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JAMA. 2019 May 28;321(20):1993-2002. doi: 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.

Author information

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

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.

PMID:
31104069
PMCID:
PMC6547077
DOI:
10.1001/jama.2019.5358
[Indexed for MEDLINE]
Free PMC Article

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