BMJ

ContextVaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported after administering ChAdOx1-S recombinant COVID-19 vaccine (marketed as Vaxzevira by Astra-Zeneca, Covishield). Estimates of incidence vary between countries, due to different age distributions chosen, case definitions and choice of denominator (persons vaccinated vs immunizations given). This study clarifies these estimates by pooling data from ten countries and examining differences by age group. MethodsWe examined case reports, press releases and immunization data and calculated pooled estimates of VITT incidence using random effects models. Sensitivity analyses considered different combinations of countries and varying assumptions on time between vaccination and reporting of cases. ResultsPooling all countries, VITT incidence was 0.73 per 100,000 persons receiving first dose of Covishield/Vaxzevira [95% CI .43,1.23]. Incidence for age 65 and over was 0.11 per 100,000 persons [95% CI .05-.26], and significantly higher among those under age 55: 1.67 per 100,000 persons [95% CI 1.30-2.14] in the UK, 5.06 per 100,000 persons in Norway [95% CI 2.16, 11.86]. The latter had the best data on counts of persons vaccinated. Incidence for age 55 to 64 years was 0.34 [95% CI 0.13, 0.85] in the UK, lower than for under age 55. ConclusionVITT is a rare vaccine-associated adverse event. Incidence estimates vary between jurisdictions. However, even the highest reported incidence from Norway is low - and in settings with high community transmission, lower than risk of serious outcomes associated with Covid-19. Policymakers and individuals can use these data to calculate risk-benefit ratios and better target vaccine distribution. EssentialsO_LIThis paper measures risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) after ChAdOx1-S recombinant COVID-19 vaccine C_LIO_LIPooled estimates of incidence were calculated with a random effects model based on data from 10 countries C_LIO_LIOverall risk is 1 in 139,000; for age 65 and over, about 1 in 1,000,000; for age under 55, between 1 in 20,000 to 60,000 C_LIO_LIVITT risk is low and varies by age. These data can inform policies around vaccination distribution. C_LI

ImportanceThere have been over 759 million confirmed cases of COVID-19 worldwide. A significant portion of these infections will lead to long COVID and its attendant morbidities and costs. ObjectiveTo empirically derive a long COVID case definition consisting of significantly increased signs, symptoms, and diagnoses to support clinical, public health, research, and policy initiatives related to the pandemic. DesignCase-Crossover Population-based study. SettingVeterans Affairs (VA) medical centers across the United States between January 1, 2020 and August 18, 2022. Participants367,148 individuals with positive COVID-19 tests and preexisting ICD-10-CM codes recorded in the VA electronic health record were enrolled. TriggerSARS-CoV-2 infection documented by positive laboratory test. Case WindowOne to seven months following positive COVID testing. Main Outcomes and MeasuresWe defined signs, symptoms, and diagnoses as being associated with long COVID if they had a novel case frequency of >= 1:1000 and they were significantly increased in our entire cohort after a positive COVID test when compared to case frequencies before COVID testing. We present odds ratios with confidence intervals for long COVID signs, symptoms, and diagnoses, organized by ICD-10-CM functional groups and medical specialty. We used our definition to assess long COVID risk based upon a patients demographics, Elixhauser score, vaccination status, and COVID disease severity. ResultsWe developed a long COVID definition consisting of 323 ICD-10-CM diagnosis codes grouped into 143 ICD-10-CM functional groups that were significantly increased in our 367,148 patient post-COVID population. We define seventeen medical-specialty long COVID subtypes such as cardiology long COVID. COVID-19 positive patients developed signs, symptoms, or diagnoses included in our long COVID definition at a proportion of at least 59.7% (based on all COVID positive patients). Patients with more severe cases of COVID-19 and multiple comorbidities were more likely to develop long COVID. Conclusions and RelevanceAn actionable, empirical definition for long COVID can help clinicians screen for and diagnose long COVID, allowing identified patients to be admitted into appropriate monitoring and treatment programs. An actionable long COVID definition can also support public health, research and policy initiatives. COVID patients with low oxygen saturation levels or multiple co-morbidities should be preferentially watched for the development of long COVID.

BACKGROUNDThe evidence for benefit of convalescent plasma for critically ill patients with Covid-19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid-19. METHODSIn an ongoing adaptive platform trial, critically ill patients with confirmed Covid-19, defined as receiving intensive care-level organ support, were randomized to open-label convalescent plasma or not (i.e., control group). The primary end point was organ support-free days (i.e., days alive and free of ICU-based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTSThe convalescent plasma intervention was stopped after pre-specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, -1 to 16) for the convalescent plasma group and 3 (interquartile range, -1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR < 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes. CONCLUSIONSIn critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes. Clinicaltrials.gov: NCT02735707

BACKGROUNDThe interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear. METHODSWe evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-{beta}1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility. RESULTSStatistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe. CONCLUSIONSIn patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population. (ClinicalTrials.gov number: NCT02735707)

Background. Recent meta-analyses of randomized controlled trials (RCTs) claimed efficacy of higher-dose fluvoxamine (2 x 100 mg/day, as opposed to 2 x 50 mg/day) in prevention of disease deterioration in adults with mild - moderate COVID-19 disease. Objectives. Investigate whether such claims are supported by the data. Methods. Systematic review and meta-analysis of RCTs evaluating higher-dose fluvoxamine in this indication. Results. Seven studies declared as RCTs were identified, one of which was severely biased (open-label, non-standardized and unreported standard of care as a control), and eventually ended as non-randomized (huge attrition). Composite endpoints of deterioration in the 6 included placebo-controlled trials contained elements susceptible to error and bias. Three trials were small (<100 patients/arm), three were larger (270 - 750 patients/arm). Deaths and need for mechanical ventilation were sporadic and observed in only one trial. Hospitalizations were also sporadic in 5/6 trials. Frequentist methods generally appropriate for random-effects analysis of low number of trials with rare outcomes (generalized linear mixed models, beta-binomial or binomial-normal) greatly underestimated heterogeneity, but still did not document benefits regarding the composite endpoints or hospitalizations. Bayesian hierarchical models revealed huge heterogeneity and indicated no benefit regarding: (i) composites of deterioration, large trials OR = 0.78 (95% CrI 0.55 - 1.21); multiplicity corrected OR = 0.87 (0.64 - 1.21); (ii) hospitalizations, small trials OR = 0.88 (0.45 - 1.72); large trials OR = 0.94 (0.52 - 1.75); all trials OR = 0.81 (0.47 - 1.43). Heterogeneity was unlikely due to clinical particulars (vaccination status, treatment duration, time horizon), and more likely due to unidentified bias. Conclusions. RCTs do not support efficacy of higher-dose fluvoxamine in prevention of disease deterioration in adults with mild - moderate COVID-19 disease.

BackgroundThrombo-inflammation may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized for Covid-19. MethodsIn an open-label adaptive multiplatform randomized controlled trial, non-critically ill patients hospitalized for Covid-19, defined by the absence of critical care-level organ support at enrollment, were randomized to a pragmatic strategy of therapeutic-dose anticoagulation with heparin or usual care pharmacological thromboprophylaxis. The primary outcome combined survival to hospital discharge and days free of organ support through 21 days, which was evaluated with Bayesian statistical models according to baseline D-dimer. ResultsThe trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation in groups defined by high ([&ge;]2-fold elevated) and low (<2-fold elevated) D-dimer. Among 2219 participants in the final analysis, the probability that therapeutic anticoagulation increased organ support-free days compared to thromboprophylaxis was 99.0% (adjusted odds ratio 1.29, 95% credible interval 1.04 to 1.61). The adjusted absolute increase in survival to hospital discharge without organ support with therapeutic-dose anticoagulation was 4.6% (95% credible interval 0.7 to 8.1). In the primary adaptive stopping groups, the final probabilities of superiority for therapeutic anticoagulation were 97.3% in the high D-dimer group and 92.9% in the low D-dimer group. Major bleeding occurred in 1.9% and 0.9% of participants randomized to therapeutic anticoagulation and thromboprophylaxis, respectively. ConclusionsIn non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increases the probability of survival to hospital discharge with reduced use of organ support. Trial registration numbers: NCT02735707, NCT04505774, NCT04359277, NCT04372589

ObjectiveTo determine if Tocilizumab treatment in patients hospitalized with laboratory confirmed SARS-CoV-2 infection and subsequent COVID-19 disease provides short-term survival benefit. DesignCase-control, observational study that includes an observation period from arrival to discharge or inpatient death. Both Cox proportional hazards and average treatment effects models were used to determine survival and treatment benefits. SettingThree Cone Health acute care hospitals including one COVID dedicated facility. PatientsPatients admitted with confirmed SARS-CoV-2 from March 16, 2020 through April 22, 2020. ExposureTocilizumab dosed at either 400 mg fixed dose or 8 mg/kg weight-based dose with maximum single dose of 800mg. Measurements and Main ResultsOverall, 86 patients were admitted during the observation period with confirmed COVID-19 disease. Of these, 21 received Tocilizumab during the hospital stay. Both the Cox model and treatment effects models showed short-term survival benefit. There was an associated 75% reduction in the risk of inpatient death when treated (HR 0.25; 95% CI 0.07-0.90) in the Cox model. This association was confirmed in the treatment effects model where we found a 52.7% reduced risk of dying while hospitalized compared to those not treated (RR 0.472; 95% CI 0.449-0.497). In both models, we show short-term survival benefit in patients with severe COVID-19 illness.

BackgroundThe spread of several SARS-CoV-2 variants of concern (VOC) led to increasing numbers of patients with coronavirus disease 2019 (COVID-19) in German intensive care units (ICU), resulting in capacity shortages and even transfers of COVID-19 ICU patients between federal states in late 2021. Comprehensive evidence on the impact of predominant VOC, in this case Delta and Omicron, on inter-hospital transfers of COVID-19 ICU patients remains scarce. MethodsA retrospective cohort study was conducted from July 01, 2021 until May 31, 2022 using nationwide reimbursement inpatient count data of COVID-19 ICU patients and weekly sequence data of VOC in Germany. A multivariable Poisson regression analysis was performed to estimate incidence rates and incidence rate ratios (IRR) for competing events of transfer, discharge and death, adjusted for VOC infection, age group and sex. For corresponding risk estimation, a multistate model for the clinical trajectory in ICU was applied. ResultsOmicron versus Delta infection yielded estimated adjusted IRR of 1.23 (95% CI, 1.16 - 1.30) for transfer, 2.27 (95% CI, 2.20 - 2.34), for discharge and 0.98 (95% CI, 0.94 - 1.02) for death. For death in ICU, estimated adjusted IRR increased progressively with age up to 4.09 (95% CI, 3.74 - 4.47) for those 90 years and older. COVID-19 ICU patients with Omicron infection were at comparatively higher estimated risk of discharge, whereas the estimated risk of transfer and death were higher for those with Delta infection. ConclusionsInter-hospital transfers and discharges occurred more frequently in COVID-19 ICU patients with Omicron infection than in those with Delta infection, who in turn had a higher estimated risk of death. Age emerges as a relevant determinant for fatal clinical trajectories in COVID-19 ICU patients and imposes close therapeutic care.

BackgroundRecent meta-analyses concluded that vitamin D supplementation can prevent acute respiratory infection (ARI). However, the findings were heavily influenced by results from two arms of a six-arm cluster-randomised trial that were analysed without accounting for the cluster trial design. We have used publicly available data to provide results from the remaining four unpublished trial arms and to reanalyse the meta-analyses, accounting for the cluster trial design. MethodsThe intracluster correlation co-efficient (ICC) and design effect were estimated. We then calculated the risk reduction (RR) of ARI from summary statistics, adjusting for the design effect, individually for the five different vitamin D treatment groups (four previously unpublished) and for all the vitamin D groups pooled. For this trial, individual patient data were used to estimate the effect of vitamin D on ARI risk and number of ARIs, adjusting for the cluster trial design, using random-effects models. Finally, we reanalysed the most recent trial-level meta-analysis, including the trial data generated by the correct analysis of the cluster randomized trial. ResultsThere were 744 trial participants (6 treatment groups, 21 clusters, mean cluster size 35.4). The ICC was 0.08 (95% CI 0.02-0.14) and design effect 3.75. In analyses based on summary statistics, there was no statistically significant effect of vitamin D on ARI risk in any individual treatment group, or when groups were pooled (RR 0.75, 95%CI 0.50-1.13). In individual patient data analyses, there was also no statistically significant effect of vitamin D on the ARI risk or number of ARIs in any treatment group, or when pooled: odds ratio 0.58 (0.26-1.29), rate ratio 0.70 (0.44-1.12), respectively. Update of the previous meta-analysis showed no effect of vitamin D on ARI either when data from the two arms of the trial, or when all trial arms were incorporated (RR 0.98, 0.96-1.00, P=0.10 both analyses). ConclusionsOverall, vitamin D supplementation had no effect on the risk of an ARI or on the number of ARIs in this trial or in a re-analysis of the most recent meta-analysis. The results of the updated meta-analysis do not suggest that vitamin D supplementation would reduce the risk of Covid 19.

BackgroundChinese studies reported predictors of severe disease and mortality associated with coronavirus disease 2019 (COVID-19). A generalizable and simple survival calculator based on data from US patients hospitalized with COVID-19 has not yet been introduced. ObjectiveDevelop and validate a clinical tool to predict 7-day survival in patients hospitalized with COVID-19. DesignRetrospective and prospective cohort study. SettingThirteen acute care hospitals in the New York City area. ParticipantsAdult patients hospitalized with a confirmed diagnosis of COVID-19. The development and internal validation cohort included patients hospitalized between March 1 and May 6, 2020. The external validation cohort included patients hospitalized between March 1 and May 5, 2020. MeasurementsDemographic, laboratory, clinical, and outcome data were extracted from the electronic health record. Optimal predictors and performance were identified using least absolute shrinkage and selection operator (LASSO) regression with receiver operating characteristic curves and measurements of area under the curve (AUC). ResultsThe development and internal validation cohort included 11{square}095 patients with a median age of 65 years [interquartile range (IQR) 54-77]. Overall 7-day survival was 89%. Serum blood urea nitrogen, age, absolute neutrophil count, red cell distribution width, oxygen saturation, and serum sodium were identified as the 6 optimal of 42 possible predictors of survival. These factors constitute the NOCOS (Northwell COVID-19 Survival) Calculator. Performance in the internal validation, prospective validation, and external validation were marked by AUCs of 0.86, 0.82, and 0.82, respectively. LimitationsAll participants were hospitalized within the New York City area. ConclusionsThe NOCOS Calculator uses 6 factors routinely available at hospital admission to predict 7-day survival for patients hospitalized with COVID-19. The calculator is publicly available at https://feinstein.northwell.edu/NOCOS. Trial registrationN/A Funding SourceThis work was supported by grants R24AG064191 from the National Institute on Aging, R01LM012836 from the National Library of Medicine, and K23HL145114 from the National Heart Lung and Blood Institute.

BackgroundThrombosis may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic anticoagulation would improve outcomes in critically ill patients with Covid-19. MethodsWe conducted an open-label, adaptive, multiplatform, randomized, clinical trial. Patients with severe Covid-19, defined as the requirement for organ support with high flow nasal cannula, non-invasive ventilation, invasive ventilation, vasopressors, or inotropes, were randomized to receive therapeutic anticoagulation with heparin or pharmacological thromboprophylaxis as per local usual care. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. ResultsTherapeutic anticoagulation met the pre-defined criteria for futility in patients with severe Covid-19. The primary outcome was available for 1,074 participants (529 randomized to therapeutic anticoagulation and 545 randomized to usual care pharmacological thromboprophylaxis). Median organ support-free days were 3 days (interquartile range -1, 16) in patients assigned to therapeutic anticoagulation and 5 days (interquartile range -1, 16) in patients assigned to usual care pharmacological thromboprophylaxis (adjusted odds ratio 0.87, 95% credible interval (CrI) 0.70-1.08, posterior probability of futility [odds ratio<1.2] 99.8%). Hospital survival was comparable between groups (64.3% vs. 65.3%, adjusted odds ratio 0.88, 95% CrI 0.67-1.16). Major bleeding occurred in 3.1% of patients assigned to therapeutic anticoagulation and 2.4% of patients assigned to usual care pharmacological thromboprophylaxis. ConclusionsIn patients with severe Covid-19, therapeutic anticoagulation did not improve hospital survival or days free of organ support compared to usual care pharmacological thromboprophylaxis. Trial registration numbers NCT02735707, NCT04505774, NCT04359277, NCT04372589

OBJECTIVETo determine whether brief attendance for outpatient radiological investigations is associated with increased risk of clinically significant coronavirus disease 2019 (covid-19) infection. DESIGNObservational cohort study with a historical control. SETTING2 large UK University Hospitals located in Nottingham and Cardiff. PARTICIPANTSAll 47,340 patients who attended an outpatient radiology appointment at Nottingham University Hospitals and University Hospital of Wales during the first wave of the pandemic in 2020, and 70,655 patients that comprised the control cohort who attended for outpatient radiology the same period in 2019. MAIN OUTCOME MEASURESThe risk of developing clinically significant covid-19 infection within 28-days of attending a radiological examination. Covid-19 infection rates for the 2020 cohort were compared against a control group who attended in 2019. RESULTS84 positive SARS-CoV-2 tests were temporally associated with 47,340 radiological examinations across two hospitals in 2020. This low infection rate was higher than the 2019 control cohort; OR 2.507 (1.766 - 3.559) and equates to an approximate 1 positive covid-19 infection per 1000 radiology investigations. CONCLUSIONSOur data suggests that attending hospitals for outpatient radiological investigations during the pandemic is associated with a very small absolute risk of acquiring clinically significant covid-19 infection. It is unlikely that this risk is directly attributable to radiology attendance, considering the reasons leading individuals to attend hospitals during the pandemic, the true attributable risk will likely be even lower. TRIAL REGISTRATIONClinicalTrials.gov NCT04544176

BackgroundSystemic racial and ethnic inequities continue to be perpetuated through scientific methodology and communication norms despite efforts by medical institutions. PurposeTo characterize methodological practices regarding race and ethnicity in U.S. research published in leading medical journals. Data sourceArticles published in Annals of Internal Medicine, BMJ, JAMA, The Lancet, and NEJM from 1995-2018 were sampled via PubMed. Study SelectionAll original, human subjects research conducted in the U.S. Data ExtractionInformation on definition, measurement, coding, use in analyses, and justifications was collected. Data SynthesisThe proportion of U.S. medical research studies including race and/or ethnicity data increased between 1995 and 2018. No studies defined race or ethnicity. and most did not state how race and/or ethnicity was measured. Common coding schemes included: "Black, other, White," "Hispanic, Non-Hispanic," and "Black, Hispanic, other, White." Race and/or ethnicity was most often used as a control variable, descriptive covariate, or matching criteria. Under 30% of studies included justification for their methodological choices regarding race and/or ethnicity. ConclusionsDespite regular efforts by medical journals to implement new policies around race and ethnicity in medical research, pertinent methodological information was systematically absent from the majority of reviewed literature. This stymies critical disciplinary reflection and progress towards equitable practice.

BackgroundThere have been recent reports of myocarditis (including myocarditis, pericarditis or myopericarditis) as a side-effect of mRNA-based COVID-19 vaccines, particularly in young males. Less information is available regarding the risk of myocarditis from COVID-19 infection itself. Such data would be helpful in developing a complete risk-benefit analysis for this population. MethodsA de-identified, limited data set was created from the TriNetX Research Network, aggregating electronic health records from 48 mostly large U.S. Healthcare Organizations (HCOs). Inclusion criteria were a first COVID-19 diagnosis during the April 1, 2020 - March 31, 2021 time period, with an outpatient visit 1 month to 2 years before, and another 6 months to 2 years before that. Analysis was stratified by sex and age (12-17, 12-15, 16-19). Patients were excluded for any prior cardiovascular condition. Primary outcome was an encounter diagnosis of myocarditis within 90 days following the index date. Rates of COVID-19 cases and myocarditis not identified in the system were estimated and the results adjusted accordingly. Wilson score intervals were used for 95% confidence intervals due to the very low probability outcome. ResultsFor the 12-17-year-old male cohort, 6/6,846 (0.09%) patients developed myocarditis overall, with an adjusted rate per million of 450 cases (Wilson score interval 206 - 982). For the 12-15 and 16-19 male age groups, the adjusted rates per million were 601 (257 - 1,406) and 561 (240 - 1,313). For 12-17-year-old females, there were 3 (0.04%) cases of myocarditis of 7,361 patients. The adjusted rate was 213 (73 - 627) per million cases. For the 12-15- and 16-19-year-old female cohorts the adjusted rates per million cases were 235 (64 - 857) and 708 (359 - 1,397). The outcomes occurred either within 5 days (40.0%) or from 19-82 days (60.0%). ConclusionsMyocarditis (or pericarditis or myopericarditis) from primary COVID19 infection occurred at a rate as high as 450 per million in young males. Young males infected with the virus are up 6 times more likely to develop myocarditis as those who have received the vaccine.

ImportanceThe overall effects of vaccination on the risk of cardiac, and venous and arterial thromboembolic complications following COVID-19 remain unclear. ObjectiveWe studied the association between COVID-19 vaccination and the risk of acute and subacute COVID-19 cardiac and thromboembolic complications. DesignMultinational staggered cohort study, based on national vaccination campaign rollouts. SettingNetwork study using electronic health records from primary care records from the UK, primary care data linked to hospital data from Spain, and national insurance claims from Estonia. ParticipantsAll adults with a prior medical history of [&ge;]180 days, with no history of COVID-19 or previous COVID-19 vaccination at the beginning of vaccine rollout were eligible. ExposureVaccination status was used as a time-varying exposure. Vaccinated individuals were classified by vaccine brand according to the first dose received. Main OutcomesPost COVID-19 complications including myocarditis, pericarditis, arrhythmia, heart failure (HF), venous (VTE) and arterial thromboembolism (ATE) up to 1 year after SARS-CoV-2 infection. MeasuresPropensity Score overlap weighting and empirical calibration based on negative control outcomes were used to minimise bias due to observed and unobserved confounding, respectively. Fine-Gray models were fitted to estimate sub-distribution Hazard Ratios (sHR) for each outcome according to vaccination status. Random effect meta-analyses were conducted across staggered cohorts and databases. ResultsOverall, 10.17 million vaccinated and 10.39 million unvaccinated people were included. Vaccination was consistently associated with reduced risks of acute (30-day) and subacute post COVID-19 VTE and HF: e.g., meta-analytic sHR 0.34 (95%CI, 0.27-0.44) and 0.59 (0.50-0.70) respectively for 0-30 days, sHR 0.58 (0.48 - 0.69) and 0.71 (0.59 - 0.85) respectively for 90-180 days post COVID-19. Additionally, reduced risks of ATE, myocarditis/pericarditis and arrhythmia were seen, but mostly in the acute phase (0-30 days post COVID-19). ConclusionsCOVID-19 vaccination reduced the risk of post COVID-19 complications, including cardiac and thromboembolic outcomes. These effects were more pronounced for acute (1-month) post COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough vs unvaccinated SARS-CoV-2 infection. RelevanceThese findings highlight the importance of COVID-19 vaccination to prevent cardiovascular outcomes after COVID-19, beyond respiratory disease. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the impact of COVID-19 vaccination to prevent cardiac complications and thromboembolic events following a SARS-CoV-2 infection? FindingsResults from this multinational cohort study showed that COVID-19 vaccination reduced risk for acute and subacute COVID-19 heart failure, as well as venous and arterial thromboembolic events following SARS-CoV-2 infection. MeaningThese findings highlight yet another benefit of vaccination against COVID-19, and support the recommendations for COVID-19 vaccination even in people at high cardiovascular risk.

BackgroundOlder patients are at risk of increased morbidity and mortality from COVID-19 disease due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There are few effective treatments for outpatients with COVID-19. ObjectiveTo evaluate the efficacy of hydroxychloroquine to reduce time in quarantine for symptomatic [&ge;]40 years-old COVID-19 patients. DesignA randomized, double-blind, placebo-controlled clinical trial. SettingOutpatients with polymerase chain reaction confirmed COVID-19 at a University of Pennsylvania affiliated testing center between April 15, 2020 and, July 14, 2020. ParticipantsOut of 5511 SARS-CoV-2 positive patients, 1072 met initial eligibility criteria for telephone-based recruitment, but only 34 subjects were able to be randomized. InterventionsHydroxychloroquine 400 mg per twice daily (n=17) or matching placebo (n=17), taken orally for up to 14 days. MeasurementsThe primary outcome was the time to release from quarantine. Secondary outcomes included the participant-reported secondary infection of co-inhabitants, hospitalization, treatment-related adverse events, time to symptom improvement, and incidence of cardiac arrhythmia. ResultsThe median time to release from quarantine for HCQ-treated vs. placebo-treated participants was 8 days (range 4-19 days) vs. 11 days (4-18 days); z-score +0.58, p=n.s. This did not meet the pre-specified criteria for early termination, however, this study was terminated early due to lack of feasibility. There was no mortality in either study arm. LimitationSince this study was terminated early due to a lack of feasibility, no conclusion can be made about the efficacy of hydroxychloroquine as a treatment for COVID-19 patients 40 years of age or older quarantined at home. ConclusionThe design of this remotely conducted study could guide testing of other more promising agents during the COVID-19 pandemic. Trial registrationClinicaltrials.gov identifier: NCT04329923

BackgroundThe role of thromboprophylaxis in the post-acute phase of COVID-19 is uncertain due to conflicting results from randomised controlled trials and observational studies. We aimed to determine the effectiveness of post-hospital apixaban in reducing the rate of death and hospital readmission of hospitalised adults with COVID-19. MethodsHEAL COVID is an adaptive randomised open label multicentre platform trial recruiting participants from National Health Service Hospitals in the United Kingdom. Here we report the preliminary results of apixaban comparison of HEAL-COVID. Participants with a hospital admission related to confirmed COVID-19 and an expected date of discharge in the subsequent five days were randomised to either apixaban 2.5 mg twice daily or standard care (no anticoagulation) for 14 days. The primary outcome was hospital free survival at 12 months obtained through routine data sources. The trial was prospectively registered with ISRCTN (15851697) and Clincialtrials.gov (NCT04801940). FindingsBetween 19 May 2021 and 21 November 2022, 402 participants from 109 sites were randomised to apixaban and 399 to standard care. Seven participants withdrew from the apixaban group and one from the standard care group. Analysis was undertaken on an intention-to-treat basis. The apixaban arm was stopped on the recommendation of the oversight committees following an interim analysis due to no indication of benefit. Of the 402 participants randomised to apixaban, 117 experienced death or rehospitalisation during a median follow-up of 344{middle dot}5 days (IQR 125 to 365), and 123 participants receiving standard care experienced death or rehospitalisation during a median follow-up of 349 days (IQR 124 to 365). There was no statistical difference in the rate of death and rehospitalisation (HR: 0{middle dot}96 99%CI 0{middle dot}69-1{middle dot}34; p=0{middle dot}75). Three participants in the apixaban arm experienced clinically significant bleeding during treatment. InterpretationFourteen days of post-hospital anticoagulation with the direct oral anticoagulant apixaban did not reduce the rate of death or rehospitalisation of adults hospitalised with COVID-19. These data do not support the use of prophylactic post-hospital anticoagulation in adults with COVID-19. FundingHEAL-COVID is funded by the National Institute for Health and Care Research [NIHR133788] and the NIHR Cambridge Biomedical Research Centre [BRC-1215-20014*].

ObjectivesTo illustrate the development of the case fatality risk (CFR) for COVID-19 over time using different assumptions for calculating the CFR. DesignObservational study. Setting Selected European countries, 28 January to October 29 2020. ParticipantsLaboratory-confirmed COVID-19 cases and deaths due to COVID-19 Main outcome measurecase fatality risk (CFR) ResultsWe show that the CFR has considerably decreased over time. This seems to be driven not only by increased testing but also by a reduced CFR among cases older than 60 years. Our data also confirm a significantly higher fatality risk for men than for women. The decline in the CFR is even more pronounced when only cases and deaths occurring in a specified time window are considered. This alternative estimation method has the advantage that early data where the bias due to the incomplete ascertainment of cases was arguably largest do not affect CFR estimates later on. We find similar results for other European countries. ConclusionCFR estimates vary considerably depending on the underlying assumptions concerning their calculation. Reliable CFR estimates should not be based on cumulative numbers from the beginning of the pandemic but rather be based on more recent data only.

ImportanceAs testing options increase for COVID-19, their interpretability is challenged by the increasing variety of clinical contexts in which results are obtained. In particular, positive COVID-19 diagnostic (RT-PCR) tests that occur after a patient has seroconverted may be indicative of reinfection. However, in the absence of SARS-CoV-2 sequence data, the possibility of prolonged viral shedding may not be excluded. We highlight a testing pattern that identifies such cases and study its statistical power in identifying potential reinfection. We also study the medical records of patients that matched the pattern. ObjectiveTo describe the frequency and demographic information of people with a testing pattern indicative of SARS-CoV-2 reinfection. DesignWe examined 4.2 million test results from a large national health insurer in the United States. Specifically, we identified the pattern of a positive RT-PCR test followed by a positive IgG test, again followed by a positive RT-PCR. SettingData from outpatient laboratories across the United States was joined with claims data from a single large commercial insurers administrative claims database. ParticipantsStudy participants are those whose insurance, either commercial or Medicare, is provided by a single US based insurer. ExposuresPeople who received at least two positive diagnostic tests via RT-PCR for SARS-Cov-2 separated by 42 or more days with at least one serological test (IgG) indicating the presence of antibodies between diagnostic tests. Main Outcomes and MeasuresCount and characteristics of people with the timeline of three tests as described in Exposures. ResultsWe identified 79 patients who had two positive RT-PCR tests separated by more than six weeks, with a positive IgG test in between. These patients tended to be older than those COVID-19 patients without this pattern (median age 56 vs. 42), and they exhibited comorbidities typically attributed to a compromised immune system and heart disease. Conclusions and RelevanceWhile the testing pattern alone was not sufficient to distinguish potential reinfection from prolonged viral shedding, we were able to identify common traits of the patients identified through the pattern.

ImportanceThe effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. ObjectiveTo assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design, Setting, and ParticipantsThe ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants [&ge;]30 years of age with confirmed SARS-CoV-2 infection and [&ge;]2 acute COVID-19 symptoms for [&le;]7 days, were included across 104 US sites to evaluate the use of montelukast. InterventionsParticipants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and MeasuresThe primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. ResultsAmong participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported [&ge;]2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial RegistrationClinicalTrials.gov (NCT04885530).