@article{Wills2022,
abstract = {Background Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. Methods We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5{\%} (501/2861) died in the intensified anticoagulation group and 18.8{\%} (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95{\%}CI, 0.79 – 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95{\%} CI, 0.49 - 1.44; I2 = 75{\%}) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95{\%}CI 0.41 – 0.69; I2 = 0{\%}). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95{\%} CI 1.17 – 2.56) with no interaction for dosing and clinical setting. Conclusion Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs. Summary In this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Clinical Protocols {\textless}https://www.crd.york.ac.uk/prospero/display{\_}record.php?ID=CRD42021273449{\textgreater} {\#}{\#}{\#} Funding Statement This work was supported by the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). Sean Wasserman was supported by the National Institutes of Health (K43TW011421). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a meta-analysis of data from randomised controlled trials with publicly available results (all available online with URLs as listed in reference lists) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This is a meta-analysis of data from randomised controlled trials with publicly available results (all available online with URLs as listed in reference lists)},
author = {Wills, Nicola K and Nair, Nikhil and Patel, Kashyap and Sikder, Omaike and Adriaanse, Marguerite and Eikelboom, John and Wasserman, Sean},
doi = {10.1101/2022.03.05.22271947},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wills et al. - 2022 - Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19.pdf:pdf},
journal = {medRxiv},
keywords = {Intensified anticoagulation,OA,bleeding,covid-19,fund{\_}ack,mortality,review,thrombosis},
mendeley-tags = {OA,fund{\_}ack,review},
month = {mar},
pages = {2022.03.05.22271947},
pmid = {35291298},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis}},
url = {https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1 https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1.abstract},
year = {2022}
}

{"_id":"i8qgmmWTJMmFpSPDW","bibbaseid":"wills-nair-patel-sikder-adriaanse-eikelboom-wasserman-efficacyandsafetyofintensifiedversusstandardprophylacticanticoagulationtherapyinpatientswithcovid19asystematicreviewandmetaanalysis-2022","author_short":["Wills, N. K","Nair, N.","Patel, K.","Sikder, O.","Adriaanse, M.","Eikelboom, J.","Wasserman, S."],"bibdata":{"bibtype":"article","type":"article","abstract":"Background Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. Methods We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5% (501/2861) died in the intensified anticoagulation group and 18.8% (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95%CI, 0.79 – 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95% CI, 0.49 - 1.44; I2 = 75%) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95%CI 0.41 – 0.69; I2 = 0%). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95% CI 1.17 – 2.56) with no interaction for dosing and clinical setting. Conclusion Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs. Summary In this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols \\textlesshttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021273449\\textgreater ### Funding Statement This work was supported by the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). Sean Wasserman was supported by the National Institutes of Health (K43TW011421). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a meta-analysis of data from randomised controlled trials with publicly available results (all available online with URLs as listed in reference lists) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This is a meta-analysis of data from randomised controlled trials with publicly available results (all available online with URLs as listed in reference lists)","author":[{"propositions":[],"lastnames":["Wills"],"firstnames":["Nicola","K"],"suffixes":[]},{"propositions":[],"lastnames":["Nair"],"firstnames":["Nikhil"],"suffixes":[]},{"propositions":[],"lastnames":["Patel"],"firstnames":["Kashyap"],"suffixes":[]},{"propositions":[],"lastnames":["Sikder"],"firstnames":["Omaike"],"suffixes":[]},{"propositions":[],"lastnames":["Adriaanse"],"firstnames":["Marguerite"],"suffixes":[]},{"propositions":[],"lastnames":["Eikelboom"],"firstnames":["John"],"suffixes":[]},{"propositions":[],"lastnames":["Wasserman"],"firstnames":["Sean"],"suffixes":[]}],"doi":"10.1101/2022.03.05.22271947","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wills et al. - 2022 - Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19.pdf:pdf","journal":"medRxiv","keywords":"Intensified anticoagulation,OA,bleeding,covid-19,fund_ack,mortality,review,thrombosis","mendeley-tags":"OA,fund_ack,review","month":"mar","pages":"2022.03.05.22271947","pmid":"35291298","publisher":"Cold Spring Harbor Laboratory Press","title":"Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis","url":"https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1 https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1.abstract","year":"2022","bibtex":"@article{Wills2022,\r\nabstract = {Background Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. Methods We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5{\\%} (501/2861) died in the intensified anticoagulation group and 18.8{\\%} (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95{\\%}CI, 0.79 – 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95{\\%} CI, 0.49 - 1.44; I2 = 75{\\%}) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95{\\%}CI 0.41 – 0.69; I2 = 0{\\%}). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95{\\%} CI 1.17 – 2.56) with no interaction for dosing and clinical setting. Conclusion Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs. Summary In this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding. {\\#}{\\#}{\\#} Competing Interest Statement The authors have declared no competing interest. {\\#}{\\#}{\\#} Clinical Protocols {\\textless}https://www.crd.york.ac.uk/prospero/display{\\_}record.php?ID=CRD42021273449{\\textgreater} {\\#}{\\#}{\\#} Funding Statement This work was supported by the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). Sean Wasserman was supported by the National Institutes of Health (K43TW011421). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. {\\#}{\\#}{\\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a meta-analysis of data from randomised controlled trials with publicly available results (all available online with URLs as listed in reference lists) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This is a meta-analysis of data from randomised controlled trials with publicly available results (all available online with URLs as listed in reference lists)},\r\nauthor = {Wills, Nicola K and Nair, Nikhil and Patel, Kashyap and Sikder, Omaike and Adriaanse, Marguerite and Eikelboom, John and Wasserman, Sean},\r\ndoi = {10.1101/2022.03.05.22271947},\r\nfile = {:C$\\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wills et al. - 2022 - Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19.pdf:pdf},\r\njournal = {medRxiv},\r\nkeywords = {Intensified anticoagulation,OA,bleeding,covid-19,fund{\\_}ack,mortality,review,thrombosis},\r\nmendeley-tags = {OA,fund{\\_}ack,review},\r\nmonth = {mar},\r\npages = {2022.03.05.22271947},\r\npmid = {35291298},\r\npublisher = {Cold Spring Harbor Laboratory Press},\r\ntitle = {{Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis}},\r\nurl = {https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1 https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1.abstract},\r\nyear = {2022}\r\n}\r\n","author_short":["Wills, N. 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