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Randomized Controlled Trial
. 2021 Aug 26;385(9):790-802.
doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4.

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

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

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

ATTACC Investigators et al. N Engl J Med. .

Abstract

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, NCT04359277, and NCT02735707.).

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Figures

Figure 1
Figure 1. Screening, Enrollment, and Randomization, According to Trial Group.
Trial sites used varying screening and documentation practices during the coronavirus disease 2019 (Covid-19) pandemic to identify eligible patients, as described in the protocol. Of the 13,373 patients who underwent screening, 7202 were assessed for eligibility in the ATTACC platform, 3799 in the ACTIV-4a platform, and 2372 in the REMAP-CAP platform. Under reasons for exclusion from the trial, “other” includes not meeting an inclusion criterion (including a lack of diagnosis of Covid-19), an anticipated duration of hospital stay of less than 72 hours, or meeting an exclusion criterion that is not specified here. Data for patients who had severe disease at baseline could be used for covariate adjustment and dynamic borrowing calculations in the primary analysis. The numbers of patients who were randomly assigned to the treatment groups were imbalanced owing to the use of response-adaptive randomization.
Figure 2
Figure 2. Days without Organ Support among All the Patients with Moderate Disease.
Panel A shows the distribution of organ support–free days among all the patients with moderate disease. The ordinal scale includes a score of –1 (in-hospital death, the worst possible outcome), a score of 0 to 21 (the numbers of days alive without organ support), and a score of 22 (survival until hospital discharge without receipt of organ support, the best possible outcome). The difference in the height of the two curves at any point represents the difference in the cumulative probability of having a value for days without organ support of less than or equal to that point on the x axis. Panel B shows the number of days without organ support as horizontally stacked proportions of patients in the two treatment groups, with the following possible outcomes: in-hospital death with or without the receipt of organ support (dark red, the worst possible outcome, corresponding to a score of −1 on the ordinal scale); survival with organ support provided in an intensive care unit (ICU) (red-to-blue gradient shading based on the number of days alive without organ support; intermediate outcome, corresponding to a score of 0 to 21 on the ordinal scale); and survival until hospital discharge without ICU-level organ support (dark blue, the best possible outcome, corresponding to a score of 22 on the ordinal scale).
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