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

当前位置： X-MOL 学术 › N. Engl. J. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19
The New England Journal of Medicine ( IF 96.2 ) Pub Date : 2021-08-04 , DOI: 10.1056/nejmoa2105911
, , , Patrick R Lawler ₁ , Ewan C Goligher ₁ , Jeffrey S Berger ₁ , Matthew D Neal ₁ , Bryan J McVerry ₁ , Jose C Nicolau ₁ , Michelle N Gong ₁ , Marc Carrier ₁ , Robert S Rosenson ₁ , Harmony R Reynolds ₁ , Alexis F Turgeon ₁ , Jorge Escobedo ₁ , David T Huang ₁ , Charlotte A Bradbury ₁ , Brett L Houston ₁ , Lucy Z Kornblith ₁ , Anand Kumar ₁ , Susan R Kahn ₁ , Mary Cushman ₁ , Zoe McQuilten ₁ , Arthur S Slutsky ₁ , Keri S Kim ₁ , Anthony C Gordon ₁ , Bridget-Anne Kirwan ₁ , Maria M Brooks ₁ , Alisa M Higgins ₁ , Roger J Lewis ₁ , Elizabeth Lorenzi ₁ , Scott M Berry ₁ , Lindsay R Berry ₁ , Aaron W Aday 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 , Todd W Costantini ₁ , Sophie de Brouwer ₁ , Lennie P G Derde ₁ , Michelle A Detry ₁ , Abhijit Duggal ₁ , Vladimír Džavík ₁ , Mark B Effron ₁ , Lise J Estcourt ₁ , Brendan M Everett ₁ , Dean A Fergusson ₁ , Mark Fitzgerald ₁ , Robert A Fowler ₁ , Jean P Galanaud ₁ , Benjamin T Galen ₁ , Sheetal Gandotra ₁ , Sebastian García-Madrona ₁ , Timothy D Girard ₁ , Lucas C Godoy ₁ , Andrew L Goodman ₁ , Herman Goossens ₁ , Cameron Green ₁ , Yonatan Y Greenstein ₁ , Peter L Gross ₁ , Naomi M Hamburg ₁ , Rashan Haniffa ₁ , George Hanna ₁ , Nicholas Hanna ₁ , Sheila M Hegde ₁ , Carolyn M Hendrickson ₁ , R Duncan Hite ₁ , Alexander A Hindenburg ₁ , Aluko A Hope ₁ , James M Horowitz ₁ , Christopher M Horvat ₁ , Kristin Hudock ₁ , Beverley J Hunt ₁ , Mansoor Husain ₁ , Robert C Hyzy ₁ , Vivek N Iyer ₁ , Jeffrey R Jacobson ₁ , Devachandran Jayakumar ₁ , Norma M Keller ₁ , Akram Khan ₁ , Yuri Kim ₁ , Andrei L Kindzelski ₁ , Andrew J King ₁ , M Margaret Knudson ₁ , Aaron E Kornblith ₁ , Vidya Krishnan 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 , Jose L Lopez-Sendon Moreno ₁ , Sylvain A Lother ₁ , Saurabh Malhotra ₁ , Miguel Marcos ₁ , Andréa Saud Marinez ₁ , John C Marshall ₁ , Nicole Marten ₁ , Michael A Matthay ₁ , Daniel F McAuley ₁ , Emily G McDonald ₁ , Anna McGlothlin ₁ , Shay P McGuinness ₁ , Saskia Middeldorp ₁ , Stephanie K Montgomery ₁ , Steven C Moore ₁ , Raquel Morillo Guerrero ₁ , Paul R Mouncey ₁ , Srinivas Murthy ₁ , Girish B Nair ₁ , Rahul Nair ₁ , Alistair D Nichol ₁ , Brenda Nunez-Garcia ₁ , Ambarish Pandey ₁ , Pauline K Park ₁ , Rachael L Parke ₁ , Jane C Parker ₁ , Sam Parnia ₁ , Jonathan D Paul ₁ , Yessica S Pérez González ₁ , Mauricio Pompilio ₁ , Matthew E Prekker ₁ , John G Quigley ₁ , Natalia S Rost ₁ , Kathryn Rowan ₁ , Fernanda O Santos ₁ , Marlene Santos ₁ , Mayler Olombrada Santos ₁ , Lewis Satterwhite ₁ , Christina T Saunders ₁ , Roger E G Schutgens ₁ , Christopher W Seymour ₁ , Deborah M Siegal ₁ , Delcio G Silva ₁ , Manu Shankar-Hari ₁ , John P Sheehan ₁ , Aneesh B Singhal ₁ , Dayna Solvason ₁ , Simon J Stanworth ₁ , Tobias Tritschler 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 , Bryan J Wells ₁ , R Jay Widmer ₁ , Jennifer G Wilson ₁ , Eugene Yuriditsky ₁ , Fernando G Zampieri ₁ , Derek C Angus ₁ , Colin J McArthur ₁ , Steven A Webb ₁ , Michael E Farkouh ₁ , Judith S Hochman ₁ , Ryan Zarychanski ₁

Affiliation

From the Peter Munk Cardiac Centre at University Health Network (P.R.L., M.E.F., V.D., J.P.G., L.C.G., G.H.), the University of Toronto (P.R.L., E.C.G., A.S.S., M.E.F., V.D., R.A.F., L.C.G., G.H., M.H.), University Health Network (E.C.G., M.H.), St. Michael's Hospital Unity Health (A.S.S., Z.B., J.C.M., M.S.), Ozmosis Research (L.B., L.P.G.D., V.W.), and 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 (Marc Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, Université Laval (A.F.T.) and CHU de Québec-Université Laval Research Center (A.F.T.), Quebec, QC, the University of Manitoba (B.L.H., A. Kumar, R.Z., S.A.L., D.S., G.V.-G.), CancerCare Manitoba (B.L.H., R.Z.), and St. Boniface Hospital (N.M.), Winnipeg, MB, McGill University, Montreal (S.R.K., E.G.M.), McMaster University (P.L.G.) and the Thrombosis and Atherosclerosis Research Institute (P.L.G.), Hamilton, ON, Université de Sherbrooke, Sherbrooke, QC (F.L.), the University of British Columbia, Vancouver (S. Murthy, K.R.), and the University of Alberta, Edmonton (S.D.) - all in Canada; NYU Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., N.M.K., S.P.), the Icahn School of Medicine at Mount Sinai and Mount Sinai Heart (R.S.R.), NYU Langone Health, NYU Langone Hospital (T.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.T.C., R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A. Hope), Bronx, and NYU Langone Long Island, Mineola (R.D.H., A. Hindenburg) - all in New York; the University of Pittsburgh (M.D.N., B.J.M., D.T.H., M.M.B., D.C.A., A.J.K., C.M.L., K.L., S.K.M., C.W.S.), UPMC (M.D.N., B.J.M., D.C.A., K.L., S.K.M.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and UPMC Children's Hospital of Pittsburgh (C. Horvat), Pittsburgh, and Emergency Medicine, Penn State Hershey Medical Center, Hershey (S.C.M.) - all in Pennsylvania; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (J.C.N., L.C.G., F.G.L.), Avanti Pesquisa Clínica (A.S.M.), Hospital de Julho (F.O.S.), and Hospital do Coracao (F.G.Z.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul and the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.J.), and Hospital Unimed Campo Grande (D.G.S.J.), Campo Grande, and INGOH, Clinical Research Center, Goiânia (M.O.S.) - all in Brazil; Instituto Mexicano del Seguro Social, Mexico City (J.E., Y.S.P.G.); the University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust (C.A.B.), Bristol, Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), the London School of Hygiene and Tropical Medicine (B.-A.K.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), the Intensive Care National Audit and Research Centre (P.R.M.), Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), and King's College London (M.S.-H.), London, Oxford University (A. Beane, S.J.S.) and NHS Blood and Transplant (L.J.E., S.J.S.), Oxford, and Queen's University Belfast and Royal Victoria Hospital, Belfast (D.F.M.) - all in the United Kingdom; Zuckerberg San Francisco General Hospital, University of California, San Francisco (L.Z.K., C. Hendrickson, M.M.K., A.E.K., M.A.M., B.N.-G.), Harbor-UCLA Medical Center, Torrance (R.J.L., S. Brouwer), 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; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., A.M.H., C.J.M., S.A.W., A. Buzgau, C.G., S.P.M., A.D.N., J.C.P., A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital (S.A.W., E. Litton) and Fiona Stanley Hospital (E. Litton), Perth, WA, and Flinders University, Bedford Park, SA (S. Bihari) - all in Australia; the University of Illinois (K.S.K., J.R.J., J.G.Q.), Cook County Health and Rush Medical College (S. Malhotra), and the University of Chicago (J.D.P.) - all in Chicago; SOCAR Research SA, Nyon (B.-A.K.), and Inselspital, Bern University Hospital, University of Bern (T.T.), Bern - all in Switzerland; Berry Consultants, Austin (R.J.L., E. Lorenzi, S.M.B., L.R.B., M.A.D., M.F., A.M., C.T.S.), University of Texas Southwestern Medical Center, Dallas (A.P.), and Baylor Scott and White Health, Temple (R.J.W.) - all 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; Vanderbilt University Medical Center (A.W.A.) and TriStar Centennial Medical Center (A.L.G.) - both in Nashville; Fédération Hospitalo Universitaire, 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, Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur, and Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal) - both in Nepal; Versiti Blood Research Institute, Milwaukee (L.B.K., L.J.E.), and the University of Wisconsin School of Medicine and Public Health, Madison (J.P.S.); National Intensive Care Surveillance-Mahidol Oxford Tropical Medicine Research Unit, Colombo, Sri Lanka (A. Beane); the University Medical Center Utrecht, Utrecht University, Utrecht (M. Bonten, R.E.G.S., W.B.-P.), and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) - both in the Netherlands; Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic (A.D.) and Case Western Reserve University, the Metro Health Medical Centre (V.K.) - both in Cleveland; Ochsner Medical Center, University of Queensland-Ochsner Clinical School, New Orleans (M.B.E.); Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S), Brigham and Women's Hospital (B.M.E., Y.K., S.M.H.), Boston University School of Medicine and Boston Medical Center (N.M.H.), and Massachusetts General Hospital (A.B.S., N.S.R.) - all in Boston; University of Alabama, Birmingham (S.G.); Hospital Ramón y Cajal (S.G.-M., J.L.L.-S.M., R.M.G.) and IdiPaz Research Institute, Universidad Autonoma (J.L.-S.), Madrid, and University Hospital of Salamanca-University of Salamanca-IBSAL, Salamanca (M.M.) - all in Spain; University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); Ascension St. John Heart and Vascular Center, Tulsa (N.H.), and the University of Oklahoma College of Medicine, Oklahoma City (N.H.); the University of Cincinnati, Cincinnati (K.H.); University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak, and the OUWB School of Medicine, Auburn Hills (G.B.N.) - all in Michigan; Mayo Clinic, Rochester (V.N.I.), and the Hennepin County Medical Center, Minneapolis (M.E.P.) - both in Minnesota; Apollo Speciality Hospital-OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan, E.S.L.); the National Heart, Lung, and Blood Institute, Bethesda, MD (A.L.K.); University of Mississippi Medical Center, Jackson (M.E.K.); University College Dublin, Dublin (A.D.N.); University of Kansas School of Medicine, Kansas City (L.S.); Duke University Hospital, Durham, NC (L.W.); and Emory University, Atlanta (B.J.W.).

Background

Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

Methods

In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. 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. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.

Results

The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.

Conclusions

In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT02735707, and NCT04359277.)

中文翻译：

Covid-19 非危重患者的肝素抗凝治疗

背景

血栓形成和炎症可能会增加 2019 年冠状病毒病 (Covid-19) 患者的死亡和并发症风险。我们假设治疗剂量的抗凝治疗可能会改善因 Covid-19 住院的非重症患者的预后。

方法

在这项开放标签、适应性、多平台对照试验中，我们随机分配因 Covid-19 住院且病情不危重（定义为入组时缺乏重症监护级器官支持）的患者接受务实的治疗明确的治疗剂量肝素抗凝或常规药物血栓预防方案。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。使用贝叶斯统计模型并根据基线d-二聚体水平对所有患者的结果进行评估。

结果

当达到治疗剂量抗凝优越性的预先设定标准时，试验停止。在最终分析的 2219 名患者中，与常规护理血栓预防相比，治疗剂量抗凝增加无器官支持天数的概率为 98.6%（调整后优势比，1.27；95% 可信区间，1.03 至 1.58）。出院前没有支持治疗剂量抗凝的器官支持的调整后的组间生存绝对差异为 4.0 个百分点（95% 可信区间，0.5 至 7.2）。在高d-二聚体队列中，治疗剂量抗凝优于常规护理血栓预防的最终概率为 97.3% ，在低d-二聚体队列中为 92.9% ，在未知d-二聚体队列中为 97.3%。接受治疗剂量抗凝治疗的患者和接受血栓预防治疗的患者中，有 1.9% 和 0.9% 的患者发生大出血。

结论

在患有 Covid-19 的非重症患者中，与常规治疗血栓预防相比，治疗剂量肝素抗凝的初始策略可增加出院生存的可能性，同时减少心血管或呼吸器官支持的使用。（ATTACC、ACTIV-4a 和 REMAP-CAP ClinicalTrials.gov 编号：NCT04372589、NCT04505774、NCT02735707 和 NCT04359277。）

更新日期：2021-08-05

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文