Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.
ATTACC Investigators None., ACTIV-4a Investigators None., REMAP-CAP Investigators None., Lawler PR., Goligher EC., Berger JS., Neal MD., McVerry BJ., Nicolau JC., Gong MN., Carrier M., Rosenson RS., Reynolds HR., Turgeon AF., Escobedo J., Huang DT., Bradbury CA., Houston BL., Kornblith LZ., Kumar A., Kahn SR., Cushman M., McQuilten Z., Slutsky AS., Kim KS., Gordon AC., Kirwan B-A., Brooks MM., Higgins AM., Lewis RJ., Lorenzi E., Berry SM., Berry LR., Angus DC., McArthur CJ., Webb SA., Farkouh ME., Hochman JS., Zarychanski R., Aday AW., Al-Beidh F., Annane D., Arabi YM., Aryal D., Baumann Kreuziger L., Beane A., Bhimani Z., Bihari S., Billett HH., Bond L., Bonten M., Brunkhorst F., Buxton M., Buzgau A., Castellucci LA., Chekuri S., Chen J-T., Cheng AC., Chkhikvadze T., Coiffard B., Costantini TW., de Brouwer S., Derde LPG., Detry MA., Duggal A., Džavík V., Effron MB., Estcourt LJ., Everett BM., Fergusson DA., Fitzgerald M., Fowler RA., Galanaud JP., Galen BT., Gandotra S., García-Madrona S., Girard TD., Godoy LC., Goodman AL., Goossens H., Green C., Greenstein YY., Gross PL., Hamburg NM., Haniffa R., Hanna G., Hanna N., Hegde SM., Hendrickson CM., Hite RD., Hindenburg AA., Hope AA., Horowitz JM., Horvat CM., Hudock K., Hunt BJ., Husain M., Hyzy RC., Iyer VN., Jacobson JR., Jayakumar D., Keller NM., Khan A., Kim Y., Kindzelski AL., King AJ., Knudson MM., Kornblith AE., Krishnan V., Kutcher ME., Laffan MA., Lamontagne F., Le Gal G., Leeper CM., Leifer ES., Lim G., Lima FG., Linstrum K., Litton E., Lopez-Sendon J., Lopez-Sendon Moreno JL., Lother SA., Malhotra S., Marcos M., Saud Marinez A., Marshall JC., Marten N., Matthay MA., McAuley DF., McDonald EG., McGlothlin A., McGuinness SP., Middeldorp S., Montgomery SK., Moore SC., Morillo Guerrero R., Mouncey PR., Murthy S., Nair GB., Nair R., Nichol AD., Nunez-Garcia B., Pandey A., Park PK., Parke RL., Parker JC., Parnia S., Paul JD., Pérez González YS., Pompilio M., Prekker ME., Quigley JG., Rost NS., Rowan K., Santos FO., Santos M., Olombrada Santos M., Satterwhite L., Saunders CT., Schutgens REG., Seymour CW., Siegal DM., Silva DG., Shankar-Hari M., Sheehan JP., Singhal AB., Solvason D., Stanworth SJ., Tritschler T., Turner AM., van Bentum-Puijk W., van de Veerdonk FL., van Diepen S., Vazquez-Grande G., Wahid L., Wareham V., Wells BJ., Widmer RJ., Wilson JG., Yuriditsky E., Zampieri FG.
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.).