Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial

The ITACTIC trial was a pragmatic, multi-centre, randomized controlled trial involving injured patients who were suspected of having haemorrhage and who required at least one RBC transfusion. The trial compared outcomes in patients who received an empiric MHP supplemented by haemostatic therapy guided by either CCTs (CCT group) or by VHAs (VHA group). The trial was registered at ClinicalTrials.gov (NCT02593877, Nov 1st, 2015) and the protocol (Supplementary Materials) has previously been published [22].

Participating centres were members of the International Trauma Research Network (www.​intrn.​org) and were chosen on the basis of their ability to deliver the study design, expected enrolment rates, and the use of a standard empiric major haemorrhage protocol conforming to relevant national guidance and including balanced blood component therapy and empiric use of tranexamic acid. The trial was conducted at seven major trauma centres in Europe (Rigshospitalet (Copenhagen, Denmark), Amsterdam University Medical Centre (Amsterdam, The Netherlands), Oslo University Hospital (Oslo, Norway), Kliniken der Stadt Köln gGmbH (Cologne, Germany), The Royal London Hospital (London, UK), John Radcliffe Hospital (Oxford, UK) and Nottingham University Hospitals, Queens Medical Centre (Nottingham, UK)). The VHA device used at each study site (Thromboelastography—TEG 6S Haemostasis Analyzer, Haemonetics® Corporation, or Rotational Thromboelastometry—ROTEM® Sigma, TEM Innovations GmbH) was determined by existing familiarity with a specific device appliance and to ensure a balanced use of the devices across the study.

The trial was designed by the authors, and the design was approved by the trial sponsor (Queen Mary University of London) and the national research ethics committees of participating institutions. Clinical trial oversight, monitoring and data management were conducted by the clinical studies unit of the Centre for Trauma Sciences, Queen Mary University of London. An independent Data Monitoring Committee and a Trial Steering Committee provided oversight of trial activities.

Adult trauma patients were enrolled if they presented with clinical signs of bleeding activating the local MHP and if RBC transfusion had been initiated. Participants had to be randomized within 3 h of injury and maximum of 1 h after admission to the emergency department. There were no additional exclusion criteria.

Consent for initial enrolment in the trial was provided on behalf of incapacitated patients by a nominated consultee, usually an independent clinician in charge of patient care. Subsequent consent was given by a personal consultee (e.g. a family member) when identified and able to go through the informed consent process. Individual informed consent was subsequently obtained if the patient regained the physical and mental capacity to provide such consent. If the patient died or was otherwise unable to give consent, previous nominated professional or personal consultee consent remained in effect. Patients who subsequently withdrew their consent were removed from the trial.

Enrolled patients were randomized in a 1:1 ratio to the VHA or the CCT groups, with block randomization by the centre. Randomization codes were generated and secured by an independent statistician. Block size was unknown to on-site study teams. Group allocation was by study personnel opening the numbered opaque sealed envelope in sequence taken from a stack held by each study site. Once an envelope had been opened, the subject was considered enrolled. The trial was un-blinded to the treating clinical teams, while research personnel collecting subsequent safety and outcome data were blinded to group allocation.

All patients received their local hospital’s standard MHP, based on the empiric delivery of tranexamic acid; blood components delivered in a 1:1:1 ratio of RBCs, plasma and platelet transfusions; and limited infusion of crystalloid fluids. In both groups, blood was drawn for coagulation analysis at baseline and after every four units of RBCs transfused, until haemostasis. In the CCT group, these were the conventional coagulation tests performed in the laboratory, while in the VHA assays, analyses were performed at the point of care. Haemostatic therapy was delivered based on results of these according to the TACTIC algorithms [21], which define triggers for additional administration of platelet, fibrinogen, plasma and antifibrinolytic therapies.

The time of haemostasis was defined as 1 h after the last RBC transfusion was given and the treating clinicians stated haemostasis had been achieved. Massive transfusion was defined as the administration of ten or more units of RBCs in the first 24 h after injury. Severe traumatic brain injury (TBI) was defined as an Abbreviated Injury Scale score in the brain of four, five, or six [23]. We used an anatomical head injury score rather than an assessment of admission level of consciousness as the latter is affected by the depth of shock in this group of patients. We used prothrombin time ratio (PTr) as a test of coagulation available in both arms of the trial [24] and defined PTr > 1.2 as abnormal. For reporting blood component therapy across study centres, one pool of cryoprecipitate was considered equivalent to two grams of fibrinogen concentrates (or fibrinogen equivalent dose in grams); and platelet concentrates are reported as administered in pooled components (one pool = four individual platelet units).

The primary outcome of this study was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion. Secondary endpoints included: all-cause mortality at 6 h, 24 h, 28 days, and 90 days post-admission; total blood components; 28-day ventilator-free, and intensive care unit (ICU)-free days; total hospital length-of-stay; and the proportion of patients with symptomatic thromboembolic events, with multiple organ dysfunction, and with serious adverse events.

The planned sample size for this study was 392, 196 in each study arm. Prior data from the study centres estimated that approximately 28% of patients die or receive a massive transfusion by 24 h. Based on an estimated reduction in this proportion to 15% in the VHA group, and with a significance level of 0.05 using a two-sided test, 170 patients per group were required to achieve 80% power, increasing to 196 per group to account for a predicted drop-out rate of 15%.

All primary and secondary outcomes were analysed as intention-to-treat and per-protocol. The per-protocol group was defined excluding patients who did not have at least one VHA or CCT test performed, who did not meet the inclusion criteria, who received the wrong test, who died within 60 min after baseline blood sampling or who achieved haemostasis within 60 min of baseline sampling.

The primary endpoint was assessed by logistic regression to produce an odds ratio with 95% confidence interval. Mortality was compared between the two arms as a binary outcome by logistic regression and using Kaplan–Meier methods and the log-rank test. Time to haemostasis, 28-day ventilator-free and ICU-free days, total hospital length-of-stay, EQ-5D quality-of-life scores, total number of blood products transfused, numbers receiving study intervention (post-hoc analysis) and time to intervention (post-hoc analysis) were compared using the Wilcoxon–Mann–Whitney or Chi-square tests. Missing data for the primary outcome were not expected. For secondary outcomes, data were assumed to be missing at random, therefore participants with missing data for a measure were excluded from any statistical comparisons regarding that measure. Denominators for analyses are presented throughout.

Pre-specified subgroups of interest were patients with and without severe TBI (defined as having an injury to the head of Abbreviated Injury Scale score of 4 or more); patients with a prolonged PTr at baseline; patients receiving a massive transfusion; and patients on prior oral anticoagulant therapies. Stratification within subgroups was not possible as laboratory and imaging results were not available at the time of randomization and enrolment. The pre-defined subgroups were analysed by intention-to-treat for the primary outcome (except for the patients receiving a massive transfusion as not applicable) and some secondary outcomes (post-hoc analyses), such as 28-day mortality, total number of blood products, numbers receiving study intervention and time to intervention. As a comparison with the opposite subgroup, patients without a prolonged PTr were also analysed (post-hoc analysis). Interaction p-values were calculated (post-hoc analysis) to inspect the effect of each subgroup on the outcome of interest. The primary endpoint and 28-day mortality analyses for the severe TBI subgroup were also performed adding covariates to the logistic regressions to adjust for any risk differences between study arms at baseline (post-hoc analysis). Statistical analyses were performed using Stata version 13. All applied tests were two-sided and p-values of less than 0.05 were considered statistically significant. A pre-defined interim analysis was performed after the enrolment of 100 patients and the Data Monitoring Committee reviewed all data on outcomes for every 50 patients enrolled. The statistical analyses plan is presented in the Supplementary Materials.