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      Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

      research-article
      The REMAP-CAP Investigators, The ACTIV-4a Investigators, The ATTACC Investigators *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 12Keyword part (keyword): Pulmonary/Critical CareKeyword part (code): 12_5Keyword part (keyword): Anticoagulation/ThromboembolismKeyword part (code): 12_6Keyword part (keyword): Critical Care , 12, Pulmonary/Critical Care, Keyword part (code): 12_5Keyword part (keyword): Anticoagulation/ThromboembolismKeyword part (code): 12_6Keyword part (keyword): Critical Care , 12_5, Anticoagulation/Thromboembolism, 12_6, Critical Care, Keyword part (code): 14Keyword part (keyword): CardiologyKeyword part (code): 14_5Keyword part (keyword): Anticoagulation/Thromboembolism , 14, Cardiology, Keyword part (code): 14_5Keyword part (keyword): Anticoagulation/Thromboembolism, 14_5, Anticoagulation/Thromboembolism, Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_12Keyword part (keyword): Coronavirus , 18, Infectious Disease, Keyword part (code): 18_12Keyword part (keyword): Coronavirus, 18_12, Coronavirus
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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.)

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          Most cited references25

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

            Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)
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              High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

              Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                04 August 2021
                : NEJMoa2103417
                Affiliations
                From the University of Toronto (E.C.G., P.R.L., L.C.G., M.E.F., V.D., R.A.F., J.P.G., M.H., A.S.S.), University Health Network (E.C.G., M.H.), Peter Munk Cardiac Centre at University Health Network (P.R.L., L.C.G., M.E.F., V.D.), Ozmosis Research (L.B., V.W.), Sunnybrook Health Sciences Centre (J.P.G.), Toronto, Ottawa Hospital Research Institute (M. Carrier, L.A.C., D.A.F., G.L.G., D.M.S.), Institut du Savoir Montfort (M. Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, the University of Manitoba (A. Kumar, B.L.H., R.Z., S.A.L., D.S., G.V.-G.) and CancerCare Manitoba (B.L.H., R.Z.), Winnipeg, Université Laval and Centre Hospitalier Universitaire de Québec–Université Laval Research Center, Quebec, QC (A.F.T.), McGill University, Montreal (S.R.K., E.G.M.), St. Michael’s Hospital Unity Health, Toronto (J.C.M., Z.B., M.S., A.S.S.), McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON (P.L.G.) Université de Sherbrooke, Sherbrooke, QC (F.L.), St. Boniface Hospital, Winnipeg, MB (N.M.), the University of British Columbia, Vancouver (S. Murthy), and the University of Alberta, Edmonton (S.D.) — all in Canada; University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (C.A.B.), the London School of Hygiene and Tropical Medicine (B.-A.K.), Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary’s Hospital (A.C.G.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), and Intensive Care National Audit and Research Centre (ICNARC) (P.R.M., K.R.), London, Queen’s University Belfast and Royal Victoria Hospital, Belfast (D.F.M.), and Oxford University (A. Beane, L.J.E., S.J.S.) and NHS Blood and Transplant (L.J.E., S. Mavromichalis, S.J.S.), Oxford — all in the United Kingdom; the University of Pittsburgh (B.J.M., D.C.A., M.M.B., M.D.N., H.F.E., J.D.F., Z.F., D.T.H., A.J.K., C.M.L., K.L., M.M., S.K.M., C.W.S., Y.Z.), University of Pittsburgh Medical Center (B.J.M., D.C.A., M.D.N., K.L.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh (C.M. Horvat) — all in Pittsburgh; New York University (NYU) Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., A.C., N.M.K., S. Mavromichalis, S.P.), NYU Langone Health, NYU Langone Hospital (T.A., T.C., A.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), Icahn School of Medicine at Mount Sinai (R.S.R.), and Mount Sinai Heart (R.S.R.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.-T.C., A.A. Hope, R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A.A. Hope), Bronx, and NYU Langone Long Island, Mineola (A.A. Hindenburg) — all in New York; Zuckerberg San Francisco General Hospital–University of California, San Francisco (L.Z.K., C.M. Hendrickson, M.M.K., A.E.K., B.N.-G., J.J.P.), Harbor–UCLA Medical Center, Torrance (R.J.L.), Global Coalition for Adaptive Research (M. Buxton) and the University of California, Los Angeles (G.L.), Los Angeles, the University of California San Diego School of Medicine, San Diego (T.W.C.), and Stanford University School of Medicine, Palo Alto (J.G.W.) — all in California; the University of Illinois (K.S.K., J.R.J., J.G.Q.), the University of Chicago (J.D.P.), and the Chartis Group (J.S.) — all in Chicago; University Medical Center Utrecht, Utrecht University (L.P.G.D., M. Bonten, R.E.G.S., W.B.-P.), and Utrecht University (R.E.G.S.), Utrecht, and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) — all in the Netherlands; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Inselspital, Bern University Hospital, University of Bern, Bern (T.T.), and SOCAR Research, Nyon (B.-A.K., S. Brouwer) — both in Switzerland; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (L.C.G., F.G.L., J.C.N.), Avanti Pesquisa Clínica (A.S.M.), and Hospital 9 de Julho (F.O.S.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul (M.P.), the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.), and Hospital Unimed Campo Grande (D.G.S.), Campo Grande, and Instituto Goiano de Oncologia e Hematologia, Clinical Research Center, Goiânia (M.O.S.) — all in Brazil; the Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., C.J.M., S.A.W., A. Buzgau, C.G., A.M.H., S.P.M., A.D.N., J.C.P.), Monash University (A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital, Subiaco, WA (S.A.W., E. Litton), Flinders University, Bedford Park, SA (S. Bihari), and Fiona Stanley Hospital, Perth, WA (E. Litton) — all in Australia; Berry Consultants, Austin (R.J.L., L.R.B., E. Lorenzi, S.M.B., M.A.D., M.F., A.M., C.T.S.), and Baylor Scott and White Health, Temple (R.J.W.) — both in Texas; Auckland City Hospital (C.J.M., S.P.M., R.L.P.) and the University of Auckland (R.L.P.), Auckland, and the Medical Research Institute of New Zealand, Wellington (C.J.M., A.M.T.) — all in New Zealand; Fédération Hospitalo-Universitaire Saclay and Paris Seine Nord Endeavour to Personalize Interventions for Sepsis (FHU-SEPSIS), Raymond Poincaré Hospital, Université de Versailles Saint-Quentin-en-Yvelines, Garches (D. Annane), and Aix-Marseille University, Marseille (B.C.) — both in France; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur (D. Aryal), and the Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal); Versiti Blood Research Institute, Milwaukee (L.B.K.); National Intensive Care Surveillance (NICS)–Mahidol Oxford Tropical Medicine Research Unit (MORU), Colombo, Sri Lanka (A. Beane); Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic, Cleveland (A.D.), and the University of Cincinnati, Cincinnati (K.H.) — both in Ohio; Ochsner Medical Center, University of Queensland–Ochsner Clinical School, New Orleans (M.B.E.); Instituto Mexicano del Seguro Social, Mexico City (J.E., E.M.G.); Brigham and Women’s Hospital (B.M.E., Y.K., S.M.H.), Massachusetts General Hospital (N.S.R., A.B.S.), and Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S.) — all in Boston; University of Alabama, Birmingham (S.G.); TriStar Centennial Medical Center, Nashville (A.L.G.); University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark, New Jersey (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); the University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak (G.B.N.), and Oakland University William Beaumont School of Medicine, Auburn Hills (G.B.N.) — all in Michigan; Apollo Speciality Hospital OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan); National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A. Kindzelski, E.S.L.); University of Mississippi Medical Center, Jackson (M.E.K.); IdiPaz Research Institute, Universidad Autonoma, Madrid (J.L.-S.); University College Dublin, Dublin (A.D.N.); the University of Kansas School of Medicine, Kansas City (L.S.); and Duke University Hospital, Durham, North Carolina (L.W.).
                Author notes
                Address reprint requests to Dr. Zarychanski at the Sections of Hematology/Oncology and Critical Care, University of Manitoba, Winnipeg, MB, Canada R3E 0V9, or at rzarychanski@ 123456cancercare.mb.ca .
                [*]

                The full list of investigators and collaborators is provided in the Supplementary Appendix, available at NEJM.org.

                Drs. Goligher, Bradbury, McVerry, Lawler, Berger, and Gong and Drs. Berry, McArthur, Neal, Hochman, Webb, and Zarychanski contributed equally to this article.

                Article
                NJ202108043850904
                10.1056/NEJMoa2103417
                8362592
                34351722
                7495c87c-d81d-405f-ab39-426d797329d7
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: Multiple funders (see Supplentary appendix page 27), FundRef ;
                Categories
                Original Article
                Custom metadata
                2021-08-04T17:00:00-04:00
                2021
                08
                04
                17
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