Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19,The New England Journal of Medicine

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Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19
The New England Journal of Medicine ( IF 158.5 ) Pub Date : 2021-08-04 , DOI: 10.1056/nejmoa2103417
, , , Ewan C Goligher ₁ , Charlotte A Bradbury ₁ , Bryan J McVerry ₁ , Patrick R Lawler ₁ , Jeffrey S Berger ₁ , Michelle N Gong ₁ , Marc Carrier ₁ , Harmony R Reynolds ₁ , Anand Kumar ₁ , Alexis F Turgeon ₁ , Lucy Z Kornblith ₁ , Susan R Kahn ₁ , John C Marshall ₁ , Keri S Kim ₁ , Brett L Houston ₁ , Lennie P G Derde ₁ , Mary Cushman ₁ , Tobias Tritschler ₁ , Derek C Angus ₁ , Lucas C Godoy ₁ , Zoe McQuilten ₁ , Bridget-Anne Kirwan ₁ , Michael E Farkouh ₁ , Maria M Brooks ₁ , Roger J Lewis ₁ , Lindsay R Berry ₁ , Elizabeth Lorenzi ₁ , Anthony C Gordon ₁ , Tania Ahuja ₁ , Farah Al-Beidh ₁ , Djillali Annane ₁ , Yaseen M Arabi ₁ , Diptesh Aryal ₁ , Lisa Baumann Kreuziger ₁ , Abi Beane ₁ , Zahra Bhimani ₁ , Shailesh Bihari ₁ , Henny H Billett ₁ , Lindsay Bond ₁ , Marc Bonten ₁ , Frank Brunkhorst ₁ , Meredith Buxton ₁ , Adrian Buzgau ₁ , Lana A Castellucci ₁ , Sweta Chekuri ₁ , Jen-Ting Chen ₁ , Allen C Cheng ₁ , Tamta Chkhikvadze ₁ , Benjamin Coiffard ₁ , Aira Contreras ₁ , Todd W Costantini ₁ , Sophie de Brouwer ₁ , Michelle A Detry ₁ , Abhijit Duggal ₁ , Vladimír Džavík ₁ , Mark B Effron ₁ , Heather F Eng ₁ , Jorge Escobedo ₁ , Lise J Estcourt ₁ , Brendan M Everett ₁ , Dean A Fergusson ₁ , Mark Fitzgerald ₁ , Robert A Fowler ₁ , Joshua D Froess ₁ , Zhuxuan Fu ₁ , Jean P Galanaud ₁ , Benjamin T Galen ₁ , Sheetal Gandotra ₁ , Timothy D Girard ₁ , Andrew L Goodman ₁ , Herman Goossens ₁ , Cameron Green ₁ , Yonatan Y Greenstein ₁ , Peter L Gross ₁ , Rashan Haniffa ₁ , Sheila M Hegde ₁ , Carolyn M Hendrickson ₁ , Alisa M Higgins ₁ , Alexander A Hindenburg ₁ , Aluko A Hope ₁ , James M Horowitz ₁ , Christopher M Horvat ₁ , David T Huang ₁ , Kristin Hudock ₁ , Beverley J Hunt ₁ , Mansoor Husain ₁ , Robert C Hyzy ₁ , Jeffrey R Jacobson ₁ , Devachandran Jayakumar ₁ , Norma M Keller ₁ , Akram Khan ₁ , Yuri Kim ₁ , Andrei Kindzelski ₁ , Andrew J King ₁ , M Margaret Knudson ₁ , Aaron E Kornblith ₁ , Matthew E Kutcher ₁ , Michael A Laffan ₁ , Francois Lamontagne ₁ , Grégoire Le Gal ₁ , Christine M Leeper ₁ , Eric S Leifer ₁ , George Lim ₁ , Felipe Gallego Lima ₁ , Kelsey Linstrum ₁ , Edward Litton ₁ , Jose Lopez-Sendon ₁ , Sylvain A Lother ₁ , Nicole Marten ₁ , Andréa Saud Marinez ₁ , Mary Martinez ₁ , Eduardo Mateos Garcia ₁ , Stavroula Mavromichalis ₁ , Daniel F McAuley ₁ , Emily G McDonald ₁ , Anna McGlothlin ₁ , Shay P McGuinness ₁ , Saskia Middeldorp ₁ , Stephanie K Montgomery ₁ , Paul R Mouncey ₁ , Srinivas Murthy ₁ , Girish B Nair ₁ , Rahul Nair ₁ , Alistair D Nichol ₁ , Jose C Nicolau ₁ , Brenda Nunez-Garcia ₁ , John J Park ₁ , Pauline K Park ₁ , Rachael L Parke ₁ , Jane C Parker ₁ , Sam Parnia ₁ , Jonathan D Paul ₁ , Mauricio Pompilio ₁ , John G Quigley ₁ , Robert S Rosenson ₁ , Natalia S Rost ₁ , Kathryn Rowan ₁ , Fernanda O Santos ₁ , Marlene Santos ₁ , Mayler O Santos ₁ , Lewis Satterwhite ₁ , Christina T Saunders ₁ , Jake Schreiber ₁ , Roger E G Schutgens ₁ , Christopher W Seymour ₁ , Deborah M Siegal ₁ , Delcio G Silva ₁ , Aneesh B Singhal ₁ , Arthur S Slutsky ₁ , Dayna Solvason ₁ , Simon J Stanworth ₁ , Anne M Turner ₁ , Wilma van Bentum-Puijk ₁ , Frank L van de Veerdonk ₁ , Sean van Diepen ₁ , Gloria Vazquez-Grande ₁ , Lana Wahid ₁ , Vanessa Wareham ₁ , R Jay Widmer ₁ , Jennifer G Wilson ₁ , Eugene Yuriditsky ₁ , Yongqi Zhong ₁ , Scott M Berry ₁ , Colin J McArthur ₁ , Matthew D Neal ₁ , Judith S Hochman ₁ , Steven A Webb ₁ , Ryan Zarychanski ₁

Affiliation

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.).

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.)

中文翻译：

Covid-19危重患者的肝素抗凝治疗

背景

血栓形成和炎症可能会导致 2019 年冠状病毒病 (Covid-19) 患者的发病率和死亡率。我们假设治疗剂量的抗凝治疗将改善 Covid-19 危重患者的预后。

方法

在一项开放标签、适应性、多平台、随机临床试验中，患有严重 Covid-19 的危重患者被随机分配到根据当地常规护理而制定的实用治疗方案，即治疗剂量的肝素抗凝或药物血栓预防。主要结局是无器官支持天数，按照顺序量表进行评估，结合了院内死亡（指定值为-1）以及存活至第21天的患者中无心血管或呼吸器官支持的天数。出院。

结果

当达到治疗剂量抗凝治疗无效的预定标准时，试验停止。可获得 1098 名患者的主要结局数据（其中 534 名患者接受治疗剂量抗凝治疗，564 名患者接受常规血栓预防治疗）。在分配至治疗剂量抗凝治疗的患者中，无器官支持天数的中值为 1（四分位距，-1 至 16）；在分配至常规治疗血栓预防的患者中，无器官支持天数的中值为 4（四分位距，-1 至 16）（调整后的比例优势比，0.83；95% 可信区间，0.67 至 1.03；无效的后验概率[定义为优势比 <1.2]，99.9%）。两组存活出院的患者百分比相似（分别为 62.7% 和 64.5%；调整后比值比，0.84；95% 可信区间，0.64 至 1.11）。接受治疗剂量抗凝治疗的患者中有 3.8% 发生大出血，接受常规药物血栓预防治疗的患者中有 2.3% 发生大出血。

结论

在 Covid-19 危重患者中，与常规治疗药物相比，治疗剂量肝素抗凝的初始策略并未导致出院存活率更高或无需心血管或呼吸器官支持的天数更高血栓预防。（REMAP-CAP、ACTIV-4a 和 ATTACC ClinicalTrials.gov 编号：NCT02735707、NCT04505774、NCT04359277 和 NCT04372589。）

更新日期：2021-08-05

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