbidities and presenting symptoms; 30-day inpatient drug utilization, maternal complications and pregnancy-related outcomes following diagnosis/hospitalization. RESULTS8,598 women diagnosed (2,031 hospitalized) with COVID-19 were included. Hospitalized women had, compared to those diagnosed, a higher prevalence sof pre-existing comorbidities including renal impairment (2.2% diagnosed vs 5.1% hospitalized) and anemia (15.5% diagnosed vs 21.3% hospitalized). The ten most common inpatient treatments were systemic corticosteroids (29.6%), enoxaparin (24.0%), immunoglobulins (21.4%), famotidine (20.9%), azithromycin (18.1%), heparin (15.8%), ceftriaxone (7.9%), aspirin (7.0%), hydroxychloroquine (5.4%) and amoxicillin (3.5%). Compared to 27,510 women with influenza, dyspnea and anosmia were more prevalent in those with COVID-19. Women with COVID-19 had higher frequency of cesarean-section (4.4% vs 3.1%), preterm delivery (0.9% vs 0.5%), and poorer maternal outcomes: pneumonia (12.0% vs 2.7%), ARDS (4.0% vs 0.3%) and sepsis (2.1% vs 0.7%). COVID-19 fatality was negligible (N<5 in each database respectively). CONCLUSIONSComorbidities that were more prevalent with COVID-19 hospitalization (compared to COVID-19 diagnosed) in pregnancy included renal impairment and anemia. Multiple medications were used to treat pregnant women hospitalized with COVID-19, some with little evidence of benefit. Anosmia and dyspnea were indicative symptoms of COVID-19 in pregnancy compared to influenza, and may aid differential diagnosis. Despite low fatality, pregnancy and maternal outcomes were worse in COVID-19 than influenza. WHAT IS ALREADY KNOWN ON THIS TOPICO_LICompared to non-pregnant women of reproductive age, pregnant women are less likely to experience typical COVID-19 symptoms, such as fever and myalgia. C_LIO_LIObesity, high maternal age, and comorbid hypertension and diabetes are risk factors for severe COVID-19 among pregnant women. C_LIO_LIDespite relatively high rates of pneumonia and need for oxygen supplementation, fatality rates in pregnant women with COVID-19 are generally low (<1%). C_LI WHAT THIS STUDY ADDSO_LIAlthough not often recorded, dyspnea and anosmia were more often seen in pregnant women with COVID-19 than in women with seasonal influenza, in 6 databases from 3 countries (US, France, Spain). C_LIO_LIRenal impairment and anemia were more common among hospitalized than diagnosed women with COVID-19 during pregnancy. C_LIO_LIDespite limited data on benefit-risk in pregnancy, a large number of medications were used for inpatient management of COVID-19 in pregnant women: approximately 1 in 3 received corticosteroids (some may have been given for a pregnancy-related indication rather than for COVID-19 treatment), 1 in 4 enoxaparin, and 1 in 5 immunoglobulin, famotidine and azithromycin. C_LIO_LICompared to influenza, there was a higher frequency of pregnancy-related complications (cesarean section and preterm deliveries), as well as poorer maternal outcomes (pneumonia, acute respiratory distress syndrome, sepsis, acute kidney injury, and cardiovascular and thromboembolic events) seen in pregnant women diagnosed with COVID-19. C_LI

Heterogeneity and temporal variation in the management of COVID-19: a multinational drug utilization study including 71,921 hospitalized patients from China, South Korea, Spain, and the United States of America

ObjectivesA plethora of medicines have been repurposed or used as adjunctive therapies for COVID-19. We characterized the utilization of medicines as prescribed in routine practice amongst patients hospitalized for COVID-19 in South Korea, China, Spain, and the USA. DesignInternational network cohort SettingHospital electronic health records from Columbia University Irving Medical Centre (NYC, USA), Stanford (CA, USA), Tufts (MA, USA), Premier (USA), Optum EHR (USA), department of veterans affairs (USA), NFHCRD (Honghu, China) and HM Hospitals (Spain); and nationwide claims from HIRA (South Korea) Participantspatients hospitalized for COVID-19 from January to June 2020 Main outcome measuresPrescription/dispensation of any medicine on or 30 days after hospital admission date AnalysesNumber and percentage of users overall and over time Results71,921 people were included: 304 from China, 2,089 from Spain, 7,599 from South Korea, and 61,929 from the USA. A total of 3,455 medicines were identified. Common repurposed medicines included hydroxychloroquine (<2% in NFHCRD to 85.4% in HM), azithromycin (4.9% in NFHCRD to 56.5% in HM), lopinavir/ritonavir (<3% in all US but 34.9% in HIRA and 56.5% in HM), and umifenovir (0% in all except 78.3% in NFHCRD). Adjunctive medicines were used with great variability, with the ten most used treatments being (in descending order): bemiparin, enoxaparin, heparin, ceftriaxone, aspirin, vitamin D, famotidine, vitamin C, dexamethasone, and metformin. Hydroxychloroquine and azithromycin increased rapidly in use in March-April but declined steeply in May-June. ConclusionsMultiple medicines were used in the first months of COVID-19 pandemic, with substantial geographic and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed medicines. Antithrombotics, antibiotics, H2 receptor antagonists and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of COVID-19. O_TEXTBOXWhat is already known in this topicO_LIDrug repurposing is a common approach in the clinical management of novel diseases and conditions for which there are no available pharmacotherapies C_LIO_LIHydroxychloroquine was widely used in the management of COVID-19 patients during the early phases of the pandemic C_LIO_LIRecent NIH (and other) guidelines recommend the use of concomitant therapies including immune-based, antithrombotic, antibiotic and other treatments C_LI What this study addsO_LIThis study demonstrates great variability and extensive drug repurposing and utilization in the management of COVID-19 patients. C_LIO_LIA wide range of adjunctive treatments has been used, including antithrombotics, antibiotics, H2 receptor antagonists, and systemic corticosteroids. C_LIO_LIEmerging clinical data on the safety and efficacy of hydroxychloroquine and azithromycin impacted their rise and rapid decline in use internationally C_LIO_LIConversely, the use of corticosteroids grew only in more recent months, with little use in the early stages of the pandemic (January to April) C_LI C_TEXTBOX

Characteristics and outcomes of 627 044 COVID-19 patients with and without obesity in the United States, Spain, and the United Kingdom

BackgroundCOVID-19 may differentially impact people with obesity. We aimed to describe and compare the demographics, comorbidities, and outcomes of obese patients with COVID-19 to those of non-obese patients with COVID-19, or obese patients with seasonal influenza. MethodsWe conducted a cohort study based on outpatient/inpatient care, and claims data from January to June 2020 from the US, Spain, and the UK. We used six databases standardized to the OMOP common data model. We defined two cohorts of patients diagnosed and/or hospitalized with COVID-19. We created corresponding cohorts for patients with influenza in 2017-2018. We followed patients from index date to 30 days or death. We report the frequency of socio-demographics, prior comorbidities, and 30-days outcomes (hospitalization, events, and death) by obesity status. FindingsWe included 627 044 COVID-19 (US: 502 650, Spain: 122 058, UK: 2336) and 4 549 568 influenza (US: 4 431 801, Spain: 115 224, UK: 2543) patients. The prevalence of obesity was higher among hospitalized COVID-19 (range: 38% to 54%) than diagnosed COVID-19 (30% to 47%), or diagnosed (15% to 47%) or hospitalized (27% to 48%) influenza patients. Obese hospitalized COVID-19 patients were more often female and younger than non-obese COVID-19 patients or obese influenza patients. Obese COVID-19 patients were more likely to have prior comorbidities, present with cardiovascular and respiratory events during hospitalization, require intensive services, or die compared to non-obese COVID-19 patients. Obese COVID-19 patients were more likely to require intensive services or die compared to obese influenza patients, despite presenting with fewer comorbidities. InterpretationWe show that obesity is more common amongst COVID-19 than influenza patients, and that obese patients present with more severe forms of COVID-19 with higher hospitalization, intensive services, and fatality than non-obese patients. These data are instrumental for guiding preventive strategies of COVID-19 infection and complications. FundingThe European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Unions Horizon 2020 research and innovation programme and EFPIA. This research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, and IQVIA. The University of Oxford received funding related to this work from the Bill & Melinda Gates Foundation (Investment ID INV-016201 and INV-019257). APU has received funding from the Medical Research Council (MRC) [MR/K501256/1, MR/N013468/1] and Fundacion Alfonso Martin Escudero (FAME) (APU). VINCI [VA HSR RES 13-457] (SLD, MEM, KEL). JCEL has received funding from the Medical Research Council (MR/K501256/1) and Versus Arthritis (21605). No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, Department of Veterans Affairs or the United States Government, NHS, or the Department of Health, England. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious evidence suggests that obese individuals are a high risk population for COVID-19 infection and complications. We searched PubMed for articles published from December 2019 until June 2020, using terms referring to SARS-CoV-2 or COVID-19 combined with terms for obesity. Few studies reported obesity and most of them were limited by small sample sizes and restricted to hospitalized patients. Further, they used different definitions for obesity (i.e. some reported together overweight and obesity, others only reported obesity with BMI>40kg/m2). To date, no study has provided detailed information on the characteristics of obese COVID-19 patients, such as the prevalence of comorbidities or COVID-19 related outcomes. In addition, despite the fact that COVID-19 has been often compared to seasonal influenza, there are no studies assessing whether obese patients with COVID-19 differ from obese patients with seasonal influenza. Added value of this studyWe report the largest cohort of obese patients with COVID-19 and provide information on more than 29 000 aggregate characteristics publicly available. Our findings were consistent across the participating databases and countries. We found that the prevalence of obesity is higher among COVID-19 compared to seasonal influenza patients. Obese patients with COVID-19 are more commonly female and have worse outcomes than non-obese patients. Further, they have worse outcomes than obese patients with influenza, despite presenting with fewer comorbidities. Implications of all the available evidenceOur results show that individuals with obesity present more comorbidities and worse outcomes for COVID-19 than non-obese patients. These findings may be useful in guiding clinical practice and future preventative strategies for obese individuals, as well as provide useful data to support subsequent association studies focussed on obesity and COVID-19.

Are countries precautionary actions against COVID-19 effective? An assessment study of 175 countries worldwide

BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has affected many countries negatively, particularly in terms of their health care and financial systems. Numerous countries have attempted to employ precautions to address this pandemic. This study was aimed at exploring and assessing the precautionary actions taken by 175 countries on six continents to prevent the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). MethodsAn observational study was conducted based on data collected during the period from December 31, 2019, until the end of April 2020. Several data were extracted, including information related to the date of the first reported case of SARS-CoV-2, total confirmed cases, total active cases, and more. In addition, seven validated indicators were used to assess the countries preparedness and precautionary actions. FindingsA total of 175 countries were included in the study. The total COVID-19 infection rate increased exponentially and rapidly in North America and Europe from March to April. The application of the precautions (indicators) varied between countries. School closures, quarantines and curfews were the most applied indicators among all countries. As for the relationship between the indicators and their effects on the infection rate, Italy and Spain were the top countries in Europe and adopted all indicators. Nevertheless, they faced high infection rates: 239,639 and 205,463 COVID-19 cases in Spain, and Italy, respectively. InterpretationThe precautionary actions might have played a role in limiting the spread of COVID-19 in several countries. However, many countries did not benefit from applying these indicators. FundingNo funding sources have been used for this work

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

IntroductionAngiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results. MethodsUsing electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) users to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments. ResultsFollowing over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 - 1.14), nor any difference for mono/combination use (1.01; 0.90 - 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 - 1.05) and marginally significant for mono/combination users (0.88; 0.79 - 0.99). We observed, however, no significant difference between drug-classes for COVID-19 hospitalization or pneumonia risk across all comparisons. ConclusionThere is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.

An international characterisation of patients hospitalised with COVID-19 and a comparison with those previously hospitalised with influenza

BackgroundIn this study we phenotyped individuals hospitalised with coronavirus disease 2019 (COVID-19) in depth, summarising entire medical histories, including medications, as captured in routinely collected data drawn from databases across three continents. We then compared individuals hospitalised with COVID-19 to those previously hospitalised with influenza. MethodsWe report demographics, previously recorded conditions and medication use of patients hospitalised with COVID-19 in the US (Columbia University Irving Medical Center [CUIMC], Premier Healthcare Database [PHD], UCHealth System Health Data Compass Database [UC HDC], and the Department of Veterans Affairs [VA OMOP]), in South Korea (Health Insurance Review & Assessment [HIRA]), and Spain (The Information System for Research in Primary Care [SIDIAP] and HM Hospitales [HM]). These patients were then compared with patients hospitalised with influenza in 2014-19. Results34,128 (US: 8,362, South Korea: 7,341, Spain: 18,425) individuals hospitalised with COVID-19 were included. Between 4,811 (HM) and 11,643 (CUIMC) unique aggregate characteristics were extracted per patient, with all summarised in an accompanying interactive website (http://evidence.ohdsi.org/Covid19CharacterizationHospitalization/). Patients were majority male in the US (CUIMC: 52%, PHD: 52%, UC HDC: 54%, VA OMOP: 94%,) and Spain (SIDIAP: 54%, HM: 60%), but were predominantly female in South Korea (HIRA: 60%). Age profiles varied across data sources. Prevalence of asthma ranged from 4% to 15%, diabetes from 13% to 43%, and hypertensive disorder from 24% to 70% across data sources. Between 14% and 33% were taking drugs acting on the renin-angiotensin system in the 30 days prior to hospitalisation. Compared to 81,596 individuals hospitalised with influenza in 2014-19, patients admitted with COVID-19 were more typically male, younger, and healthier, with fewer comorbidities and lower medication use. ConclusionsWe provide a detailed characterisation of patients hospitalised with COVID-19. Protecting groups known to be vulnerable to influenza is a useful starting point to minimize the number of hospital admissions needed for COVID-19. However, such strategies will also likely need to be broadened so as to reflect the particular characteristics of individuals hospitalised with COVID-19.

Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study

BackgroundHydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin. MethodsNew user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine-azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%. ResultsOverall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45]) ConclusionsShort-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19. Trial registration numberRegistered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine. Funding sourcesThis research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and Senior Research Fellowship (DPA), US National Institutes of Health, Janssen Research & Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C0992]. Personal funding included Versus Arthritis [21605] (JL), MRC-DTP [MR/K501256/1] (JL), MRC and FAME (APU). The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Unions Horizon 2020 research and innovation programme and EFPIA. No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, NHS or the Department of Health, England.