//Background//---
SARS-CoV-2 is “foreign
compound” for our body. Therefore, immune system
including innate one and adaptive one becomes reactive due to exposure of
SARS-CoV-2 virus. If virus road is significantly increasing due to
immunodeficiency including defective IFN response(2), immune system is skewed
and indicates inflammation, resulting organ damage mainly in the respiratory
system. Immune cells and cytokine also exist in vascular system. Therefore,
inflammatory response severely affects vascular system including thrombosis.
Therefore, physician needs to carefully monitor vascular condition, and
administrate heparin in accordance with need.
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 for moderate ill patients with
SARS-CoV-2(1).
//Criteria of moderate disease
severity(1)//---
*Hospitalization for Covid-19 without the
need for ICU-level care.
//Period//---
From April 21, 2020 to January 22, 2021
//Condition(Special note)//
*Only therapeutic dose anticoagulation
group for similarity
(Treatment)
Antiplatelet agent: 13.0% / Remdesivir:
36.3% / Glucocorticoid: 60.6% / Tocilizumab: 0.5%
(Respiratory support)
None: 13.2%
Low-flow / High flow cannula: 66.8%/2.1%
Noninvasive mechanical ventilation: 1.8%
//Result(1)//---
Therapeutic dose anticoagulation /
Usual-care Thromboprophylaxis
(left/right in this order)
(Organ support-free days up to 21 days)
*D-dimer high level: 77.9%/72.2%
*D-dimer Low level: 81.2%/79.8%
*Unknown level: 80.9%/74.6%
-
*Survival until hospital discharge:
92.7%/91.8%
*Survival without organ support at 28 days:
79.3%/75.4%
*Progression to intubation or death:
10.9%/12.1%
*Major thrombotic event 1.1%/2.1%
*Death in hospital: 7.3%/8.2%
*Major bleeding: 1.9%/0.9%
(Evaluation)
Low-molecular-weight heparin is positive clinical outcome including
survival rate and progression to severe symptom in moderate ill patients more
than usual-care thromboprophylaxis. However, bleeding event is higher in
heparin group. High D-dimer group shows positive clinical outcome in heparin
administration for usual-care thromboprophylaxis compare to low D-dimer group.
//Discussion//---
The
bleeding event is almost half compared to severe ill patients(3), and the
clinical outcome is different between severe and moderate ill patients, in
which heparin is superior in moderate case. These results indicate that in the
case where risk of bleeding is low, heparin may be effective. Heparin may not
influence the cascade of immune inflammation, thrombosis itself and organ
repair in patients(4-6). Therefore, both control of blood flow with being
careful of bleeding by heparin and control of immune activity/reduction of
viral road is needed for the clinical treatment.
//Support(1)//---
The ATTACC platform was supported by grants
from the Canadian Institutes of Health Research, LifeArc Foundation,
Thistledown Foundation, Research Manitoba, Ontario Ministry of Health, Peter
Munk Cardiac Centre, CancerCare Manitoba Foundation, and Victoria General
Hospital Foundation. The ACTIV-4a platform was sponsored by the National Heart,
Lung, and Blood Institute, National Institutes of Health (NIH) (grant numbers,
OTA-20-011 and 1OT2HL156812-01). The pilot program (PROTECT) was funded in part
by a grant (UL1TR001445) from the New York University Clinical and
Translational Science Award program, supported by the National Center for
Advancing Translational Sciences of the NIH. The REMAP-CAP platform was supported
by the European Union through FP7-HEALTH-2013-INNOVATION: the Platform for
European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium
(602525) and the Horizon 2020 research and innovation program: the Rapid
European Covid-19 Emergency Research response (RECOVER) consortium (101003589);
by 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 Learning While Doing Program at the
University of Pittsburgh Medical Center, the Breast Cancer Research Foundation,
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). Dr. Goligher is the recipient of an Early Career
Investigator award from the Canadian Institutes of Health Research (grant
AR7-162822). Dr. Gordon is supported by an NIHR Research Professorship
(RP-2015-06-18), Dr. Shankar-Hari by an NIHR Clinician Scientist Fellowship
(CS-2016-16-011), and Dr. Turgeon by a Canada Research Chair (Tier 2). Dr.
Zarychanski is the recipient of the Lyonel G. Israels Research Chair in
Hematology (University of Manitoba).
//Members(1)//---
The members of the executive writing
committee are as follows:
Patrick R. Lawler, M.D., M.P.H., Ewan C.
Goligher, M.D., Ph.D., Jeffrey S. Berger, M.D., Matthew D. Neal, M.D., Bryan J.
McVerry, M.D, Jose C. Nicolau, M.D., Ph.D., Michelle N. Gong, M.D., Marc
Carrier, M.D., Robert S. Rosenson, M.D., Harmony R. Reynolds, M.D., Alexis F.
Turgeon, M.D., Jorge Escobedo, M.D., David T. Huang, M.D., M.P.H., Charlotte A.
Bradbury, M.B., Ch.B., Ph.D., Brett L. Houston, M.D., Lucy Z. Kornblith, M.D.,
Anand Kumar, M.D., Susan R. Kahn, M.D., Mary Cushman, M.D., Zoe McQuilten,
Ph.D., Arthur S. Slutsky, M.D., Keri S. Kim, Pharm.D., Anthony C. Gordon, M.B.,
B.S., M.D., Bridget-Anne Kirwan, Ph.D., Maria M. Brooks, Ph.D., Alisa M. Higgins,
Ph.D., Roger J. Lewis, M.D., Ph.D., Elizabeth Lorenzi, Ph.D., Scott M. Berry,
Ph.D., Lindsay R. Berry, Ph.D., Derek C. Angus, M.D., M.P.H., Colin J.
McArthur, M.B., Ch.B., Steven A. Webb, M.P.H., Ph.D., Michael E. Farkouh, M.D.,
Judith S. Hochman, M.D., and Ryan Zarychanski, M.D.
The members of the block writing committee
are as follows:
Aaron W. Aday, M.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., Todd W.
Costantini, M.D., Sophie de Brouwer, Ph.D., Lennie P.G. Derde, M.D., Ph.D.,
Michelle A. Detry, Ph.D., Abhijit Duggal, M.D., M.P.H., Vladimír Džavík, M.D.,
Mark B. Effron, 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., Jean P. Galanaud, M.D., Benjamin T. Galen, M.D., Sheetal
Gandotra, M.D., Sebastian García-Madrona, M.D., Timothy D. Girard, M.D., Lucas
C. Godoy, M.D., Andrew L. Goodman, M.D., Herman Goossens, M.D., Cameron Green,
M.Sc., Yonatan Y. Greenstein, M.D., Peter L. Gross, M.D., Naomi M. Hamburg,
M.D., Rashan Haniffa, Ph.D., George Hanna, M.D., Nicholas Hanna, M.D., Sheila
M. Hegde, M.D., M.P.H., Carolyn M. Hendrickson, M.D., R. Duncan Hite, M.D.,
Alexander A. Hindenburg, M.D., Aluko A. Hope, M.D., James M. Horowitz, M.D.,
Christopher M. Horvat, M.D., M.H.A., Kristin Hudock, M.D., Beverley J. Hunt,
M.D., Mansoor Husain, M.D., Robert C. Hyzy, M.D., Vivek N. Iyer, M.D., M.P.H.,
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 L. Kindzelski, M.D., Ph.D.,
Andrew J. King, Ph.D., M. Margaret Knudson, M.D., Aaron E. Kornblith, M.D.,
Vidya Krishnan, M.D., M.H.S., 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.,
Jose L. Lopez-Sendon Moreno, M.D., Sylvain A. Lother, M.D., Saurabh Malhotra,
M.D., M.P.H., Miguel Marcos, Ph.D., Andréa Saud Marinez, Pharm.D., John C.
Marshall, M.D., Nicole Marten, R.N., Michael A. Matthay, M.D., 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., Steven C. Moore, M.D., Raquel Morillo Guerrero, Ph.D., 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., Brenda Nunez-Garcia, B.A., Ambarish
Pandey, M.D., 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., Yessica S. Pérez González,
M.D., Mauricio Pompilio, Ph.D., Matthew E. Prekker, M.D., M.P.H., John G.
Quigley, M.D., Natalia S. Rost, M.D., Kathryn Rowan, Ph.D., Fernanda O. Santos,
M.D., Marlene Santos, M.D., Mayler Olombrada Santos, M.Sc., Lewis Satterwhite,
M.D., Christina T. Saunders, Ph.D., Roger E.G. Schutgens, M.D., Ph.D.,
Christopher W. Seymour, M.D., Deborah M. Siegal, M.D., Delcio G. Silva, Jr.,
M.Med., Manu Shankar-Hari, Ph.D., John P. Sheehan, M.D., Aneesh B. Singhal,
M.D., Dayna Solvason, Simon J. Stanworth, D.Phil., Tobias Tritschler, M.D.,
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., Bryan J. Wells, M.D., R. Jay Widmer,
M.D., Ph.D., Jennifer G. Wilson, M.D., Eugene Yuriditsky, M.D., and Fernando G.
Zampieri, M.D., Ph.D.
//Acknowledgement(1)//---
We thank the patients and their families
who participated in this trial and the members of the data and safety
monitoring board for each platform.
(Reference)
(1)
The ATTACC, ACTIV-4a, and REMAP-CAP
Investigators*
Therapeutic Anticoagulation with Heparin in
Noncritically Ill Patients with Covid-19
The New England Journal of Medicine August
4, 2021
---
Author Affiliations
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.).
(2)
COVID-19 Host Genetics Initiative
Mapping the human genetic architecture of
COVID-19
Nature (2021)
(3)
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
(4)
Xue M, Zeng Y, Qu H-Q, et al.
Heparin-binding protein levels correlate
with aggravation and multiorgan damage in severe COVID-19.
ERJ Open Res 2021; 7(1): 00741-2020.
(5)
White D, MacDonald S, Bull T, et al.
Heparin resistance in COVID-19 patients
in the
intensive care unit.
J Thromb Thrombolysis 2020; 50: 287-91.
(6)
Fisher J, Linder A.
Heparin-binding protein: a key player in
the pathophysiology of organ dysfunction in sepsis.
J Intern Med 2017; 281: 562-74.
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