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

BackgroundWe aimed at estimating the risk of venous thromboembolism (VTE), thrombocytopenia (TCP), and VTE associated with TCP, by age and sex, after the first dose of both adenovirus vector-based and mRNA-based Covid-19 vaccines, and after the second dose of m-RNA vaccines. MethodsIn this population-based retrospective cohort study in the national health care databases in Catalonia, we examined three groups: 1 662 719 people 10 years of age and over vaccinated with the first dose of a Covid-19 vaccine, 622 778 with the second dose, and 190 616 diagnosed of Covid-19 in the same period (between1 January 2021 and 18 April 2021). The rates of various clinical presentations of VTE and TCP were compared with those in the reference population (7 013 040 people served by the health care system in 2019). The two primary outcomes were the observed 21 day rate of a composite variable of cerebral venous sinus thrombosis, mesenteric thrombosis, portal vein thrombosis, or any venous thromboembolism (VTE) associated with thrombocytopenia (TCP), and the rate of any VTE associated with TCP (VTE+TCP). Analyses were standardised by age and sex. ResultsThe 21 day rate per 100 000 of the primary composite variable was 2.15 in the reference population, 5.65 following the first vaccine dose (standardised difference, 2.53 (95% CI [CI], 1.04 to 4.00), and 7.23 following the second dose (standardised difference, 4.07 (95% CI, 1.43 to 6.70). The event rates of VTE+TCP and of all the secondary variables showed the same patterns. Excess event rates were higher in men than in women, and they were not especially increased in any particular age group. All Covid-19 vaccines were associated with increased rates of the outcome variables. Excess event rates were much higher in the Covid-19 cohort (35.60 per 100 000 (95% CI, 26.15 to 45.06). ConclusionsWe observed increases of rates of venous thromboembolism in usual and unusual anatomical sites and of thrombocytopenia in recipients of both adenovirus vector and mRNA vaccines against Covid-19. Excess rates were higher in men than in women and they were not particularly elevated in any specific age group.

IntroductionThis study aims to explore the impact of COVID-19 vaccination on critical care by examining associations between vaccination and admission to critical care with COVID-19 during Englands Delta wave, by age group, dose, and over time. MethodsWe used linked routinely-collected data to conduct a population cohort study of patients admitted to adult critical care in England for management of COVID-19 between 1 May and 15 December 2021. Included participants were the whole population of England aged 18 years or over (44.7 million), including 10,141 patients admitted to critical care with COVID-19. The intervention was vaccination with one, two, or a booster/three doses of any COVID-19 vaccine. ResultsCompared with unvaccinated patients, vaccinated patients were older (median 64 years for patients receiving two or more doses versus 50 years for unvaccinated), with higher levels of severe comorbidity (20.3% versus 3.9%) and immunocompromise (15.0% versus 2.3%). Compared with patients who were unvaccinated, those vaccinated with two doses had a relative risk reduction (RRR) of between 90.1% (patients aged 18-29, 95% CI, 86.8% to 92.7%) and 95.9% (patients aged 60-69, 95% CI, 95.5% to 96.2%). Waning was only observed for those aged 70+, for whom the RRR reduced from 97.3% (91.0% to 99.2%) to 86.7% (85.3% to 90.1%) between May and December but increased again to 98.3% (97.6% to 98.8%) with a booster/third dose. ConclusionImportant demographic and clinical differences exist between vaccinated and unvaccinated patients admitted to critical care with COVID-19. While not a causal analysis, our findings are consistent with a substantial and sustained impact of vaccination on reducing admissions to critical care during Englands Delta wave, with evidence of waning predominantly restricted to those aged 70+.

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.

Tranexamic acid (TXA) is well-established as a safe intervention for reducing transfusion requirements in surgeries with high-risk for blood loss. However, its role in surgeries classified as low-risk for blood loss remains uncertain. Given the frequency of such procedures, even small clinical benefits could have substantial cumulative impact. We assessed the clinical and cost-effectiveness of TXA in surgeries with low expected blood loss A systematic review and meta-analysis of randomised controlled trials (RCTs) for adults or children undergoing low-risk surgeries, comparing peri-operative TXA (any route or dose) with placebo or standard care informed the clinical effectiveness and a decision model adapted from NICE NG24, focusing on short-term hospital costs informed the cost-effectiveness analysis. We included 82 RCTs comprising 8506 participants. TXA significantly reduced blood loss (ratio of means 0{middle dot}73, 95% CI 0{middle dot}68,0{middle dot}79) and transfusion rates (odds ratio 0{middle dot}39, 95% CI 0{middle dot}25,0{middle dot}61). It also reduced hospital stay by 0{middle dot}4 days (MD = -0{middle dot}40 days, 95% CI = -0{middle dot}77, -0{middle dot}02) and improved pain scores at 1 and 2 weeks postoperatively. Evidence for thrombotic events was limited and inconclusive. The cost-effectiveness analysis showed TXA was cost-saving ({pound}156 per patient) and had a 99% probability of being cost-effective at the {pound}20lJ000 per QALY threshold. Reduction in bleeding and improved recovery outcomes even in surgeries with low anticipated blood loss support broader use of TXA in surgical care and suggests revisiting existing guidelines to include surgeries with any bleeding risk. Further research should examine long-term safety and patient-reported outcomes.

BACKGROUND. In patients with venous thromboembolism (VTE), renal impairment increases the risks for both recurrence and bleeding. Because these patients are underrepresented in clinical trials, we assessed whether standard direct factor Xa inhibitor (DXI) lead-in followed by early dose reduction was noninferior to standard anticoagulation in patients with acute VTE and moderate-to-severe renal impairment. METHODS. The VERDICT trial was a randomized, prospective, multicenter, open-label, blinded-endpoint, noninferiority trial. Consecutive patients with acute proximal deep-vein thrombosis or pulmonary embolism and chronic renal impairment (creatinine clearance 15?50 mL/min) were randomized 1:1 to an early DXI dose reduction strategy or standard therapy (heparin plus a vitamin K antagonist). Patients allocated to the DXI strategy underwent a second 1:1 randomization to apixaban or rivaroxaban, each administered at an initial standard lead-in dose followed by early dose reduction. The primary outcome was net clinical benefit at 3 months, defined as the composite of major bleeding and symptomatic recurrent VTE. RESULTS. Due to slow recruitment, the trial was prematurely terminated after enrolling 200 of the planned 800 patients (DXI: n=104; standard: n=96). The median age was 85.9 years, 31% were male, and 29.0% had severe renal impairment. The primary outcome occurred in 8 patients (7.7%) in the DXI group and 9 patients (9.3%) in the standard therapy group (adjusted subhazard ratio [sHR], 0.87; 95% CI, 0.26 to 2.87; P = 0.19 for noninferiority; noninferiority margin 1.30). Major bleeding occurred in 6.7% and 6.2% of patients and recurrent VTE occurred in 1.0% and 3.1% of patients, respectively. CONCLUSION. In patients with VTE and moderate-to-severe renal impairment, noninferiority of an early DXI dose-reduction strategy versus standard therapy could not be demonstrated for net clinical benefit. Although no major differences in efficacy or safety outcomes were observed between groups, the reduced sample size precludes definitive conclusions.

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 assess the early vaccine administration coverage and vaccine effectiveness and outcome data across an integrated care system of eight CCGs leveraging a unique population-level care dataset DesignRetrospective cohort study. SettingIndividuals eligible for COVID 19 vaccination in North West London based on linked primary and secondary care data. Participants2,183,939 individuals eligible for COVID 19 vaccination ResultsDuring the NWL vaccine programme study time period 5.88% of individuals declined and did not receive a vaccination. Black or black British individuals had the highest rate of declining a vaccine at 16.14% (4,337). There was a strong negative association between deprivation and rate of declining vaccination (r=-0.94, p<0.01) with 13.5% of individuals declining vaccination in the most deprived postcodes compared to 0.98% in the least deprived postcodes. In the first six days after vaccination 344 of 389587 individuals tested positive for COVID-19 (0.09%). The rate increased to 0.13% (525/389,243) between days 7 and 13, before then gradually falling week on week. At 28 days post vaccination there was a 74% (HR 0.26 (0.19-0.35)) and 78% (HR 0.22 (0.18-0.27)) reduction in risk of testing positive for COVID-19 for individuals that received the Oxford/Astrazeneca and Pfizer/BioNTech vaccines respectively, when compared with unvaccinated individuals. After vaccination very low rates of hospital admission were seen in individuals testing positive for COVID-19 (0.01% of all patients vaccinated). ConclusionsThis study provides further evidence that a single dose of either the Pfizer/BioNTech vaccine or the Oxford/Astrazeneca vaccine is effective at reducing the risk of testing positive for COVID-19 up to 60 days across all adult age groups, ethnic groups, and risk categories in an urban UK population. There was no difference in effectiveness up to 28 days between the Oxford/Astrazeneca and Pfizer/BioNtech vaccines. In those declining vaccination higher rates were seen in those living in the most deprived areas and in Black and Black British groups. There was no definitive evidence to suggest COVID-19 was transmitted as a result of vaccination hubs during vaccine the administration roll-out in NWL, and the risk of contracting COVID-19 and/or becoming hospitalised after vaccination has been demonstrated to be very low in the vaccinated population.

The terms personalized, individualized and precision medicine are increasingly used to describe health interventions, yet their operational meaning in clinical research remains unclear. Despite extensive conceptual discussion, there is limited empirical evidence on how these labels are applied in randomized controlled trials (RCTs) and whether such trials meet standards of transparency and methodological rigor. We systematically examined 262 RCTs published between 2020 and 2022 that used the terms "personalized", "individualized", or "precision" in the title to describe an intervention. The term "personalized" was used most frequently (49.2%), followed by "individualized" (45.8%) and "precision" (5.0%). In most trials, personalization involved behavioral, digital, or pharmacological interventions, with few studies employing -omics approaches. Personalization was most often based on individual lifestyle factors, psychological characteristics, or disease classification. We also found that in most trials, personalization consisted of tailoring a single intervention to individuals (82.8%), often through individualized dosage (73.2%). Most included RCTs were judged to be at high risk of bias and showed limited transparency with respect to data and code sharing. Our study suggests that, in contemporary RCTs, the labels "personalized", "individualized", and "precision" are applied interchangeably to a wide range of heterogeneous interventions that are predominantly non-genomic. Greater conceptual clarity and stronger methodological standards are needed to ensure that claims of personalization in clinical research are empirically meaningful and reliable.

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 calculate the observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2, infection with SARS-CoV-2, and to compare them to background (expected) rates in the general population. DesignCohort study using routinely collected primary care records. SettingRoutine practice in the United Kingdom. ParticipantsTwo mutually exclusive vaccinated cohorts included people vaccinated with either ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A third cohort consisted of people newly infected with SARS-Cov-2 identified by a first positive RT-PCR test between 1 September 2020 and 28 February 2021. The fourth general population cohort for background rates included those people with a visit between 1 January 2017 and 31 December 2019. In total, we included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population. InterventionsFirst-dose of either ChAdOx1 or BNT162b2 Main outcome measuresOutcomes included venous thrombosis, arterial thrombosis, thrombocytopenia, and thrombosis with thrombocytopenia. Outcome rates were estimated for recipients of the ChAdOx1 or BNT162b2 vaccines, for people infected with SARS-CoV-2, and background rates in the general population. Indirectly standardized incidence ratios (SIR) were estimated. ResultsWe included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population for background rates. The SIRs for pulmonary embolism were 1.23 [95% CI, 1.09-1.39] after vaccination with ChAdOx1, 1.21 [1.07-1.36] after vaccination with BNT162b2, and 15.31 [14.08 to 16.65] for infection with SARS-CoV-2. The SIRs for thrombocytopenia after vaccination were 1.25 [1.19 to 1.31] for ChAdOx1 and 0.99 (0.94 to 1.04) for BNT162b2. Rates of deep vein thrombosis and arterial thrombosis were similar among those vaccinated and the general population. ConclusionsChAdOx1 and BNT162b2 had broadly similar safety profiles. Thrombosis rates after either vaccine were mostly similar to those of the general population. Rates of pulmonary embolism increased 1.2-fold after either vaccine and 15-fold with SARS-CoV-2 infection. Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISpontaneous reports of unusual and severe thrombosis with thrombocytopenia syndrome (TTS) raised concerns regarding the safety of adenovirus-based vaccines against SARS-CoV-2 C_LIO_LIIn a cohort study including over 280,000 people aged 18-65 years vaccinated with ChAdOx1 in Denmark and Norway, Potteg[a]rd et al reported increased rates of venous thromboembolic events as well as thrombocytopenia among vaccine recipients. C_LI What this study addsO_LIIn this cohort study, ChAdOx1 and BNT162b2 were seen to have broadly similar safety profiles. C_LIO_LIRates of thrombosis after either vaccine were generally similar to those of the general population. Rates of pulmonary embolism were though 1.2-fold higher than background rates after either vaccine, which compared to 15-fold higher after SARS-CoV-2 infection. C_LIO_LIThrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2. C_LI

ObjectiveTo create case definitions for confirmed COVID diagnoses, COVID vaccination status, and three separate definitions of high risk of severe COVID, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID epidemiology in England. DesignRetrospective cohort study SettingElectronic healthcare records from primary care (Clinical Practice Research Datalink, or CPRD) linked to secondary care data (Hospital Episode Statistics, or HES) data covering 24% of the population in England Participants2,271,072 persons aged 1 year and older diagnosed with COVID in CPRD Aurum between August 1, 2020 through January 31, 2022. Main Outcome MeasuresAge, sex, and regional distribution of COVID cases and COVID vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalized for COVID (primary diagnosis code of ICD-10 U07.1 "COVID-19"). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the United Kingdom (NHS Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritization for vaccination). ResultsCompared to national estimates, CPRD case estimates underrepresented older adults in both the primary care (age 65-84: 6% in CPRD vs 9% nationally) and hospitalized (31% vs 40%) cohorts, and overrepresented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East, vs 15% nationally). The majority of non-hospitalized cases and all hospitalized cases had not completed primary series vaccination. In primary care, persons meeting high risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score. ConclusionsCPRD primary care data is a robust real-world data source and can be used for some COVID research questions, however limitations of the data availability should be carefully considered. Included in this publication are supplemental files for atotal of over 28,000 codes to define each of three definitions of high risk of severe disease. SUMMARY BOXESO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIThe UK Government publishes data on cases, hospital admissions and vaccinations related to COVID in England. C_LIO_LIThere are at least three definitions of persons at high-risk of severe COVID in use in England. C_LI What this study addsO_LIOur study created case definitions for COVID diagnoses, COVID vaccination, and three separate definitions of high risk of severe COVID for use in the Clinical Practice Research Datalink (CPRD), a database covering 24% of England. C_LIO_LIThe COVID population in the CPRD has a different age and regional distribution than national case reports, which future studies may need to consider. C_LI

BackgroundCOVID-19 reinfections have emerged as a critical concern, particularly in relation to post-acute sequelae of SARS-CoV-2 infection, commonly known as long COVID. Long COVID is known to manifest diverse, debilitating symptoms across all demographics. Limited studies have investigated the causal relationship of COVID-19 reinfections and long COVID. MethodsWe leveraged demographically diverse electronic health records from the COVID-19 enclave of the National Clinical Cohort Collaborative, part of the RECOVER initiative, to create a matched cohort of reinfected and control adults. All participants had at least one documented COVID-19 infection. We used one-to-one coarsened exact matching on sex, race/ethnicity, age, healthcare utilization, existing comorbidities, site of care, and the timing and severity of first infection. Index dates were assigned to each matched pair as the date of reinfection for the reinfected case. Long COVID was defined using a machine learning computable phenotype trained on clinically diagnosed long COVID cases. Cumulative incidence one year after index was calculated using an Aalen-Johansen estimator. Risk ratios were calculated by taking the ratio of long COVID incidence among reinfected and control cases. ResultsWe found that reinfection resulted in a significantly higher risk of long COVID compared to not being reinfected (risk ratio, 1.35, 95% CI, 1.32-1.39; risk difference, 0.029, 95% CI, 0.027-0.031). This effect was consistent across most stratifications. ConclusionsWe found that COVID-19 reinfection resulted in a roughly 35% increase in the incidence of long COVID in a matched cohort using observational electronic health records.

IntroductionRecent evidence from randomized controlled trials and meta-analyses in the critically ill suggest small but clinically important differences in death and requirement for renal replacement therapy that favor Ringers lactate as compared to normal saline. To futher contribute to this evidence base, we will perform a secondary analysis of the FLUID trial with a focus on critically ill patients (FLUID - ICU). The FLUID trial was hospital wide cluster randomized cross-over trial that compared normal saline to Ringers lactate. ObjectivesThe primary objectives of FLUID-ICU are to examine the effect of Ringers lactate compared to normal saline compared to on the primary composite outcome and secondary outcomes in critically ill patients. As secondary exploratory objectives, we will evaluate the primary composite outcome and secondary outcomes within prespecified subgroups defined by age, sex, case mix group, Elixhauser Co-morbidity Index, presence of infection with organ dysfunction, traumatic brain injury, and trauma with an injury severity score of >= 12. MethodsFLUID was an open-label two-period, two-sequence, cross sectional, cluster-randomized cross over trial that was conducted in 7 hospitals in the province of Ontario, Canada. Hospitals were assigned to either Ringers lactate or normal saline for a period of 12 weeks and after a washout period, switched to the other fluid at 12 weeks. The primary composite outcome was death or re-admission to hospital within 90 days after the index admission. Secondary outcomes were individual components of the primary outcome as well as length of stay in hospital, an incident emergency department visit post hospital discharge, initiation of dialysis within 90 days after the index admission, and discharge to a facility other than home. All data were obtained from health administrative databases. In FLUID-ICU, we will examine the primary and secondary outcomes in a cohort of critically ill patients, defined as patients admitted to the ICU within 1 day after admission to hospital. A sensitivity analysis will relax this definition to 2 days after admission to hospital. The analyses will be performed at the individual patient level using random effects logistic regression with adjustment for prespecified covariates. Ethics and DisseminationThe results of FLUID-ICU will be published in a peer-reviewed journal. As a secondary analysis of anonymized data, this study does not require research ethics board approval. All data is obtained from a population based health administrative database (ICES) in the province of Ontario, in aggregate and without patient identifiers.

Conducting systematic reviews of clinical trials is arduous and resource consuming. One potential solution is to design databases that are continuously and automatically populated with clinical trial data from harmonised and structured datasets. We aimed to map publicly available, continuously updated, topic-specific databases of randomised clinical trials (RCTs). We systematically searched PubMed, Embase, the preprint servers medRxiv, ArXiv, and Open Science Framework, and Google. We described seven features (access model, database architecture, data input sources, retrieval methods, data extraction methods, trial presentation, and export options) and narratively summarised the results. We did not register a protocol for this review. We identified 14 continuously updated clinical trial databases, seven related to COVID-19 (first active in 2020) and seven non-COVID databases (first active in 2009). All databases, except one, were publicly funded and accessible without restrictions. They mainly employed methods similar to those from static article-based systematic reviews and retrieved data from journal publications and trial registries. The COVID-19 databases and some non-COVID databases implemented semi-automated features of data import, which combined automated and manual data curation, whereas the non-COVID databases mainly relied on manual workflows. Most reported information was metadata, such as author names, years of publication, and link to publication or trial registry. Two databases included trial appraisal information (risk of bias assessments). Six databases reported aggregate group level results, but only one database provided individual participant data on request. We identified few continuously updated trial databases, and existing initiatives mainly employ methods known from static article -based reviews. The main limitation to create truly live evidence synthesis is the access and import of machine-readable and harmonised clinical trial data.

Background and Aims SARS-CoV-2 infection is associated with an increased risk of cardiovascular, cerebrovascular and venous thromboembolism events. We aimed to assess the impact of COVID-19 vaccination prior to SARS-CoV-2 infection on the risk of these events post-infection. Methods Embase and MEDLINE were searched from January 2021 to 11 September 2025, supplemented by citation searching. Observational studies were included if they reported risks of cardiovascular, cerebrovascular, or venous thromboembolic events after SARS-CoV-2 infection between different vaccination groups (e.g. unvaccinated, vaccinated, or booster vaccinated), or reported risk of events after SARS-CoV-2 infection compared with no infection, stratified by vaccination status. Random-effects meta-analyses were conducted to estimate pooled hazard ratios (HRs) comparing vaccinated and unvaccinated individuals across prespecified outcomes. Results Twenty-three studies were included in the systematic review; most reported an association between vaccination and a reduced risk of post-infection vascular events. Ten studies were included across meta-analyses comparing vaccinated and unvaccinated individuals. Pre-infection vaccination was associated with significantly reduced risks of composite cardiovascular/cerebrovascular events (HR 0.60, 95% confidence intervals [CI] 0.51-0.69), stroke (HR 0.75, 95% CI 0.64-0.88), acute coronary syndrome (HR 0.70, 95% CI 0.52-0.95), arrhythmias (HR 0.82, 95% CI 0.69-0.98), and venous thromboembolism (HR 0.51, 95% CI 0.36-0.73). No statistically significant reduction was observed for heart failure (HR 0.72 [95% CI 0.47-1.10]). Conclusions Pre-infection COVID-19 vaccination is associated with lower risks of cardiovascular, cerebrovascular and venous thromboembolism events following SARS-CoV-2 infection in the pre- and post-Omicron eras, supporting its role within broader prevention strategies

BackgroundAspirin has been proposed as a treatment for COVID-19 on the basis of its antithrombotic properties. MethodsIn this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care plus 150mg aspirin once daily until discharge or usual standard of care alone using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 01 November 2020 and 21 March 2021, 7351 patients were randomly allocated to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) patients allocated to aspirin and 1299 (17%) patients allocated to usual care died within 28 days (rate ratio 0{middle dot}96; 95% confidence interval [CI] 0{middle dot}89-1{middle dot}04; p=0{middle dot}35). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 vs. 9 days) and a higher proportion were discharged from hospital alive within 28 days (75% vs. 74%; rate ratio 1{middle dot}06; 95% CI 1{middle dot}02-1{middle dot}10; p=0{middle dot}0062). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0{middle dot}96; 95% CI 0{middle dot}90-1{middle dot}03; p=0{middle dot}23). Aspirin use was associated with an absolute reduction in thrombotic events of 0.6% (SE 0.4%) and an absolute increase in major bleeding events of 0.6% (SE 0.2%). InterpretationIn patients hospitalised with COVID-19, aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death but was associated with a small increase in the rate of being discharged alive within 28 days. FundingUK Research and Innovation (Medical Research Council), National Institute of Health Research (Grant ref: MC_PC_19056), and the Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.

We describe our analyses of data from over 49.7 million people in England, representing near-complete coverage of the relevant population, to assess the risk of myocarditis and pericarditis following BNT162b2 and ChAdOx1 COVID-19 vaccination. A self-controlled case series (SCCS) design has previously reported increased risk of myocarditis after first ChAdOx1, BNT162b2, and mRNA-1273 dose and after second doses of mRNA COVID-19 vaccines in England. Here, we use a cohort design to estimate hazard ratios for hospitalised or fatal myocarditis/pericarditis after first and second doses of BNT162b2 and ChAdOx1 vaccinations. SCCS and cohort designs are subject to different assumptions and biases and therefore provide the opportunity for triangulation of evidence. In contrast to the findings from the SCCS approach previously reported for England, we found evidence for lower incidence of hospitalised or fatal myocarditis/pericarditis after first ChAdOx1 and BNT162b2 vaccination, as well as little evidence to suggest higher incidence of these events after second dose of either vaccination.

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

A novel coronavirus was reported in Wuhan, China in December 2019 to cause severe acute respiratory symptoms (COVID-19). In this meta-analysis, we estimated case fatality rate from COVID-19 infection by random effect meta-analysis model with country level data. Publicly accessible web database WorldOMeter (https://www.worldometers.info/coronavirus/) was accessed on 24th March 2020 GMT and reported total number of cases, total death, active cases and seriously ill/ critically ill patients were retrieved. Primary outcome of this meta-analysis was case fatality rate defined by total number of deaths divided by total number of diagnosed cases. Pooled case fatality rate (95% CI) was 1.78 (1.34-2.22) %. Between country heterogeneity was 0.018 (p<0.0001). Pooled estimate of composite poor outcome (95% CI) was 4.06 (3.24-4.88) % at that point of time after exclusion of countries reported small number of cases. Pooled mortality rate (95% CI) was 33.97 (27.44-40.49) % amongst closed cases (where patients have recovered or died) with. Meta regression analysis identified statistically significant association between health expenditure and case fatality rate (p=0.0017).