tetano
Editor, Senior Moderator
N Engl J Med
. 2021 Aug 4.
doi: 10.1056/NEJMoa2103417. Online ahead of print.
Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19
REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Ewan C Goligher[SUP] 1 [/SUP], Charlotte A Bradbury[SUP] 1 [/SUP], Bryan J McVerry[SUP] 1 [/SUP], Patrick R Lawler[SUP] 1 [/SUP], Jeffrey S Berger[SUP] 1 [/SUP], Michelle N Gong[SUP] 1 [/SUP], Marc Carrier[SUP] 1 [/SUP], Harmony R Reynolds[SUP] 1 [/SUP], Anand Kumar[SUP] 1 [/SUP], Alexis F Turgeon[SUP] 1 [/SUP], Lucy Z Kornblith[SUP] 1 [/SUP], Susan R Kahn[SUP] 1 [/SUP], John C Marshall[SUP] 1 [/SUP], Keri S Kim[SUP] 1 [/SUP], Brett L Houston[SUP] 1 [/SUP], Lennie P G Derde[SUP] 1 [/SUP], Mary Cushman[SUP] 1 [/SUP], Tobias Tritschler[SUP] 1 [/SUP], Derek C Angus[SUP] 1 [/SUP], Lucas C Godoy[SUP] 1 [/SUP], Zoe McQuilten[SUP] 1 [/SUP], Bridget-Anne Kirwan[SUP] 1 [/SUP], Michael E Farkouh[SUP] 1 [/SUP], Maria M Brooks[SUP] 1 [/SUP], Roger J Lewis[SUP] 1 [/SUP], Lindsay R Berry[SUP] 1 [/SUP], Elizabeth Lorenzi[SUP] 1 [/SUP], Anthony C Gordon[SUP] 1 [/SUP], Scott M Berry[SUP] 1 [/SUP], Colin J McArthur[SUP] 1 [/SUP], Matthew D Neal[SUP] 1 [/SUP], Judith S Hochman[SUP] 1 [/SUP], Steven A Webb[SUP] 1 [/SUP], Ryan Zarychanski[SUP] 1 [/SUP], Tania Ahuja[SUP] 1 [/SUP], Farah Al-Beidh[SUP] 1 [/SUP], Djillali Annane[SUP] 1 [/SUP], Yaseen M Arabi[SUP] 1 [/SUP], Diptesh Aryal[SUP] 1 [/SUP], Lisa Baumann Kreuziger[SUP] 1 [/SUP], Abi Beane[SUP] 1 [/SUP], Zahra Bhimani[SUP] 1 [/SUP], Shailesh Bihari[SUP] 1 [/SUP], Henny H Billett[SUP] 1 [/SUP], Lindsay Bond[SUP] 1 [/SUP], Marc Bonten[SUP] 1 [/SUP], Frank Brunkhorst[SUP] 1 [/SUP], Meredith Buxton[SUP] 1 [/SUP], Adrian Buzgau[SUP] 1 [/SUP], Lana A Castellucci[SUP] 1 [/SUP], Sweta Chekuri[SUP] 1 [/SUP], Jen-Ting Chen[SUP] 1 [/SUP], Allen C Cheng[SUP] 1 [/SUP], Tamta Chkhikvadze[SUP] 1 [/SUP], Benjamin Coiffard[SUP] 1 [/SUP], Aira Contreras[SUP] 1 [/SUP], Todd W Costantini[SUP] 1 [/SUP], Sophie de Brouwer[SUP] 1 [/SUP], Michelle A Detry[SUP] 1 [/SUP], Abhijit Duggal[SUP] 1 [/SUP], Vladimír Džavík[SUP] 1 [/SUP], Mark B Effron[SUP] 1 [/SUP], Heather F Eng[SUP] 1 [/SUP], Jorge Escobedo[SUP] 1 [/SUP], Lise J Estcourt[SUP] 1 [/SUP], Brendan M Everett[SUP] 1 [/SUP], Dean A Fergusson[SUP] 1 [/SUP], Mark Fitzgerald[SUP] 1 [/SUP], Robert A Fowler[SUP] 1 [/SUP], Joshua D Froess[SUP] 1 [/SUP], Zhuxuan Fu[SUP] 1 [/SUP], Jean P Galanaud[SUP] 1 [/SUP], Benjamin T Galen[SUP] 1 [/SUP], Sheetal Gandotra[SUP] 1 [/SUP], Timothy D Girard[SUP] 1 [/SUP], Andrew L Goodman[SUP] 1 [/SUP], Herman Goossens[SUP] 1 [/SUP], Cameron Green[SUP] 1 [/SUP], Yonatan Y Greenstein[SUP] 1 [/SUP], Peter L Gross[SUP] 1 [/SUP], Rashan Haniffa[SUP] 1 [/SUP], Sheila M Hegde[SUP] 1 [/SUP], Carolyn M Hendrickson[SUP] 1 [/SUP], Alisa M Higgins[SUP] 1 [/SUP], Alexander A Hindenburg[SUP] 1 [/SUP], Aluko A Hope[SUP] 1 [/SUP], James M Horowitz[SUP] 1 [/SUP], Christopher M Horvat[SUP] 1 [/SUP], David T Huang[SUP] 1 [/SUP], Kristin Hudock[SUP] 1 [/SUP], Beverley J Hunt[SUP] 1 [/SUP], Mansoor Husain[SUP] 1 [/SUP], Robert C Hyzy[SUP] 1 [/SUP], Jeffrey R Jacobson[SUP] 1 [/SUP], Devachandran Jayakumar[SUP] 1 [/SUP], Norma M Keller[SUP] 1 [/SUP], Akram Khan[SUP] 1 [/SUP], Yuri Kim[SUP] 1 [/SUP], Andrei Kindzelski[SUP] 1 [/SUP], Andrew J King[SUP] 1 [/SUP], M Margaret Knudson[SUP] 1 [/SUP], Aaron E Kornblith[SUP] 1 [/SUP], Matthew E Kutcher[SUP] 1 [/SUP], Michael A Laffan[SUP] 1 [/SUP], Francois Lamontagne[SUP] 1 [/SUP], Grégoire Le Gal[SUP] 1 [/SUP], Christine M Leeper[SUP] 1 [/SUP], Eric S Leifer[SUP] 1 [/SUP], George Lim[SUP] 1 [/SUP], Felipe Gallego Lima[SUP] 1 [/SUP], Kelsey Linstrum[SUP] 1 [/SUP], Edward Litton[SUP] 1 [/SUP], Jose Lopez-Sendon[SUP] 1 [/SUP], Sylvain A Lother[SUP] 1 [/SUP], Nicole Marten[SUP] 1 [/SUP], Andréa Saud Marinez[SUP] 1 [/SUP], Mary Martinez[SUP] 1 [/SUP], Eduardo Mateos Garcia[SUP] 1 [/SUP], Stavroula Mavromichalis[SUP] 1 [/SUP], Daniel F McAuley[SUP] 1 [/SUP], Emily G McDonald[SUP] 1 [/SUP], Anna McGlothlin[SUP] 1 [/SUP], Shay P McGuinness[SUP] 1 [/SUP], Saskia Middeldorp[SUP] 1 [/SUP], Stephanie K Montgomery[SUP] 1 [/SUP], Paul R Mouncey[SUP] 1 [/SUP], Srinivas Murthy[SUP] 1 [/SUP], Girish B Nair[SUP] 1 [/SUP], Rahul Nair[SUP] 1 [/SUP], Alistair D Nichol[SUP] 1 [/SUP], Jose C Nicolau[SUP] 1 [/SUP], Brenda Nunez-Garcia[SUP] 1 [/SUP], John J Park[SUP] 1 [/SUP], Pauline K Park[SUP] 1 [/SUP], Rachael L Parke[SUP] 1 [/SUP], Jane C Parker[SUP] 1 [/SUP], Sam Parnia[SUP] 1 [/SUP], Jonathan D Paul[SUP] 1 [/SUP], Mauricio Pompilio[SUP] 1 [/SUP], John G Quigley[SUP] 1 [/SUP], Robert S Rosenson[SUP] 1 [/SUP], Natalia S Rost[SUP] 1 [/SUP], Kathryn Rowan[SUP] 1 [/SUP], Fernanda O Santos[SUP] 1 [/SUP], Marlene Santos[SUP] 1 [/SUP], Mayler O Santos[SUP] 1 [/SUP], Lewis Satterwhite[SUP] 1 [/SUP], Christina T Saunders[SUP] 1 [/SUP], Jake Schreiber[SUP] 1 [/SUP], Roger E G Schutgens[SUP] 1 [/SUP], Christopher W Seymour[SUP] 1 [/SUP], Deborah M Siegal[SUP] 1 [/SUP], Delcio G Silva Jr[SUP] 1 [/SUP], Aneesh B Singhal[SUP] 1 [/SUP], Arthur S Slutsky[SUP] 1 [/SUP], Dayna Solvason[SUP] 1 [/SUP], Simon J Stanworth[SUP] 1 [/SUP], Anne M Turner[SUP] 1 [/SUP], Wilma van Bentum-Puijk[SUP] 1 [/SUP], Frank L van de Veerdonk[SUP] 1 [/SUP], Sean van Diepen[SUP] 1 [/SUP], Gloria Vazquez-Grande[SUP] 1 [/SUP], Lana Wahid[SUP] 1 [/SUP], Vanessa Wareham[SUP] 1 [/SUP], R Jay Widmer[SUP] 1 [/SUP], Jennifer G Wilson[SUP] 1 [/SUP], Eugene Yuriditsky[SUP] 1 [/SUP], Yongqi Zhong[SUP] 1 [/SUP]
Collaborators, Affiliations
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.).
. 2021 Aug 4.
doi: 10.1056/NEJMoa2103417. Online ahead of print.
Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19
REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Ewan C Goligher[SUP] 1 [/SUP], Charlotte A Bradbury[SUP] 1 [/SUP], Bryan J McVerry[SUP] 1 [/SUP], Patrick R Lawler[SUP] 1 [/SUP], Jeffrey S Berger[SUP] 1 [/SUP], Michelle N Gong[SUP] 1 [/SUP], Marc Carrier[SUP] 1 [/SUP], Harmony R Reynolds[SUP] 1 [/SUP], Anand Kumar[SUP] 1 [/SUP], Alexis F Turgeon[SUP] 1 [/SUP], Lucy Z Kornblith[SUP] 1 [/SUP], Susan R Kahn[SUP] 1 [/SUP], John C Marshall[SUP] 1 [/SUP], Keri S Kim[SUP] 1 [/SUP], Brett L Houston[SUP] 1 [/SUP], Lennie P G Derde[SUP] 1 [/SUP], Mary Cushman[SUP] 1 [/SUP], Tobias Tritschler[SUP] 1 [/SUP], Derek C Angus[SUP] 1 [/SUP], Lucas C Godoy[SUP] 1 [/SUP], Zoe McQuilten[SUP] 1 [/SUP], Bridget-Anne Kirwan[SUP] 1 [/SUP], Michael E Farkouh[SUP] 1 [/SUP], Maria M Brooks[SUP] 1 [/SUP], Roger J Lewis[SUP] 1 [/SUP], Lindsay R Berry[SUP] 1 [/SUP], Elizabeth Lorenzi[SUP] 1 [/SUP], Anthony C Gordon[SUP] 1 [/SUP], Scott M Berry[SUP] 1 [/SUP], Colin J McArthur[SUP] 1 [/SUP], Matthew D Neal[SUP] 1 [/SUP], Judith S Hochman[SUP] 1 [/SUP], Steven A Webb[SUP] 1 [/SUP], Ryan Zarychanski[SUP] 1 [/SUP], Tania Ahuja[SUP] 1 [/SUP], Farah Al-Beidh[SUP] 1 [/SUP], Djillali Annane[SUP] 1 [/SUP], Yaseen M Arabi[SUP] 1 [/SUP], Diptesh Aryal[SUP] 1 [/SUP], Lisa Baumann Kreuziger[SUP] 1 [/SUP], Abi Beane[SUP] 1 [/SUP], Zahra Bhimani[SUP] 1 [/SUP], Shailesh Bihari[SUP] 1 [/SUP], Henny H Billett[SUP] 1 [/SUP], Lindsay Bond[SUP] 1 [/SUP], Marc Bonten[SUP] 1 [/SUP], Frank Brunkhorst[SUP] 1 [/SUP], Meredith Buxton[SUP] 1 [/SUP], Adrian Buzgau[SUP] 1 [/SUP], Lana A Castellucci[SUP] 1 [/SUP], Sweta Chekuri[SUP] 1 [/SUP], Jen-Ting Chen[SUP] 1 [/SUP], Allen C Cheng[SUP] 1 [/SUP], Tamta Chkhikvadze[SUP] 1 [/SUP], Benjamin Coiffard[SUP] 1 [/SUP], Aira Contreras[SUP] 1 [/SUP], Todd W Costantini[SUP] 1 [/SUP], Sophie de Brouwer[SUP] 1 [/SUP], Michelle A Detry[SUP] 1 [/SUP], Abhijit Duggal[SUP] 1 [/SUP], Vladimír Džavík[SUP] 1 [/SUP], Mark B Effron[SUP] 1 [/SUP], Heather F Eng[SUP] 1 [/SUP], Jorge Escobedo[SUP] 1 [/SUP], Lise J Estcourt[SUP] 1 [/SUP], Brendan M Everett[SUP] 1 [/SUP], Dean A Fergusson[SUP] 1 [/SUP], Mark Fitzgerald[SUP] 1 [/SUP], Robert A Fowler[SUP] 1 [/SUP], Joshua D Froess[SUP] 1 [/SUP], Zhuxuan Fu[SUP] 1 [/SUP], Jean P Galanaud[SUP] 1 [/SUP], Benjamin T Galen[SUP] 1 [/SUP], Sheetal Gandotra[SUP] 1 [/SUP], Timothy D Girard[SUP] 1 [/SUP], Andrew L Goodman[SUP] 1 [/SUP], Herman Goossens[SUP] 1 [/SUP], Cameron Green[SUP] 1 [/SUP], Yonatan Y Greenstein[SUP] 1 [/SUP], Peter L Gross[SUP] 1 [/SUP], Rashan Haniffa[SUP] 1 [/SUP], Sheila M Hegde[SUP] 1 [/SUP], Carolyn M Hendrickson[SUP] 1 [/SUP], Alisa M Higgins[SUP] 1 [/SUP], Alexander A Hindenburg[SUP] 1 [/SUP], Aluko A Hope[SUP] 1 [/SUP], James M Horowitz[SUP] 1 [/SUP], Christopher M Horvat[SUP] 1 [/SUP], David T Huang[SUP] 1 [/SUP], Kristin Hudock[SUP] 1 [/SUP], Beverley J Hunt[SUP] 1 [/SUP], Mansoor Husain[SUP] 1 [/SUP], Robert C Hyzy[SUP] 1 [/SUP], Jeffrey R Jacobson[SUP] 1 [/SUP], Devachandran Jayakumar[SUP] 1 [/SUP], Norma M Keller[SUP] 1 [/SUP], Akram Khan[SUP] 1 [/SUP], Yuri Kim[SUP] 1 [/SUP], Andrei Kindzelski[SUP] 1 [/SUP], Andrew J King[SUP] 1 [/SUP], M Margaret Knudson[SUP] 1 [/SUP], Aaron E Kornblith[SUP] 1 [/SUP], Matthew E Kutcher[SUP] 1 [/SUP], Michael A Laffan[SUP] 1 [/SUP], Francois Lamontagne[SUP] 1 [/SUP], Grégoire Le Gal[SUP] 1 [/SUP], Christine M Leeper[SUP] 1 [/SUP], Eric S Leifer[SUP] 1 [/SUP], George Lim[SUP] 1 [/SUP], Felipe Gallego Lima[SUP] 1 [/SUP], Kelsey Linstrum[SUP] 1 [/SUP], Edward Litton[SUP] 1 [/SUP], Jose Lopez-Sendon[SUP] 1 [/SUP], Sylvain A Lother[SUP] 1 [/SUP], Nicole Marten[SUP] 1 [/SUP], Andréa Saud Marinez[SUP] 1 [/SUP], Mary Martinez[SUP] 1 [/SUP], Eduardo Mateos Garcia[SUP] 1 [/SUP], Stavroula Mavromichalis[SUP] 1 [/SUP], Daniel F McAuley[SUP] 1 [/SUP], Emily G McDonald[SUP] 1 [/SUP], Anna McGlothlin[SUP] 1 [/SUP], Shay P McGuinness[SUP] 1 [/SUP], Saskia Middeldorp[SUP] 1 [/SUP], Stephanie K Montgomery[SUP] 1 [/SUP], Paul R Mouncey[SUP] 1 [/SUP], Srinivas Murthy[SUP] 1 [/SUP], Girish B Nair[SUP] 1 [/SUP], Rahul Nair[SUP] 1 [/SUP], Alistair D Nichol[SUP] 1 [/SUP], Jose C Nicolau[SUP] 1 [/SUP], Brenda Nunez-Garcia[SUP] 1 [/SUP], John J Park[SUP] 1 [/SUP], Pauline K Park[SUP] 1 [/SUP], Rachael L Parke[SUP] 1 [/SUP], Jane C Parker[SUP] 1 [/SUP], Sam Parnia[SUP] 1 [/SUP], Jonathan D Paul[SUP] 1 [/SUP], Mauricio Pompilio[SUP] 1 [/SUP], John G Quigley[SUP] 1 [/SUP], Robert S Rosenson[SUP] 1 [/SUP], Natalia S Rost[SUP] 1 [/SUP], Kathryn Rowan[SUP] 1 [/SUP], Fernanda O Santos[SUP] 1 [/SUP], Marlene Santos[SUP] 1 [/SUP], Mayler O Santos[SUP] 1 [/SUP], Lewis Satterwhite[SUP] 1 [/SUP], Christina T Saunders[SUP] 1 [/SUP], Jake Schreiber[SUP] 1 [/SUP], Roger E G Schutgens[SUP] 1 [/SUP], Christopher W Seymour[SUP] 1 [/SUP], Deborah M Siegal[SUP] 1 [/SUP], Delcio G Silva Jr[SUP] 1 [/SUP], Aneesh B Singhal[SUP] 1 [/SUP], Arthur S Slutsky[SUP] 1 [/SUP], Dayna Solvason[SUP] 1 [/SUP], Simon J Stanworth[SUP] 1 [/SUP], Anne M Turner[SUP] 1 [/SUP], Wilma van Bentum-Puijk[SUP] 1 [/SUP], Frank L van de Veerdonk[SUP] 1 [/SUP], Sean van Diepen[SUP] 1 [/SUP], Gloria Vazquez-Grande[SUP] 1 [/SUP], Lana Wahid[SUP] 1 [/SUP], Vanessa Wareham[SUP] 1 [/SUP], R Jay Widmer[SUP] 1 [/SUP], Jennifer G Wilson[SUP] 1 [/SUP], Eugene Yuriditsky[SUP] 1 [/SUP], Yongqi Zhong[SUP] 1 [/SUP]
Collaborators, Affiliations
- PMID: 34351722
- DOI: 10.1056/NEJMoa2103417
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.).