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. Opal; Joseph 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

doi:https://doi.org/10.1001/jama.2019.5358

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 journal › Article › Academic › peer-review

197 Citations (Scopus)

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 language	English
Pages (from-to)	1993-2002
Number of pages	10
Journal	JAMA
Volume	321
Issue number	20
DOIs	https://doi.org/10.1001/jama.2019.5358
Publication status	Published - 28 May 2019

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https://doi.org/10.1001/jama.2019.5358

Cite this

Vincent, J.-L., Francois, B., Zabolotskikh, I., Daga, M. K., Lascarrou, J.-B., Kirov, M. Y., Pettila, V., Wittebole, X., Meziani, F., Mercier, E., Lobo, S. M., Barie, P. S., Crowther, M., Esmon, C. T., Fareed, J., Gando, S., Gorelick, K. J., Levi, M., Mira, J.-P., ... 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

@article{f199ac3b54d34740ac7a70e14fd3272a,

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

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. ",

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

note = "Funding Information: Author Affiliations: Department of Intensive Care, Erasme Hospital, Universit{\'e} libre de Bruxelles, Brussels, Belgium (Vincent); ICU Department, Inserm CIC-1435 & UMR-1092, CHU Dupuytren, Limoges, France (Francois); Department of Anesthesiology, Intensive Care and Transfusiology, Kuban State Medical University, Krasnodar, Russia (Zabolotskikh); Department of Medicine, Maulana Azad Medical College and associated hospitals, New Delhi, India (Daga); Centre Hospitalier Universitaire de Nantes, Nantes, France (Lascarrou); Department of Anesthesiology and Intensive Care Medicine, Northern State Medical University, Arkhangelsk, Russia (Kirov); Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland (Pettil{\"a}); Department of Critical Care Medicine, St Luc University Hospital, Universit{\'e} Catholique de Louvain, Brussels, Belgium (Wittebole); Facult{\'e} de M{\'e}decine, Universit{\'e} de Strasbourg (UNISTRA), H{\^o}pitaux Universitaires de Strasbourg, Service de R{\'e}animation, Nouvel H{\^o}pital Civil, Strasbourg, France (Meziani); M{\'e}decine Intensive R{\'e}animation, CHRU de Tours, Tours, France (Mercier); Intensive Care Division, Hospital de Base, S{\~a}o Jos{\'e} do Rio Preto, SP, Brazil (Lobo); Departments of Surgery and Medicine, Weill Cornell Medicine, New York, New York (Barie); Department of Medicine, McMaster University and St Joseph{\textquoteright}s Hospital, Hamilton, Canada (Crowther); Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (Esmon); Pathology and Pharmacology, Loyola University Medical Center, Maywood, Illinois (Fareed); Acute and Critical Care Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan (Gando); Zymo Consulting Group LLC, Newtown Square, Massachusetts (Gorelick); Department of Medicine, University College London Hospitals and Cardiometabolic Programme-NIHR UCLH/UCL BRC, London, United Kingdom (Levi); Universit{\'e}Paris Descartes, Sorbonne Paris Cit{\'e}, Facult{\'e} de M{\'e}-decine Cochin University Hospital, AP-HP, Paris, France (Mira); Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island (Opal); Department of Medicine, New Jersey Medical School of Rutgers University, Hackenseck (Parrillo); Heart and Vascular Hospital, Hackensack University Medical Center, Hackensack, New Jersey (Parrillo); Department of Medicine, Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada (Russell); National Hospital Organization, Nagoya Medical Center, Nagoya, Japan (Saito); Asahi-Kasei Pharma Corporation, Tokyo, Japan (Tsuruta, Sakai); Asahi-Kasei Pharma America Corporation, Waltham, Massachusetts (Fineberg). Funding Information: (CHU de Dijon, Hopital Bocage Central); Jean Reignier (CHU Hotel Dieu); Carole Schwebel (CH-H{\^o}pital Albert Michallon); Germany: Gernot Marx (University Hospital Aachen; Andreas Meier-Hellmann, Helios Klinikum Erfurt); Kai Zacharowski (Universit{\"a}tsklinikum Frankfurt); Greece: Apostolos Armaganidis (ATTIKON University General Hospital); Apostolos Komnos (General Hospital of Larissa ''Koutlimpanio & Triantafyllio''); Hungary: Csaba Fej{\'e}r (Szent Imre Hospital); India: Jayaprakash Appajigol (KLES Dr Prabhakar Kore Hospital & Medical Research Centre); Sarat Kumar Behera (Hi-tech Medical College & Hospital); Shivprasad ChandraShekhar (Mazumdar Shaw Medical Centre); Sanmay Chowdhury (Grant Medical Foundation, Ruby Hall Clinic, Pune); Mradul Kumar Daga (Maulana Azad Medical College and Associated L N Hospital); Pradeep Micheal D'costa (King Edward Memorial Hospital); Hari Shankar Shivkumar Gupta (Care Hospital); Shivakumar Iyer (Bharti Hospital and Research Centre); Zafer A Khan (Noble Hospital); Minesh Mehta (Shalby Hospital); Sudharshan Murthy (JSS Hospital); Sambit Sahu (St Theresa Hospital); Reshma Tewari (Artemis Hospital); Israel: Yaron Bar-Lavie (Rambam Medical Center); Gennady Bregman (Kaplan Medical Center); Jonathan Cohen (Rabin Medical Center); Arie Eden (The Lady Davis Carmel Medical Center); Sharon Einav-Bromiker (Shaare Zedek Medical Center 12 Bayit St Jerusalem); Daniel Jakobson (Barzilai Medical Center); Adi Nimrod (Kaplan Medical Center); The Netherlands: Albertus Beishuizen (Medisch Spectrum Twente); Richard Gerritsen (Medisch Centrum Leeuwarden); Peter Pickkers (UMC St. Radboud); Wim Rozendaal (Jeroen Bosch Ziekenhuis); FJ Schoonderbeek (Ikazia Ziekenhuis); Angelique Spoelstra-de Man (VUMC; Birkitt-Linn ten Tusscher, VUMC); ArthurRHvan Zanten (Ziekenhuis Gelderse Vallei); Jan G. Zijlstra (University Medical Center Groningen); New Zealand: Ross Freebairn (Hawkes Bay Regional Hospital); Seton Henderson (Christchurch Hospital); Colin McArthur (Auckland District Health Board); Paul Young (Wellington District Health Board); Peru: Manuel Jes{\'u}s Mayorga (Hospital Nacional FAP); Russia: Alina S Agafina (City Hospital); Natalia Bubnova (St George City Hospital); Alexey Gritsan (Krasnoyarsk Regional Clinocal Hospital); Evgenia Kameneva (Regional Clinical Hospital of Emergency Care N.A. M.A. Podgorbunskiy); Sergey P Katasonov (Aleksandrovskaya City Hospital); Nina M Khasanova (Arkhangelsk Regional Clinical Hospital affiliated with Northern State Medical University); Mikhail Y Kirov (City Clinical Hospita n.a. E.E.Volosevich); Lilly Kruberg (City Hospital No 4); Vladimir V Kulabukhov (Vishnevsky Institute of Surgery); Konstantin Lebedinskii (Mechnikov North West State Medical University); Yuri A Spesivtsev (Mariinskaya City Hospital); Igor Zabolotskikh (Kuban State Medical University, Site Facility: Krasnodar Territorial Hospital # 2); Serbia: Zarko Rankovic (Clinical Center Nis); South Korea: Sang Bum Hong (Asan Medical Center); Min-Ja Kim (Korea University Anam Hospital); Gee Young Suh (Samsung Medical Center); Chul-Gyu Yoo (Seoul National University Hospital); Spain: Antonio Artigas Ravent{\'o}s (Hospital de Sabadell); Ricard Ferrer (Hospital Universitario Vall de Hebron); Rita Galeiras V{\'a}zquez (Complexo Hospitalario Universitario A Coru{\~n}a); Marianela Hernandez (Hospital de Txagorritxu); Enrique Piacentini (Hospital Universitario Mutua Terrassa Intensive Care); Alejandro Hugo Rodriguez Oviedo (Hospital Universitari de Tarragona Joan XXIII); Miguel Sanchez Garcia (Hospital Cl{\'i}nico San Carlos); Taiwan: Ming-Cheng Chan (Taichung Veterans General Hospital); Kuo-Chen Cheng (Chi Mei Medical Center Yong Kang); Chong-Jen Yu (National Taiwan University Hospital); United Kingdom: Jane Eddleston (Manchester Royal Infirmary); Fang Gao Smith (Birmingham Heartlands Hospital); Peter MacNaughton (Derriford Hospital); Ingeborg Welters (Royal Liverpool University Hospital); United States: Karen Allen (University of Oklahoma Medical Center); Grant Bochicchio (Washington University in St. Louis); Richard Carlson (Maricopa Integrated Health System); Stephanie Eaton (Northside Hospital, Inc); Ryan Fink (Duke University Medical Center); Carmine Gianatiempo (Englewood Hospital and Medical Center); Rajat Kapoor (Indiana University Health, Inc, d/b/a Methodist Research Institute); Gary Kinasewitz (University of Oklahoma Medical Center); Firas Koura (Hazard Regional Medical Center); Kenneth Krell (Eastern Idaho Medical Consultants); Niels Martin (Hospital of the University Of Pennsylvania); Santosh Nepal (Rapid City Regional Hospital); Stephen M Pastores (Memorial Sloan Kettering Cancer Center); Ithan Peltan (Intermountain Medical Center); John Pullman (St James Healthcare); Allan Seibert (Pulmonary Associates of Mobile, PC); Jason Smith (University of Louisville Hospital); Steven Tennenberg (Wayne State University School of Medicine, Detroit Receiving Hospital, Sinai-Grace Hospital); Andrew Wilhelm (University of MS Medical Center); Brian Zeno (Riverside Methodist Hospital); Pam Allton (Clinical Operation, Asahi-Kasei Pharma America); David Carruthers (Medical Operations, Asahi-Kasei Pharma America); Osamu Matsuki (Scientific Affairs and Program Management, Asahi-Kasei Pharma America); Toshihiko Kayanoki (Scientific Affairs and Program Management, Asahi-Kasei Pharma America). Publisher Copyright: {\textcopyright} 2019 American Medical Association. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = may,

day = "28",

doi = "https://doi.org/10.1001/jama.2019.5358",

language = "English",

volume = "321",

pages = "1993--2002",

journal = "JAMA",

issn = "0098-7484",

publisher = "American Medical Association",

number = "20",

}

Vincent, J-L, Francois, B, Zabolotskikh, I, Daga, MK, Lascarrou, J-B, Kirov, MY, Pettila, V, Wittebole, X, Meziani, F, Mercier, E, Lobo, SM, Barie, PS, Crowther, M, Esmon, CT, Fareed, J, Gando, S, Gorelick, KJ, Levi, M, Mira, J-P, Opal, SM, Parrillo, J, Russell, JA, Saito, H, Tsuruta, K, Sakai, T, Fineberg, D, Bertuzzi, R, Bellomo, R, Chapman, M, Ernest, D, Fletcher, J, French, C, Gowardman, J, Shehabi, Y, Venkatesh, B, Walsham, J, Vij, S, Chochrad, D, Creteur, J, Devriendt, J, Dive, A-M, Dugernier, T, Foret, F, Hoste, E, Jorens, P, Simon, M, Spapen, H, Vincent, J-L, Wittebole, X, Dias, F, Freire, A, Lobo, SM, Simeonov, G, Stefanov, C, Aslanian, P, Berthiaume, L, Martin, C, Chittock, D, Dhar, A, Doig, C, Jones, G, Hall, R, Boyd, J, Shin, P, Wood, G, Zarychanski, R, Quinteros, GA, Gasparovic, V, Husedzinovic, I, Balik, M, Burget, I, Dlouhy, P, Pachl, J, Karlsson, S, Laru-Sompa, R, Parviainen, I, Pettila, V, Ruokone, E, Skrifvars, M, Bohe, J, Dellamonica, J, Duguet, A, Durand-Gasselin, J, Fiancette, M, Francois, B, Joannes-Boyau, O, Lascarrou, J-B, Lefrant, J-Y, Mercat, A, Mercier, E, Meziani, F, Nseir, S, Quenot, J-P, Reignier, J, Schwebel, C, Marx, G, Zacharowski, K, Armaganidis, A, Komnos, A, Fejer, C, Appajigol, J, Behera, SK, ChandraShekhar, S, Chowdhury, S, Daga, MK, D'costa, PM, Gupta, HSS, Iyer, S, Khan, ZA, Mehta, M, Murthy, S, Sahu, S, Tewari, R, Bar-Lavie, Y, Bregman, G, Cohen, J, Eden, A, Einav-Bromiker, S, Jakobson, D, Nimrod, A, Beishuizen, A, Gerritsen, R, Pickkers, P, Rozendaal, W, Schoonderbeek, FJ, Spoelstra-de Man, A, van Zanten, ARH, Zijlstra, JG, Freebairn, R, Henderson, S, McArthur, C, Young, P, Mayorga, MJ, Agafina, AS, Bubnova, N, Gritsan, A, Kameneva, E, Katasonov, SP, Khasanova, NM, Kirov, MY, Kruberg, L, Kulabukhov, VV, Lebedinskii, K, Spesivtsev, YA, Zabolotskikh, I, Rankovic, Z, Hong, SB, Kim, M-J, Suh, GY, Yoo, C-G, Raventos, AA, Ferrer, R, Vazquez, RG, Hernandez, M, Piacentini, E, Rodriguez Oviedo, AH, Garcia, MS, Chan, M-C, Cheng, K-C, Yu, C-J, Eddleston, J, Smith, FG, MacNaughton, P, Welters, I, Allen, K, Bochicchio, G, Carlson, R, Eaton, S, Fink, R, Gianatiempo, C, Kapoor, R, Kinasewitz, G, Koura, F, Krell, K, Martin, N, Nepal, S, Pastores, SM, Peltan, I, Pullman, J, Seibert, A, Smith, J, Tennenberg, S, Wilhelm, A, Zeno, B, Allton, P, Carruthers, D, Matsuki, O & Kayanoki, T 2019, 'Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy The SCARLET Randomized Clinical Trial', JAMA, vol. 321, no. 20, pp. 1993-2002. https://doi.org/10.1001/jama.2019.5358

TY - JOUR

T1 - Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy The SCARLET Randomized Clinical Trial

AU - Vincent, Jean-Louis

AU - Francois, Bruno

AU - Zabolotskikh, Igor

AU - Daga, Mradul Kumar

AU - Lascarrou, Jean-Baptiste

AU - Kirov, Mikhail Y.

AU - Pettila, 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, Frederic

AU - Hoste, Eric

AU - Jorens, Philippe

AU - Simon, Marc

AU - Spapen, Herbert

AU - Vincent, Jean-Louis

AU - Wittebole, Xavier

AU - Dias, Fernando

AU - Freire, Antonio

AU - Lobo, Suzana Margarth

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 - Pettila, Ville

AU - Ruokone, Esko

AU - Skrifvars, Markus

AU - Bohe, Julien

AU - Dellamonica, Jean

AU - Duguet, Alexandre

AU - Durand-Gasselin, Jacques

AU - Fiancette, Maud

AU - Francois, Bruno

AU - Joannes-Boyau, Olivier

AU - Lascarrou, Jean-Baptiste

AU - Lefrant, Jean-Yves

AU - Mercat, Alain

AU - Mercier, Emmanuelle

AU - Meziani, Ferhat

AU - Nseir, Saad

AU - Quenot, Jean-Pierre

AU - Reignier, Jean

AU - Schwebel, Carole

AU - Marx, Gernot

AU - Zacharowski, Kai

AU - Armaganidis, Apostolos

AU - Komnos, Apostolos

AU - Fejer, Csaba

AU - Appajigol, Jayaprakash

AU - Behera, Sarat Kumar

AU - ChandraShekhar, Shivprasad

AU - Chowdhury, Sanmay

AU - Daga, Mradul Kumar

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 - van Zanten, Arthur R. H.

AU - Zijlstra, Jan G.

AU - Freebairn, Ross

AU - Henderson, Seton

AU - McArthur, Colin

AU - Young, Paul

AU - Mayorga, Manuel Jesus

AU - Agafina, Alina S.

AU - Bubnova, Natalia

AU - Gritsan, Alexey

AU - Kameneva, Evgenia

AU - Katasonov, Sergey P.

AU - Khasanova, Nina M.

AU - Kirov, Mikhail Y.

AU - Kruberg, Lilly

AU - Kulabukhov, Vladimir V.

AU - Lebedinskii, Konstantin

AU - Spesivtsev, Yuri A.

AU - Zabolotskikh, Igor

AU - Rankovic, Zarko

AU - Hong, Sang Bum

AU - Kim, Min-Ja

AU - Suh, Gee Young

AU - Yoo, Chul-Gyu

AU - Raventos, Antonio Artigas

AU - Ferrer, Ricard

AU - Vazquez, Rita Galeiras

AU - Hernandez, Marianela

AU - Piacentini, Enrique

AU - Rodriguez Oviedo, Alejandro Hugo

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

N1 - Funding Information: Author Affiliations: Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium (Vincent); ICU Department, Inserm CIC-1435 & UMR-1092, CHU Dupuytren, Limoges, France (Francois); Department of Anesthesiology, Intensive Care and Transfusiology, Kuban State Medical University, Krasnodar, Russia (Zabolotskikh); Department of Medicine, Maulana Azad Medical College and associated hospitals, New Delhi, India (Daga); Centre Hospitalier Universitaire de Nantes, Nantes, France (Lascarrou); Department of Anesthesiology and Intensive Care Medicine, Northern State Medical University, Arkhangelsk, Russia (Kirov); Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland (Pettilä); Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium (Wittebole); Faculté de Médecine, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, France (Meziani); Médecine Intensive Réanimation, CHRU de Tours, Tours, France (Mercier); Intensive Care Division, Hospital de Base, São José do Rio Preto, SP, Brazil (Lobo); Departments of Surgery and Medicine, Weill Cornell Medicine, New York, New York (Barie); Department of Medicine, McMaster University and St Joseph’s Hospital, Hamilton, Canada (Crowther); Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma (Esmon); Pathology and Pharmacology, Loyola University Medical Center, Maywood, Illinois (Fareed); Acute and Critical Care Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan (Gando); Zymo Consulting Group LLC, Newtown Square, Massachusetts (Gorelick); Department of Medicine, University College London Hospitals and Cardiometabolic Programme-NIHR UCLH/UCL BRC, London, United Kingdom (Levi); UniversitéParis Descartes, Sorbonne Paris Cité, Faculté de Mé-decine Cochin University Hospital, AP-HP, Paris, France (Mira); Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island (Opal); Department of Medicine, New Jersey Medical School of Rutgers University, Hackenseck (Parrillo); Heart and Vascular Hospital, Hackensack University Medical Center, Hackensack, New Jersey (Parrillo); Department of Medicine, Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada (Russell); National Hospital Organization, Nagoya Medical Center, Nagoya, Japan (Saito); Asahi-Kasei Pharma Corporation, Tokyo, Japan (Tsuruta, Sakai); Asahi-Kasei Pharma America Corporation, Waltham, Massachusetts (Fineberg). Funding Information: (CHU de Dijon, Hopital Bocage Central); Jean Reignier (CHU Hotel Dieu); Carole Schwebel (CH-Hôpital Albert Michallon); Germany: Gernot Marx (University Hospital Aachen; Andreas Meier-Hellmann, Helios Klinikum Erfurt); Kai Zacharowski (Universitätsklinikum Frankfurt); Greece: Apostolos Armaganidis (ATTIKON University General Hospital); Apostolos Komnos (General Hospital of Larissa ''Koutlimpanio & Triantafyllio''); Hungary: Csaba Fejér (Szent Imre Hospital); India: Jayaprakash Appajigol (KLES Dr Prabhakar Kore Hospital & Medical Research Centre); Sarat Kumar Behera (Hi-tech Medical College & Hospital); Shivprasad ChandraShekhar (Mazumdar Shaw Medical Centre); Sanmay Chowdhury (Grant Medical Foundation, Ruby Hall Clinic, Pune); Mradul Kumar Daga (Maulana Azad Medical College and Associated L N Hospital); Pradeep Micheal D'costa (King Edward Memorial Hospital); Hari Shankar Shivkumar Gupta (Care Hospital); Shivakumar Iyer (Bharti Hospital and Research Centre); Zafer A Khan (Noble Hospital); Minesh Mehta (Shalby Hospital); Sudharshan Murthy (JSS Hospital); Sambit Sahu (St Theresa Hospital); Reshma Tewari (Artemis Hospital); Israel: Yaron Bar-Lavie (Rambam Medical Center); Gennady Bregman (Kaplan Medical Center); Jonathan Cohen (Rabin Medical Center); Arie Eden (The Lady Davis Carmel Medical Center); Sharon Einav-Bromiker (Shaare Zedek Medical Center 12 Bayit St Jerusalem); Daniel Jakobson (Barzilai Medical Center); Adi Nimrod (Kaplan Medical Center); The Netherlands: Albertus Beishuizen (Medisch Spectrum Twente); Richard Gerritsen (Medisch Centrum Leeuwarden); Peter Pickkers (UMC St. Radboud); Wim Rozendaal (Jeroen Bosch Ziekenhuis); FJ Schoonderbeek (Ikazia Ziekenhuis); Angelique Spoelstra-de Man (VUMC; Birkitt-Linn ten Tusscher, VUMC); ArthurRHvan Zanten (Ziekenhuis Gelderse Vallei); Jan G. Zijlstra (University Medical Center Groningen); New Zealand: Ross Freebairn (Hawkes Bay Regional Hospital); Seton Henderson (Christchurch Hospital); Colin McArthur (Auckland District Health Board); Paul Young (Wellington District Health Board); Peru: Manuel Jesús Mayorga (Hospital Nacional FAP); Russia: Alina S Agafina (City Hospital); Natalia Bubnova (St George City Hospital); Alexey Gritsan (Krasnoyarsk Regional Clinocal Hospital); Evgenia Kameneva (Regional Clinical Hospital of Emergency Care N.A. M.A. Podgorbunskiy); Sergey P Katasonov (Aleksandrovskaya City Hospital); Nina M Khasanova (Arkhangelsk Regional Clinical Hospital affiliated with Northern State Medical University); Mikhail Y Kirov (City Clinical Hospita n.a. E.E.Volosevich); Lilly Kruberg (City Hospital No 4); Vladimir V Kulabukhov (Vishnevsky Institute of Surgery); Konstantin Lebedinskii (Mechnikov North West State Medical University); Yuri A Spesivtsev (Mariinskaya City Hospital); Igor Zabolotskikh (Kuban State Medical University, Site Facility: Krasnodar Territorial Hospital # 2); Serbia: Zarko Rankovic (Clinical Center Nis); South Korea: Sang Bum Hong (Asan Medical Center); Min-Ja Kim (Korea University Anam Hospital); Gee Young Suh (Samsung Medical Center); Chul-Gyu Yoo (Seoul National University Hospital); Spain: Antonio Artigas Raventós (Hospital de Sabadell); Ricard Ferrer (Hospital Universitario Vall de Hebron); Rita Galeiras Vázquez (Complexo Hospitalario Universitario A Coruña); Marianela Hernandez (Hospital de Txagorritxu); Enrique Piacentini (Hospital Universitario Mutua Terrassa Intensive Care); Alejandro Hugo Rodriguez Oviedo (Hospital Universitari de Tarragona Joan XXIII); Miguel Sanchez Garcia (Hospital Clínico San Carlos); Taiwan: Ming-Cheng Chan (Taichung Veterans General Hospital); Kuo-Chen Cheng (Chi Mei Medical Center Yong Kang); Chong-Jen Yu (National Taiwan University Hospital); United Kingdom: Jane Eddleston (Manchester Royal Infirmary); Fang Gao Smith (Birmingham Heartlands Hospital); Peter MacNaughton (Derriford Hospital); Ingeborg Welters (Royal Liverpool University Hospital); United States: Karen Allen (University of Oklahoma Medical Center); Grant Bochicchio (Washington University in St. Louis); Richard Carlson (Maricopa Integrated Health System); Stephanie Eaton (Northside Hospital, Inc); Ryan Fink (Duke University Medical Center); Carmine Gianatiempo (Englewood Hospital and Medical Center); Rajat Kapoor (Indiana University Health, Inc, d/b/a Methodist Research Institute); Gary Kinasewitz (University of Oklahoma Medical Center); Firas Koura (Hazard Regional Medical Center); Kenneth Krell (Eastern Idaho Medical Consultants); Niels Martin (Hospital of the University Of Pennsylvania); Santosh Nepal (Rapid City Regional Hospital); Stephen M Pastores (Memorial Sloan Kettering Cancer Center); Ithan Peltan (Intermountain Medical Center); John Pullman (St James Healthcare); Allan Seibert (Pulmonary Associates of Mobile, PC); Jason Smith (University of Louisville Hospital); Steven Tennenberg (Wayne State University School of Medicine, Detroit Receiving Hospital, Sinai-Grace Hospital); Andrew Wilhelm (University of MS Medical Center); Brian Zeno (Riverside Methodist Hospital); Pam Allton (Clinical Operation, Asahi-Kasei Pharma America); David Carruthers (Medical Operations, Asahi-Kasei Pharma America); Osamu Matsuki (Scientific Affairs and Program Management, Asahi-Kasei Pharma America); Toshihiko Kayanoki (Scientific Affairs and Program Management, Asahi-Kasei Pharma America). Publisher Copyright: © 2019 American Medical Association. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., 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 × 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.

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 × 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.

UR - http://www.scopus.com/inward/record.url?scp=85065820427&partnerID=8YFLogxK

U2 - https://doi.org/10.1001/jama.2019.5358

DO - https://doi.org/10.1001/jama.2019.5358

M3 - Article

C2 - 31104069

SN - 0098-7484

VL - 321

SP - 1993

EP - 2002

JO - JAMA

JF - JAMA

IS - 20

ER -

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

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