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BackgroundLow-dose corticosteroids have been shown to reduce mortality for hypoxic COVID-19 patients requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (i.e. receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality. On 11 May 2022, the independent Data Monitoring Committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only to this comparison due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support continues. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 25 May 2021 and 12 May 2022, 1272 COVID-19 patients with hypoxia and receiving no oxygen (1%) or simple oxygen only (99%) were randomly allocated to receive usual care plus higher dose corticosteroids versus usual care alone (of whom 87% received low dose corticosteroids during the follow-up period). Of those randomised, 745 (59%) were in Asia, 512 (40%) in the UK and 15 (1%) in Africa. 248 (19%) had diabetes mellitus. Overall, 121 (18%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio [RR] 1{middle dot}56; 95% CI 1{middle dot}18-2{middle dot}06; p=0{middle dot}0020). There was also an excess of pneumonia reported to be due to non-COVID infection (10% vs. 6%; absolute difference 3.7%; 95% CI 0.7-6.6) and an increase in hyperglycaemia requiring increased insulin dose (22% vs. 14%; absolute difference 7.4%; 95% CI 3.2-11.5). InterpretationIn patients hospitalised for COVID-19 with clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).
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Outcome prediction for individual patient groups is of paramount importance in terms of selection of appropriate therapeutic options, risk communication to patients and families, and allocating resource through optimum triage. This has become even more necessary in the context of the current COVID-19 pandemic. Widening the spectrum of predictor variables by including radiological parameters alongside the usually utilized demographic, clinical and biochemical ones can facilitate building a comprehensive prediction model. Automation has the potential to build such models with applications to time-critical environments so that a clinician will be able to utilize the model outcomes in real-time decision making at bedside. We show that amalgamation of computed tomogram (CT) data with clinical parameters (CP) in generating a Machine Learning model from 302 COVID-19 patients presenting to an acute care hospital in India could prognosticate the need for invasive mechanical ventilation. Models developed from CP alone, CP and radiologist derived CT severity score and CP with automated lesion-to-lung ratio had AUC of 0.87 (95% CI: 0.85-0.88), 0.89 (95% CI: 0.87-0.91), and 0.91 (95% CI: 0.89-0.93), respectively. We show that an operating point on the ROC can be chosen to aid clinicians in risk characterization according to the resource availability and ethical considerations. This approach can be deployed in more general settings, with appropriate calibrations, to predict outcomes of severe COVID-19 patients effectively.
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BackgroundREGEN-COV is a combination of 2 monoclonal antibodies (casirivimab and imdevimab) that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike protein. We aimed to evaluate the efficacy and safety of REGEN-COV in patients admitted to hospital with COVID-19. 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 patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus a single dose of REGEN-COV 8g (casirivimab 4g and imdevimab 4g) by intravenous infusion (REGEN-COV group). The primary outcome was 28-day mortality assessed first among patients without detectable antibodies to SARS-CoV-2 at randomisation (seronegative) and then in the overall population. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 18 September 2020 and 22 May 2021, 9785 patients were randomly allocated to receive usual care plus REGEN-COV or usual care alone, including 3153 (32%) seronegative patients, 5272 (54%) seropositive patients and 1360 (14%) patients with unknown baseline antibody status. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to REGEN-COV and 451 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio 0{middle dot}80; 95% CI 0{middle dot}70-0{middle dot}91; p=0{middle dot}0010). In an analysis involving all randomised patients (regardless of baseline antibody status), 944 (20%) of 4839 patients allocated to REGEN-COV and 1026 (21%) of 4946 patients allocated to usual care died within 28 days (rate ratio 0{middle dot}94; 95% CI 0{middle dot}86-1{middle dot}03; p=0{middle dot}17). The proportional effect of REGEN-COV on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity = 0{middle dot}001). InterpretationIn patients hospitalised with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab (REGEN-COV) reduced 28-day mortality among patients who were seronegative at baseline. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).
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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.
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Findings: Between 23 April 2020 and 25 January 2021, 4116 adults were included in the assessment of tocilizumab, including 562 (14%) patients receiving invasive mechanical ventilation, 1686 (41%) receiving non-invasive respiratory support, and. 1868 (45%) receiving no respiratory support other than oxygen. Median CRP was 143 [IQR 107-205] mg/L and 3385 (82%) patients were receiving systemic corticosteroids at randomisation. Overall, 596 (29%) of the 2022 patients allocated tocilizumab and 694 (33%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0.86; 95% confidence interval [CI] 0.77-0.96; p=0.007). Consistent results were seen in all pre-specified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days (54% vs. 47%; rate ratio 1.23; 95% CI 1.12-1.34; p<0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (33% vs. 38%; risk ratio 0.85; 95% CI 0.78-0.93; p=0.0005). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes regardless of the level of respiratory support received and in addition to the use of systemic corticosteroids.
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BackgroundThis paper describes the construction of a model used to estimate the number of excess deaths that could be expected as a direct consequence of a lack of hospital bed and intensive care unit (ICU) capacity. MethodsA series of compartmental models was used to estimate the number of deaths under different combinations of care required (ICU or ward), and care received (ICU, ward or no care) in England up to the end of April 2021. Model parameters were sourced from publicly available government information, organisations collating COVID-19 data and calculations using existing parameters. A compartmental sub-model was used to estimate the mortality scalars that represent the increase in mortality that would be expected from a lack of provision of an ICU or general ward bed when one is required. Three illustrative scenarios for admissions numbers, Optimistic, Middling and Pessimistic, are described showing how the model can be used to estimate mortality rates under different scenarios of capacity. ResultsThe key output of our collaboration was the model itself rather than the results of any of the scenarios. The model allows a user to understand the excess mortality impact arising as a direct consequence of capacity being breached under various scenarios or forecasts of hospital admissions. The scenarios described in this paper are illustrative and are not forecasts. There were no excess deaths from a lack of capacity in any of the Optimistic scenario applications in sensitivity analysis. Several of the Middling scenario applications under sensitivity testing resulted in excess deaths directly attributable to a lack of capacity. Most excess deaths arose when we modelled a 20% reduction compared to best estimate ICU capacity. This led to 597 deaths (0.7% increase). All the Pessimistic scenario applications under sensitivity analysis had excess deaths. These ranged from 49,219 (19.4% increase) when we modelled a 20% increase in ward bed availability over the best-estimate, to 103,845 (40.9% increase) when we modelled a 20% shortfall in ward bed availability below the best-estimate. The emergence of a new, more transmissible variant (VOC 202012/01) increases the likelihood of real world outcomes at, or beyond, those modelled in our Pessimistic scenario. The results can be explained by considering how capacity evolves in each of the scenarios. In the Middling scenario, whilst ICU capacity may be approached and even possibly breached, there remains sufficient ward capacity to take lives who need either ward or ICU support, keeping excess deaths relatively low. However, the Pessimistic scenario sees ward capacity breached, and in many scenarios for a period of several weeks, resulting in much higher mortality in those lives who require care but do not receive it. ConclusionsNo excess deaths from breaching capacity would be expected under the unadjusted Optimistic assumptions of demand. The Middling scenario could result in some excess deaths from breaching capacity, though these would be small (0.7% increase) relative to the total number of deaths in that scenario. The Pessimistic scenario would certainly result in significant excess deaths from breaching capacity. Our sensitivity analysis indicated a range between 49,219 (19.4% increase) and 103,845 (40.9% increase) excess deaths. Without the new variant, exceeding capacity for hospital and ICU beds did not appear to be the most likely outcome but given the new variant it now appears more plausible and, if so, would result in a substantial increase in the number of deaths from COVID-19.
