Background Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. Methods In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. Results The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. Conclusions In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707 , NCT04505774 , NCT04359277 , and NCT04372589 .)
The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.).
IMPORTANCE Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. OBJECTIVE To determine whether hydrocortisone improves outcome for patients with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. INTERVENTIONS The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned-1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). RESULTS After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR,-1 to 15), 0 (IQR,-1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. CONCLUSIONS AND RELEV...
Analysis 5.1. Comparison 5: Subgroup analysis: antibodies in recipients detected at baseline for the comparison of convalescent plasma versus placebo or standard care alone for individuals with moderate to severe disease, Outcome 1: All-cause mortality at up to day 28..
SummaryPlatelet refractoriness can represent a significant clinical problem that complicates the provision of platelet transfusions, is associated with adverse clinical outcomes and increases health care costs. Although it is most frequently due to non-immune platelet consumption, immunological factors are also often involved. Human leucocyte antigen (HLA) alloimmunization is the most important immune cause. Despite the fact that systematic reviews of the clinical studies evaluating different techniques for selecting HLA compatible platelets have not been powered to demonstrate improved clinical outcomes, platelet refractoriness is currently managed by the provision of HLA-matched or cross matched platelets. This review will address a practical approach to the diagnosis and management of platelet refractoriness while highlighting on-going dilemmas and knowledge gaps.
BackgroundOverviews of systematic reviews are a relatively new approach to synthesising evidence, and research methods and associated guidance are developing. Within this paper we aim to help readers understand key issues which are essential to consider when taking the first steps in planning an overview. These issues relate to the development of clear, relevant research questions and objectives prior to the development of an overview protocol.MethodsInitial discussions and key concepts for this paper were formed during a workshop on overview methods at the 2016 UK Cochrane Symposium, at which all members of this author group presented work and contributed to wider discussions. Detailed descriptions of the various key features of overviews and their different objectives were created by the author group based upon current evidence (Higgins J, Green S. Cochrane Handbook Syst Rev Interv. 2011;4:5, Pollock M, et al. Sys Rev. 2016;5:190-205, Pollock A, et al. Cochrane overviews of reviews: exploring the methods and challenges. UK and Ireland: Cochrane Symposium; 2016, Pieper D, et al. Res Syn Meth. 2014;5:187–99, Lunny C, et al. Sys Rev. 2016;5:4-12, Hartling L, et al. Comparing multiple treatments: an introduction to overviews of reviews. In 23rd Cochrane Colloquium; 2015, Hartling L, et al. Plos One. 2012;7:1-8, Ballard M, Montgomery P. Res Syn Meth. 2017;8:92-108) and author experiences conducting overviews.ResultsWithin this paper we introduce different types of overviews and suggest common research questions addressed by these overviews. We briefly reflect on the key features and objectives of the example overviews discussed.ConclusionsClear decisions relating to the research questions and objectives are a fundamental first step during the initial planning stages for an overview. Key stakeholders should be involved at the earliest opportunity to ensure that the planned overview is relevant and meaningful to the potential end users of the overview. Following best practice in common with other forms of systematic evidence synthesis, an overview protocol should be published, ensuring transparency and reducing opportunities for introduction of bias in the conduct of the overview.
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