Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy The SCARLET Randomized Clinical Trial

Jean-Louis Vincent, Bruno Francois, Igor Zabolotskikh, Mradul Kumar Daga, Jean-Baptiste Lascarrou, Mikhail Y. Kirov, Ville Pettila, Xavier Wittebole, Ferhat Meziani, Emmanuelle Mercier, Suzana M. Lobo, Philip S. Barie, Mark Crowther, Charles T. Esmon, Jawed Fareed, Satoshi Gando, Kenneth J. Gorelick, Marcel Levi, Jean-Paul Mira, Steven M. OpalJoseph Parrillo, James A. Russell, Hidehiko Saito, Kazuhisa Tsuruta, Takumi Sakai, David Fineberg, Romina Bertuzzi, Rinaldo Bellomo, Marianne Chapman, David Ernest, Jason Fletcher, Craig French, John Gowardman, Yahya Shehabi, Bala Venkatesh, James Walsham, Sanjiv Vij, Didier Chochrad, Jacques Creteur, Jacques Devriendt, Alain-Michel Dive, Thierry Dugernier, Frederic Foret, Eric Hoste, Philippe Jorens, Marc Simon, Herbert Spapen, Jean-Louis Vincent, Xavier Wittebole, Fernando Dias, Antonio Freire, Suzana Margarth Lobo, Georgi Simeonov, Chavdar Stefanov, Pierre Aslanian, Luc Berthiaume, Claudio Martin, Dean Chittock, Anil Dhar, Christopher Doig, Gwynne Jones, Richard Hall, John Boyd, Phil Shin, Gordon Wood, Ryan Zarychanski, Guillermo Agamenon Quinteros, Vladimir Gasparovic, Ino Husedzinovic, Martin Balik, Ivo Burget, Pavel Dlouhy, Jan Pachl, Sari Karlsson, Raili Laru-Sompa, Ilkka Parviainen, Ville Pettila, Esko Ruokone, Markus Skrifvars, Julien Bohe, Jean Dellamonica, Alexandre Duguet, Jacques Durand-Gasselin, Maud Fiancette, Bruno Francois, Olivier Joannes-Boyau, Jean-Baptiste Lascarrou, Jean-Yves Lefrant, Alain Mercat, Emmanuelle Mercier, Ferhat Meziani, Saad Nseir, Jean-Pierre Quenot, Jean Reignier, Carole Schwebel, Gernot Marx, Kai Zacharowski, Apostolos Armaganidis, Apostolos Komnos, Csaba Fejer, Jayaprakash Appajigol, Sarat Kumar Behera, Shivprasad ChandraShekhar, Sanmay Chowdhury, Mradul Kumar Daga, Pradeep Micheal D'costa, Hari Shankar Shivkumar Gupta, Shivakumar Iyer, Zafer A. Khan, Minesh Mehta, Sudharshan Murthy, Sambit Sahu, Reshma Tewari, Yaron Bar-Lavie, Gennady Bregman, Jonathan Cohen, Arie Eden, Sharon Einav-Bromiker, Daniel Jakobson, Adi Nimrod, Albertus Beishuizen, Richard Gerritsen, Peter Pickkers, Wim Rozendaal, F. J. Schoonderbeek, Angelique Spoelstra-de Man, Arthur R. H. van Zanten, Jan G. Zijlstra, Ross Freebairn, Seton Henderson, Colin McArthur, Paul Young, Manuel Jesus Mayorga, Alina S. Agafina, Natalia Bubnova, Alexey Gritsan, Evgenia Kameneva, Sergey P. Katasonov, Nina M. Khasanova, Mikhail Y. Kirov, Lilly Kruberg, Vladimir V. Kulabukhov, Konstantin Lebedinskii, Yuri A. Spesivtsev, Igor Zabolotskikh, Zarko Rankovic, Sang Bum Hong, Min-Ja Kim, Gee Young Suh, Chul-Gyu Yoo, Antonio Artigas Raventos, Ricard Ferrer, Rita Galeiras Vazquez, Marianela Hernandez, Enrique Piacentini, Alejandro Hugo Rodriguez Oviedo, Miguel Sanchez Garcia, Ming-Cheng Chan, Kuo-Chen Cheng, Chong-Jen Yu, Jane Eddleston, Fang Gao Smith, Peter MacNaughton, Ingeborg Welters, Karen Allen, Grant Bochicchio, Richard Carlson, Stephanie Eaton, Ryan Fink, Carmine Gianatiempo, Rajat Kapoor, Gary Kinasewitz, Firas Koura, Kenneth Krell, Niels Martin, Santosh Nepal, Stephen M. Pastores, Ithan Peltan, John Pullman, Allan Seibert, Jason Smith, Steven Tennenberg, Andrew Wilhelm, Brian Zeno, Pam Allton, David Carruthers, Osamu Matsuki, Toshihiko Kayanoki

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 × 10 9/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.

Original languageEnglish
Pages (from-to)1993-2002
Number of pages10
JournalJAMA
Volume321
Issue number20
DOIs
Publication statusPublished - 28 May 2019

Cite this

Vincent, J-L., Francois, B., Zabolotskikh, I., Daga, M. K., Lascarrou, J-B., Kirov, M. Y., ... Kayanoki, T. (2019). Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy The SCARLET Randomized Clinical Trial. JAMA, 321(20), 1993-2002. https://doi.org/10.1001/jama.2019.5358