Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality: a cluster-randomized clinical trial (TRIAGE III)

Abstract

Background: Risk stratification of patients in the emergency department can be strengthened using prognostic biomarkers, but the impact on patient prognosis is unknown. The aim of the TRIAGE III trial was to investigate whether the introduction of the prognostic and nonspecific biomarker: soluble urokinase plasminogen activator receptor (suPAR) for risk stratification in the emergency department reduces mortality in acutely admitted patients.

Methods: The TRIAGE III trial was a cluster-randomized interventional trial conducted at emergency departments in the Capitol Region of Denmark. Eligible hospitals were required to have an emergency department with an intake of acute medical and surgical patients and no previous access to suPAR measurement. Three emergency departments were randomized; one withdrew shortly after the trial began. The inclusion period was from January through June of 2016 consisting of twelve cluster-periods of 3-weeks alternating between intervention and control and a subsequent follow-up of ten months. Patients were allocated to the intervention if they arrived in interventional periods, where suPAR measurement was routinely analysed at arrival. In the control periods suPAR measurement was not performed. The main outcome was all-cause mortality 10 months after arrival of the last patient in the inclusion period. Secondary outcomes included 30-day mortality.

Results: The trial enrolled a consecutive cohort of 16,801 acutely admitted patients; all were included in the analyses. The intervention group consisted of 6 cluster periods with 8900 patients and the control group consisted of 6 cluster periods with 7901 patients. After a median follow-up of 362 days, death occurred in 1241 patients (13.9%) in the intervention group and in 1126 patients (14.3%) in the control group. The weighted Cox model found a hazard ratio of 0.97 (95% confidence interval, 0.89 to 1.07; p = 0.57). Analysis of all subgroups and of 30-day all-cause mortality showed similar results.

Conclusions: The TRIAGE III trial found no effect of introducing the nonspecific and prognostic biomarker suPAR in emergency departments on short- or long-term all-cause mortality among acutely admitted patients. Further research is required to evaluate how prognostic biomarkers can be implemented in routine clinical practice.

Trial registration: clinicaltrials.gov, NCT02643459 . Registered 31 December 2015.

Keywords: Emergency department; Prognostic biomarkers; Risk stratification.

Conflict of interest statement

Ethics approval and consent to participate

The trial was approved by the board of directors at each participating hospital and the head of each participating department provided consent. The trial was presented to the Regional Ethics Committee, which decided that no formal approval was needed for this cluster-randomized study and in accordance with Danish law it could be conducted without consent of the patients (ref. no. FSP-15003590). At the start of the trial at least one other hospital performed suPAR analysis as a routine test. All processing of personal data followed national guidelines in accordance with Danish law, and the data access and processing were approved by the Danish Data Protection Agency (ref. no. HGH-2015-042, I-Suite 04087) and by the Danish Patient Safety Authority without explicit consent from the participants (ref. no. 3–3013-1744/1).

Consent for publication

Not applicable.

Competing interests

MS, LJHR, MA, and JM have received funding for travel from ViroGates A/S, Denmark. JE-O is named as an inventor in patents for the use of suPAR as a prognostic biomarker. The patents are owned by Copenhagen University Hospital, Amager and Hvidovre, Denmark, and are licensed to ViroGates A/S. JE-O is co-founder, shareholder, and CSO of ViroGates A/S. The remaining authors have no conflicts of interest to declare.

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Figures

Fig. 1

CONSORT flow diagram of the TRIAGE III trial population of patients acutely admitted. EDs: emergency departments, DNPR: National Patient Registry, LABKA: Electronical laboratory database. Full CONSORT checklist is provided in Additional file 3

Fig. 2

Kaplan-Meier plot displaying survival until end of follow-up. The Kaplan-Meier plot shows survival of patients acutely admitted to two emergency departments stratified by intervention period (measurement of soluble urokinase plasminogen activator receptor, suPAR) and control period (no suPAR measurement). Log-rank test: P = 0.61

Fig. 3

Plot of all Cox regressions from the TRIAGE III trial. Patients acutely admitted to two emergency departments were allocated to intervention (measurement of soluble urokinase plasminogen activator receptor (suPAR)) or control (no suPAR measurement). The red squares indicate point estimates and the black horizontal lines indicate 95% confidence intervals (CIs). The figure shows hazard ratios based on unadjusted weighted Cox regression models with all-cause mortality at the end of follow-up. The primary outcome of all-cause mortality assessed at the end of follow-up and sensitivity analyses (censoring and per-protocol) are included, as are the subgroups, including cluster and age. The unadjusted model with 30-day all-cause mortality as outcome is also included

Fig. 4

The area under the curve for mortality in patients acutely admitted. Comparison of prognostic ability of four biomarkers and age at 2 days, 30 days, 60 days, 90 days, and at the end of follow-up. suPAR vs. CRP, all time points: P < 0.001. suPAR vs. haemoglobin, all time points: P < 0.001. SuPAR vs albumin: 2 days: P = 0.37, suPAR vs. albumin at other time points: P < 0.001. CRP: C-reactive protein, suPAR: soluble urokinase plasminogen activator receptor