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Randomized Controlled Trial
. 2021 Aug 26;385(9):777-789.
doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4.

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

REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; 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 Jr  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
Collaborators, Affiliations
Randomized Controlled Trial

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

REMAP-CAP Investigators et al. N Engl J Med. .

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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Figures

Figure 1
Figure 1. Screening, Enrollment, Randomization, and Inclusion in Analysis.
Sites used varying screening and documentation practices during the pandemic to identify eligible patients (shown in the protocol); as reported, 3799 were assessed for eligibility in ACTIV-4a, 7202 in ATTACC, and 2372 in REMAP-CAP. “Other” exclusion criteria included an absence of a diagnosis of coronavirus disease 2019 (Covid-19) and a duration of hospital stay anticipated to be less than 72 hours. Patients who had moderate Covid-19 at baseline may have been included in calculations for covariate adjustment and dynamic borrowing.
Figure 2
Figure 2. Organ Support–free Days Up to Day 21.
Panel A shows the proportions of patients in each intervention group with each value for organ support–free days, with death listed first on the x axis (−1). Curves that rise more slowly indicate a more favorable distribution in the number of days alive and free of organ support. The height of each curve at −1 indicates the in-hospital mortality associated with each intervention. The height of each curve at any point from 0 to 21 days indicates the proportion of patients with that number of organ support–free days or fewer (e.g., at 10 days, the curve indicates the proportion of patients with ≤10 organ support–free days). The difference in height between the two curves at any point represents the difference in the cumulative probability of having a number of organ support–free days less than or equal to that number on the x axis. Panel B shows the values for organ support–free days as horizontally stacked proportions for each intervention group. Red represents worse outcomes and blue better outcomes. The median adjusted odds ratio in the primary analysis was 0.83 (95% credible interval, 0.67 to 1.03; posterior probability of futility, 99.9%). Among the patients in REMAP-CAP, 12 patients assigned to receive therapeutic-dose anticoagulation and 19 patients assigned to receive usual-care pharmacologic thromboprophylaxis had 21 organ support–free days; the cardiovascular or respiratory organ support these patients had been receiving at the time of randomization was discontinued within 12 hours after randomization.
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