//Background//---
The
common symptom in critically ill patients with SARS-CoV-2 is decreasing of
oxygen level in the pulmonary artery system. Therefore, we need to monitor this
oxygen level by pulse oximeter. One of causes is thrombosis in this artery
system. The patients with severe symptom has high risk for thrombosis despite
receiving standard-dose pharmacologic thromboprophylaxis including enoxaparin(2-5).
According to some COVID-19 guidance statements,
enhanced-dose anticoagulation strategies are recommended(6,7). However, the
effectiveness and safety of this therapy remains elusive.
The
international collaboration teams by The REMAP-CAP, ACTIV-4a, and ATTACC
Investigators conducted an international, adaptive, multiplatform, randomized,
controlled trial to evaluate of efficacy of therapeutic dose anticoagulation or
low-molecular-weight heparin including the duration of ICU, level
cardiovascular or respiratory organ support(1).
//Criteria of severe symptom(1)//---
*Receipt of ICU-level respiratory
cardiovascular organ support (oxygen through a high-flow nasal cannula,
noninvasive or invasive mechanical ventilation, extracorporeal life support,
vasopressors, or inotropes) in an ICU.
//Administration(1)//---
*1: Therapeutic-dose anticoagulation(Heparin)
Local site protocols for the treatment of
acute venous thromboembolism for up to 14 days or until recovery (defined as
either hospital discharge or discontinuation of supplemental oxygen for at
least 24 hours)
*2: Usual-care thromboprophylaxis
Dose and duration determined by the
treating clinician according to local practice, which included either standard
low-dose thromboprophylaxis or enhanced intermediate-dose thromboprophylaxis
In
this report, *1 and *2 condition are compared.
//Condition(Special note)(1)//---
*1: Therapeutic-dose anticoagulation/*2:
Usual-care thromboprophylaxis in this order
(Baseline organ support)
*High-flow nasal cannula 31.7%/33.2%
*Noninvasive ventilation 40.1%/35.3%
*Invasive mechanical ventilation
26.7%/30.3%
*Vesopressors or inotropes 17.5%/19.2%
-
*Median PaO2:FiO2 ratio (IQR): 118/118.5
*D-dimer level ng/ml 823/890
*Neutrophil count per mm3 7900/7800
*Lymphocyte count per mm3 700/700
*Platelet count per mm3 247,000/244,000
//Result(1)//---
*1: Therapeutic-dose anticoagulation/*2:
Usual-care thromboprophylaxis in this order
*Survival to hospital discharge:
62.7%/64.5%
*Major thrombotic events: 6.4%/10.4%
*Death in hospital: 37.3%/35.5%
*Any thrombotic event: 7.2%/11.1%
*Death in hospital: 37.3%/35.5%
*Major bleeding 3.8%/2.3%
(Evaluation)
Heparin is relatively high risk of death,
which reflects the survival to hospital discharge.
//Discussion//---
Heparin administration group is higher
bleeding event than usual-care thromboprophylaxis. In this report, it is said
that this bleeding event may be associated with the non-superior result despite
some usual guideline. Autopsy in patients with severe symptom have included
alveolar hemorrhage(8). Usually, heparin administration needs to be careful of
bleeding. As the pulmonary damage is high in severe symptom, heparin
administration may not be suitable for some of patients with severe symptom.
//Supports(1)//---
REMAP-CAP was supported by the European
Union through FP7-HEALTH-2013-INNOVATION: the Platform for European
Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium (grant
602525) and the Horizon 2020 research and innovation program: the Rapid
European Covid-19 Emergency Research response (RECOVER) consortium (grant
101003589) and by grants from the Australian National Health and Medical
Research Council (APP1101719 and APP1116530), the Health Research Council of
New Zealand (16/631), the Canadian Institutes of Health Research (Strategy for
Patient-Oriented Research Innovative Clinical Trials Program Grant 158584 and
COVID-19 Rapid Research Operating Grant 447335), the U.K. National Institute
for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre,
the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While
Doing Program, the Translational Breast Cancer Research Consortium, the French
Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Amgen, Eisai, the
Global Coalition for Adaptive Research, and the Wellcome Trust Innovations
Project (215522). The ATTACC platform was supported by grants from the Canadian
Institutes of Health Research, LifeArc, Thistledown Foundation, Research
Manitoba, CancerCare Manitoba Foundation, Victoria General Hospital Foundation,
Ontario Ministry of Health, and the Peter Munk Cardiac Centre. The ACTIV-4a
platform was supported by the National Heart, Lung, and Blood Institute of the
National Institutes of Health (NIH) and administered through OTA-20-011 and was
supported in part by NIH agreement 1OT2HL156812-01. Dr. Goligher is the
recipient of an Early Career Investigator award from the Canadian Institutes of
Health Research (grant AR7-162822). Dr. Gordon is funded by an NIHR Research
Professorship (RP-2015-06-18). Dr. Turgeon is funded by a Canada Research
Chair–Tier 2. Dr. Zarychanski is the recipient of the Lyonel G. Israels
Research Chair in Hematology (University of Manitoba).
//Special note(1)//---
The members of the executive writing
committee are as follows:
Ewan C. Goligher, M.D., Ph.D., Charlotte A.
Bradbury, M.D., Ph.D., Bryan J. McVerry, M.D., Patrick R. Lawler, M.D., M.P.H.,
Jeffrey S. Berger, M.D., Michelle N. Gong, M.D., Marc Carrier, M.D., Harmony R.
Reynolds, M.D., Anand Kumar, M.D., Alexis F. Turgeon, M.D., Lucy Z. Kornblith,
M.D., Susan R. Kahn, M.D., John C. Marshall, M.D., Keri S. Kim, Pharm.D., Brett
L. Houston, M.D., Lennie P.G. Derde, M.D., Ph.D., Mary Cushman, M.D., Tobias
Tritschler, M.D., Derek C. Angus, M.D., M.P.H., Lucas C. Godoy, M.D., Zoe
McQuilten, Ph.D., Bridget-Anne Kirwan, Ph.D., Michael E. Farkouh, M.D., Maria
M. Brooks, Ph.D., Roger J. Lewis, M.D., Ph.D., Lindsay R. Berry, Ph.D.,
Elizabeth Lorenzi, Ph.D., Anthony C. Gordon, M.B., B.S., M.D., Scott M. Berry,
Ph.D., Colin J. McArthur, M.B., Ch.B., Matthew D. Neal, M.D., Judith S.
Hochman, M.D., Steven A. Webb, M.P.H., Ph.D., and Ryan Zarychanski, M.D.
The members of the block writing committee
are as follows:
Tania Ahuja, Pharm.D., Farah Al-Beidh,
Ph.D., Djillali Annane, M.D., Ph.D., Yaseen M. Arabi, M.D., Diptesh Aryal,
M.D., Lisa Baumann Kreuziger, M.D., Abi Beane, Ph.D., Zahra Bhimani, M.P.H.,
Shailesh Bihari, Ph.D., Henny H. Billett, M.D., Lindsay Bond, H.B.Sc., Marc
Bonten, Ph.D., Frank Brunkhorst, M.D., Meredith Buxton, Ph.D., Adrian Buzgau,
B.A.S., Lana A. Castellucci, M.D., Sweta Chekuri, M.D., Jen-Ting Chen, M.D.,
Allen C. Cheng, Ph.D., Tamta Chkhikvadze, M.D., Benjamin Coiffard, M.D., Aira
Contreras, M.A., Todd W. Costantini, M.D., Sophie de Brouwer, Ph.D., Michelle
A. Detry, Ph.D., Abhijit Duggal, M.D., M.P.H., Vladimír Džavík, M.D., Mark B.
Effron, M.D., Heather F. Eng, B.A., Jorge Escobedo, M.D., Lise J. Estcourt,
M.B., B.Chir., D.Phil., Brendan M. Everett, M.D., M.P.H., Dean A. Fergusson,
Ph.D., Mark Fitzgerald, Ph.D., Robert A. Fowler, M.D., Joshua D. Froess, M.S.,
Zhuxuan Fu, M.S., M.P.H., Jean P. Galanaud, M.D., Benjamin T. Galen, M.D.,
Sheetal Gandotra, M.D., Timothy D. Girard, M.D., M.S.C.I., Andrew L. Goodman,
M.D., Herman Goossens, M.D., Cameron Green, M.Sc., Yonatan Y. Greenstein, M.D.,
Peter L. Gross, M.D., Rashan Haniffa, Ph.D., Sheila M. Hegde, M.D., M.P.H.,
Carolyn M. Hendrickson, M.D., Alisa M. Higgins, Ph.D., Alexander A. Hindenburg,
M.D., Aluko A. Hope, M.D., M.S.C.E., James M. Horowitz, M.D., Christopher M.
Horvat, M.D., M.H.A., David T. Huang, M.D., M.P.H., Kristin Hudock, M.D.,
M.S.T.R., Beverley J. Hunt, M.D., Mansoor Husain, M.D., Robert C. Hyzy, M.D.,
Jeffrey R. Jacobson, M.D., Devachandran Jayakumar, M.D., Norma M. Keller, M.D.,
Akram Khan, M.D., Yuri Kim, M.D., Ph.D., Andrei Kindzelski, M.D., Ph.D., Andrew
J. King, Ph.D., M. Margaret Knudson, M.D., Aaron E. Kornblith, M.D., Matthew E.
Kutcher, M.D., Michael A. Laffan, D.M., Francois Lamontagne, M.D., Grégoire Le
Gal, M.D., Ph.D., Christine M. Leeper, M.D., Eric S. Leifer, Ph.D., George Lim,
M.D., Felipe Gallego Lima, M.D., Kelsey Linstrum, M.S., Edward Litton, Ph.D.,
Jose Lopez-Sendon, Ph.D., Sylvain A. Lother, M.D., Nicole Marten, R.N., Andréa
Saud Marinez, Pharm.D., Mary Martinez, M.S., Eduardo Mateos Garcia, M.D.,
Stavroula Mavromichalis, M.A., Daniel F. McAuley, M.D., Emily G. McDonald,
M.D., Anna McGlothlin, Ph.D., Shay P. McGuinness, M.B., Ch.B., Saskia
Middeldorp, M.D., Ph.D., Stephanie K. Montgomery, M.Sc., Paul R. Mouncey,
M.Sc., Srinivas Murthy, M.D., Girish B. Nair, M.D., Rahul Nair, M.D., Alistair
D. Nichol, M.B., Ph.D., Jose C. Nicolau, M.D., Ph.D., Brenda Nunez-Garcia,
B.A., John J. Park, B.S., Pauline K. Park, M.D., Rachael L. Parke, Ph.D., Jane
C. Parker, B.N., Sam Parnia, M.D., Ph.D., Jonathan D. Paul, M.D., Mauricio
Pompilio, Ph.D., John G. Quigley, M.D., Robert S. Rosenson, M.D., Natalia S.
Rost, M.D., Kathryn Rowan, Ph.D., Fernanda O. Santos, M.D., Marlene Santos,
M.D., Mayler O. Santos, M.Sc., Lewis Satterwhite, M.D., Christina T. Saunders,
Ph.D., Jake Schreiber, M.P.H., Roger E.G. Schutgens, M.D., Ph.D., Christopher
W. Seymour, M.D., Deborah M. Siegal, M.D., Delcio G. Silva, Jr., M.Med., Aneesh
B. Singhal, M.D., Arthur S. Slutsky, M.D., Dayna Solvason, Simon J. Stanworth,
F.R.C.P., D.Phil., Anne M. Turner, M.P.H., Wilma van Bentum-Puijk, M.Sc., Frank
L. van de Veerdonk, M.D., Ph.D., Sean van Diepen, M.D., Gloria Vazquez-Grande,
M.D., Lana Wahid, M.D., Vanessa Wareham, H.B.Sc., R. Jay Widmer, M.D., Ph.D.,
Jennifer G. Wilson, M.D., Eugene Yuriditsky, M.D., and Yongqi Zhong, M.B.,
M.P.H.
//Acknowledgement(1)//---
We thank the patients and their families
who participated in this trial and the members of the data and safety
monitoring boards of each platform.
(Reference)
(1)
The REMAP-CAP, ACTIV-4a, and ATTACC
Investigators*
Therapeutic Anticoagulation with Heparin in
Critically Ill Patients with Covid-19
The New England Journal of Medicine August
4, 2021
---
Author 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.).
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National Institute for Health and Care
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Nadkarni GN, Lala A, Bagiella E, et al.
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