TY - JOUR
T1 - Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients with Sepsis-Associated Coagulopathy
T2 - The SCARLET Randomized Clinical Trial
AU - SCARLET Trial Group
AU - Vincent, Jean Louis
AU - Francois, Bruno
AU - Zabolotskikh, Igor
AU - Daga, Mradul Kumar
AU - Lascarrou, Jean Baptiste
AU - Kirov, Mikhail Y.
AU - Pettilä, Ville
AU - Wittebole, Xavier
AU - Meziani, Ferhat
AU - Mercier, Emmanuelle
AU - Lobo, Suzana M.
AU - Barie, Philip S.
AU - Crowther, Mark
AU - Esmon, Charles T.
AU - Fareed, Jawed
AU - Gando, Satoshi
AU - Gorelick, Kenneth J.
AU - Levi, Marcel
AU - Mira, Jean Paul
AU - Opal, Steven M.
AU - Parrillo, Joseph
AU - Russell, James A.
AU - Saito, Hidehiko
AU - Tsuruta, Kazuhisa
AU - Sakai, Takumi
AU - Fineberg, David
AU - Bertuzzi, Romina
AU - Bellomo, Rinaldo
AU - Chapman, Marianne
AU - Ernest, David
AU - Fletcher, Jason
AU - French, Craig
AU - Gowardman, John
AU - Shehabi, Yahya
AU - Venkatesh, Bala
AU - Walsham, James
AU - Vij, Sanjiv
AU - Chochrad, DIdier
AU - Creteur, Jacques
AU - Devriendt, Jacques
AU - DIve, Alain Michel
AU - Dugernier, Thierry
AU - Foret, Frédéric
AU - Hoste, Eric
AU - Jorens, Philippe
AU - Simon, Marc
AU - Spapen, Herbert
AU - DIas, Fernando
AU - Freire, Antonio
AU - Simeonov, Georgi
AU - Stefanov, Chavdar
AU - Aslanian, Pierre
AU - Berthiaume, Luc
AU - Martin, Claudio
AU - Chittock, Dean
AU - Dhar, Anil
AU - Doig, Christopher
AU - Jones, Gwynne
AU - Hall, Richard
AU - Boyd, John
AU - Shin, Phil
AU - Wood, Gordon
AU - Zarychanski, Ryan
AU - Quinteros, Guillermo Agamenon
AU - Gasparovic, Vladimir
AU - Husedzinovic, Ino
AU - Balik, Martin
AU - Burget, Ivo
AU - Dlouhy, Pavel
AU - Pachl, Jan
AU - Karlsson, Sari
AU - Laru-Sompa, Raili
AU - Parviainen, Ilkka
AU - Ruokone, Esko
AU - Skrifvars, Markus
AU - Bohé, Julien
AU - Dellamonica, Jean
AU - Duguet, Alexandre
AU - Durand-Gasselin, Jacques
AU - Fiancette, Maud
AU - Joannes-Boyau, Olivier
AU - Lefrant, Jean Yves
AU - Mercat, Alain
AU - Nseir, Saad
AU - Quenot, Jean Pierre
AU - Reignier, Jean
AU - Schwebel, Carole
AU - Marx, Gernot
AU - Meier-Hellmann, Andreas
AU - Armaganidis, Apostolos
AU - Komnos, Apostolos
AU - Fejér, Csaba
AU - Appajigol, Jayaprakash
AU - Behera, Sarat Kumar
AU - Shekhar, Shivprasad Chandra
AU - Chowdhury, Sanmay
AU - D'Costa, Pradeep Micheal
AU - Gupta, Hari Shankar Shivkumar
AU - Iyer, Shivakumar
AU - Khan, Zafer A.
AU - Mehta, Minesh
AU - Murthy, Sudharshan
AU - Sahu, Sambit
AU - Tewari, Reshma
AU - Bar-Lavie, Yaron
AU - Bregman, Gennady
AU - Cohen, Jonathan
AU - Eden, Arie
AU - Einav-Bromiker, Sharon
AU - Jakobson, Daniel
AU - Nimrod, Adi
AU - Beishuizen, Albertus
AU - Gerritsen, Richard
AU - Pickkers, Peter
AU - Rozendaal, Wim
AU - Schoonderbeek, F. J.
AU - Spoelstra-De Man, Angelique
AU - Ten Tusscher, Birkitt Linn
AU - Van Zanten, Arthur R.H.
AU - Zijlstra, Jan G.
AU - Freebairn, Ross
AU - Henderson, Seton
AU - McArthur, Colin
AU - Young, Paul
AU - Mayorga, Manuel Jesús
AU - Agafina, Alina S.
AU - Bubnova, Natalia
AU - Gritsan, Alexey
AU - Kameneva, Evgenia
AU - Katasonov, Sergey P.
AU - Khasanova, Nina M.
AU - Kruberg, Lilly
AU - Kulabukhov, Vladimir V.
AU - Lebedinskii, Konstantin
AU - Spesivtsev, Yuri A.
AU - Rankovic, Zarko
AU - Hong, Sang Bum
AU - Kim, Min Ja
AU - Suh, Gee Young
AU - Yoo, Chul Gyu
AU - Raventós, Antonio Artigas
AU - Ferrer, Ricard
AU - Vázquez, Rita Galeiras
AU - Hernandez, Marianela
AU - Piacentini, Enrique
AU - Oviedo, Alejandro Hugo Rodriguez
AU - Garcia, Miguel Sanchez
AU - Chan, Ming Cheng
AU - Cheng, Kuo Chen
AU - Yu, Chong Jen
AU - Eddleston, Jane
AU - Smith, Fang Gao
AU - MacNaughton, Peter
AU - Welters, Ingeborg
AU - Allen, Karen
AU - Bochicchio, Grant
AU - Carlson, Richard
AU - Eaton, Stephanie
AU - Fink, Ryan
AU - Gianatiempo, Carmine
AU - Kapoor, Rajat
AU - Kinasewitz, Gary
AU - Koura, Firas
AU - Krell, Kenneth
AU - Martin, Niels
AU - Nepal, Santosh
AU - Pastores, Stephen M.
AU - Peltan, Ithan
AU - Pullman, John
AU - Seibert, Allan
AU - Smith, Jason
AU - Tennenberg, Steven
AU - Wilhelm, Andrew
AU - Zeno, Brian
AU - Allton, Pam
AU - Carruthers, David
AU - Matsuki, Osamu
AU - Kayanoki, Toshihiko
AU - Zacharowski, Kai
N1 - Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. Main Outcome and Measures: The primary end point was 28-day all-cause mortality. Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P =.32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.
AB - Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. Main Outcome and Measures: The primary end point was 28-day all-cause mortality. Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P =.32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.
UR - http://www.scopus.com/inward/record.url?scp=85065820427&partnerID=8YFLogxK
U2 - 10.1001/jama.2019.5358
DO - 10.1001/jama.2019.5358
M3 - Article
C2 - 31104069
AN - SCOPUS:85065820427
SN - 0098-7484
VL - 321
SP - 1993
EP - 2002
JO - JAMA
JF - JAMA
IS - 20
ER -