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Original Investigation
Caring for the Critically Ill Patient
May 19, 2019

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

Author Affiliations
  • 1Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium
  • 2ICU Department, Inserm CIC-1435 & UMR-1092, CHU Dupuytren, Limoges, France
  • 3Department of Anesthesiology, Intensive Care and Transfusiology, Kuban State Medical University, Krasnodar, Russia
  • 4Department of Medicine, Maulana Azad Medical College and associated hospitals, New Delhi, India
  • 5Centre Hospitalier Universitaire de Nantes, Nantes, France
  • 6Department of Anesthesiology and Intensive Care Medicine, Northern State Medical University, Arkhangelsk, Russia
  • 7Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 8Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
  • 9Faculté de Médecine, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, France
  • 10Médecine Intensive Réanimation, CHRU de Tours, Tours, France
  • 11Intensive Care Division, Hospital de Base, São José do Rio Preto, SP, Brazil
  • 12Departments of Surgery and Medicine, Weill Cornell Medicine, New York, New York
  • 13Department of Medicine, McMaster University and St Joseph’s Hospital, Hamilton, Canada
  • 14Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
  • 15Pathology and Pharmacology, Loyola University Medical Center, Maywood, Illinois
  • 16Acute and Critical Care Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
  • 17Zymo Consulting Group LLC, Newtown Square, Massachusetts
  • 18Department of Medicine, University College London Hospitals and Cardiometabolic Programme-NIHR UCLH/UCL BRC, London, United Kingdom
  • 19Universite´Paris Descartes, Sorbonne Paris Cite´, Faculte´ de Me´-decine Cochin University Hospital, AP-HP, Paris, France
  • 20Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island
  • 21Department of Medicine, New Jersey Medical School of Rutgers University, Hackenseck
  • 22Heart and Vascular Hospital, Hackensack University Medical Center, Hackensack, New Jersey
  • 23Department of Medicine, Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada
  • 24National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
  • 25Asahi-Kasei Pharma Corporation, Tokyo, Japan
  • 26Asahi-Kasei Pharma America Corporation, Waltham, Massachusetts
JAMA. 2019;321(20):1993-2002. doi:10.1001/jama.2019.5358
Key Points

Question  Does administration of a recombinant human soluble thrombomodulin reduce mortality of critically ill patients with sepsis-associated coagulopathy?

Findings  In this randomized clinical trial that included 800 patients with sepsis-associated coagulopathy, treatment with thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality (26.8% in the thrombomodulin group vs 29.4% in the placebo group).

Meaning  Use of a recombinant human soluble thrombomodulin did not significantly reduce 28-day all-cause mortality in critically ill patients with sepsis-associated coagulopathy.

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 × 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

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