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December 2016

Trauma is the world’s 4th leading cause of death and the number one cause of lost life years. The burden of disease is highest in children and young adults, with half of all trauma deaths being related to blood loss. Furthermore, one in four severely injured and shocked patients develop a clotting dysfunction (i.e. trauma-induced coagulopathy; TIC) within minutes of injury that exacerbates on-going blood loss and makes surgical repair very difficult. European research for the global enhancement of trauma care, and specifically bleeding coagulopathic patients, needs to be coordinated, conducted and translated into clinical practice and policy and the TACTIC project addresses this pivotal challenge.

The TACTIC project final results will transform trauma management and research internationally. Firstly, a unique European research infrastructure encompassing leading trauma centres in 5 European countries is established with a validated online data registry (Partner 5) and biobank (Partner 1). This will enable future research possibilities in the European trauma population and will also attract new European trauma sites to the existing network. Furthermore, for the first time it will become possible to analyse in detail the molecular biomarkers of TIC and to couple this to results from functional viscoelastical haemostatic assays. Consequently, we have already developed novel haemostatic resuscitation algorithms (WP4-WP6) that will be evaluated in the first randomized clinical trial (RCT) addressing this topic (WP8).

The main objectives are in work package one (WP1) to ensure the timely and complete delivery of the TACTIC program, according to legal and ethical requirements, as well as those of the FP7 Health program.  In WP2 the main objectives are to establish and maintain a sustainable infrastructure to ensure the standardized collection, consolidation, and distribution of the Consortium’s clinical samples and associated trauma patient data. In WP3 the overall aim is to compare trauma patient coagulation, outcomes and costs in response to different existing transfusion strategies and in WP4 to determine trauma patient biomarker profiles of coagulation, endothelial damage and shock. In WP5 we should define Viscoelastic Haemostatic Assay (VHA) diagnostic criteria of ‘normal’ and ‘coagulopathic’ patients and also map biomarker signatures to the VHA profiles. In WP6 the objectives are to define the functional and molecular changes due to the existing therapy, and to deliver patient-matched treatment algorithms to be used in WP8. WP7 should determine barriers to the acceptance of VHA by trauma clinicians to develop a “trauma” display. WP8 should conduct a clinical trial comparing the effect of VHA treatment algorithm versus local empiric treatment on patient outcome. WP9 should disseminate information and results generated within the project to relevant parties.

The management of TACTIC (WP1) is coordinated by Partner 1 who has efficiently administered this task including implementing an organizational structure encompassing a project steering committee, executive committee and a management steering group. Project steering group meetings are organized every six months and chaired by WP1. The coordinator advises and supports the other Partners in all aspects concerning fulfilling the administrative requirements of the TACTIC project.

In WP2 we have designed and implemented a centralised project Biobank (Partner 1 in Copenhagen) and a tissue-linked study patient Registry (Partner 5 in London) that enable the robust collection, transfer, storage and analysis of both pre‐existing locally‐housed trauma patients’ materials and prospective TACTIC study materials. The biobank and the registry now successfully underpin work on the TACTIC project at multiple sites, and will continue to be updated and developed to provide maximum support to and benefit for all consortium partners

WP3 focused on the comparison of existing clinical management strategies regarding trauma haemorrhage across the six project participating European Level 1 trauma centres. Results are available in the publication “Diversity in clinical management and protocols for the treatment of major bleeding trauma patients across European level I Trauma Centres” by Schäfer et al. Costs of the current local treatment were calculated for each study site considering in-hospital resource use items such as blood products, surgical interventions, days spent on ICH, overall in-hospital and on ventilation, medications. To allow a comparison between the six centres, patients were sub-grouped with respect to their risk for massive transfusion and their survival probability by using self-developed and validated stratification scores. Additionally, a health economic model was developed to assess the costs and effects of the two treatment algorithms of the TACTIC-embedded clinical trial iTACTIC (WP8), which also includes patients’ outcomes. For this, quality of life questionnaires were designed by WP3 partners accordingly.

In WP4 more than 4,000 blood samples from ~1,600 trauma patients admitted to Trauma Centers at six different Partner sites were analysed and statistically investigated. Partner 5 measured 25 biomarkers of bleeding coagulopathy and Partner 1 measured 6 biomarkers of vasculopathic coagulopathy. Partner 5 has used cluster analysis to analyse data and has identified several potentially different patterns of the coagulation system in trauma patients.  Specifically in period 2, Partner 5 has been working on dimensionality reduction and has successfully reduced the number of identified clusters. Half of these are found to be associated with coagulopathy. Furthermore, the underlying patterns of coagulation proteins and admission injury characteristics and physiology are being used by Partner 5 to determine putative mechanisms for each coagulopathy for future investigation. The final step will be to match these to diagnostic criteria using the viscoelastic devices which Partner 5 is currently working on. Data are currently being collated for preparation into manuscripts. Partner 1 initiated preliminary analysis of the endothelial biomarkers measured over time, but due to database issues, Partner 1 is currently awaiting a cleaned dataset to continue the analysis. It is expected that the data analyses will be conducted in the next Reporting Period and reveal critical pathophysiologic traits of the different types of coagulopathy.

In WP5 data has been analysed on 2287 prospectively followed trauma patients in the TACTIC database and it was managed to define coagulopathy on both ROTEM and TEG profiles, in terms of relationship to admission INR.  We have also assessed performance of the devices in the identification of hypofibrinogenaemia, hyperfibrinolysis and thrombocytopenia, and identified thresholds for each of these.  These have been incorporated into new algorithms for ROTEM, TEG and conventional coagulation tests.  This constitutes one of the main outputs of the TACTIC programme. A paper describing the performance of both devices (ROTEM® and TEG®) and including the resulting algorithms will be submitted to peer review journal shortly. The algorithms are utilized in the ongoing RCT (WP8). Furthermore, we have worked on refining the published „TASH“-Score (Maegele et al., Vox Sang 2011) developed to predict the need for massive transfusion (MT).  In order to increase its clinical applicability we have reduced the number of variables from seven to three and including, for the first time, a functional parameter of coagulation, e.g. the ROTEMÒ variable FIBTEM, which indicates fibrin polymerisation. The novel score, termed „TASH-neo“-Score, was developed based upon 349 datasets from trauma patients, yielding an AUCROC of 0.920, which was superior to the conventional „TASH“-Score. The current and ongoing work aims to increase the predictive power of the newly introduced „TASH-neo“-Score.

WP6 has described results of viscoelastic values in response to transfusion therapy in the first periodic report. WP6 collaborates with WP5 on the above mentioned paper on treatment algorithms. Another aim of this WP was to personalize treatment, results were stratified according to age, the presence of shock or the presence of traumatic brain injury (TBI). Differential responses of viscoelastic values to treatment was identified within these subgroups, which can be summarized as follows:

-          Administration of a high ratio of platelets to red blood cells  has a more profound effect on improving deranged ROTEM values of clot formation than high ratio of plasma to red blood cells

-          Patients with traumatic brain injury show a greater response to platelets and fibrinogen in terms of correction of deranged ROTEM values of coagulopathy when compared to other patient populations. 

-          Patients with shock show a greater response to tranexamic acid in terms of correction of deranged ROTEM values of coagulopathy when compared to patients without shock

-          It was not feasible to study the effect of dose, which would enable recommendations of the use of different doses in specific patient populations.

For TEG, data did not allow for stratification according to patient group, as there were insufficient data. The paper on personalized treatment is also being edited by the group. The paper on the control arm is accepted for publication.

In WP7 we have made various improvements to the app interface in the light of user feedback and the more complex logical expression required by the revised iTACTIC algorithm. Progress has also been made interfacing the application to the new ROTEM Sigma, and we have had enthusiastic support from TEM in this activity. Finally, a ‘gamification’ of the app is being developed to enable both evaluation of the app outside the operating room and future training with the app. Development of the app is continuing, and is on track to provide a solution that will greatly assist clinicians in the rapid and successful identification and management of coagulopathic bleeding.

The RCT iTACTIC (WP8) aims at comparing resuscitation of massively bleeding trauma patients monitored by Viscoelastic Haemostatic Assays (VHAs) versus conventional coagulation tests (CCTs). iTACTIC is one of the main goals of the TACTIC project, and is the first RCT to apply algorithms developed based on a large cohort of trauma patients (WP5) in the attempt to optimize resuscitation of critically ill trauma patients.  As the trial is aiming at improving the treatment of Trauma Induced Coaguloptahy (TIC), the primary endpoint is the proportion of subjects alive and free of massive transfusion at 24 hours. Secondary endpoints include other relevant outcome measures. Both study arms (VHA and CCT) are based on optimal empiric resuscitation based on a MTP aiming at a ratio of 1:1:1 of blood components (RBC 1 : plasma 1 : platelets 1) in addition to Tranexamic Acid (TXA). The Intervention arm applies VHA-guiding of further resuscitation with blood products, procoagulant factors and antifibrinolytics. In the Control arm, CCTs are used to guide further resuscitation with blood products and procoagulant factors. All final approvals for the RCT were in place on 31st May 2016, and enrolment into the RCT started on 1st June 2016. As of 31st October 2016 a total of 88 participants have been enrolled, with a safety analysis of the first 50 enrolled patients currently being performed by an independent DSMB. Due to a delayed trial start we will not hit our goal recruitment number on time and thus have invited 4 new clinical sites to participate in iTACTIC.

WP9 focuses on the dissemination of information and results generated within the project, to fundamental and clinical scientific colleagues, to the media (e.g. popular scientific and lay press, TV, radio), to the key stakeholders on health policy and decision making levels and to other interested parties. In this reporting period the TACTIC research exchange program was successfully continued, with 2 placements in London and Copenhagen. Due to this program young researchers increased their experience in clinical research. These exchanges also promote the exchange of knowledge and ideas between EC centres. Several publications from the TACTIC group were accepted by high ranking peer-reviewed scientific journals. In addition, attention was given to the TACTIC project at various national meetings in and outside the partners’ hospitals, as well as at international trauma courses and conferences. This has facilitated our aim of reaching out to (future) end-users of the knowledge gained in the TACTIC project, with the fundamental aim to save lives from trauma casualties with life threatening bleeding!

 

June 2015

Trauma is the world’s 4th leading cause of death and the number one cause of lost life years. The burden of disease is highest in children and young adults, with half of all trauma deaths being related to blood loss. Furthermore, one in four severely injured and shocked patients develop a clotting dysfunction (i.e. trauma-induced coagulopathy; TIC) within minutes of injury that exacerbates on-going blood loss and makes surgical repair very difficult. European research for the global enhancement of trauma care, and specifically bleeding coagulopathic patients, needs to be coordinated, conducted and translated into clinical practice and policy and the TACTIC project addresses this pivotal challenge.

The TACTIC project final results will transform trauma management and research internationally. Firstly, a unique European research infrastructure encompassing leading trauma centres in 6 European countries is established with a validated online data registry (Partner 5) and biobank (Partner 1). This will enable future research possibilities in the European trauma population and will also attract new European trauma sites to the existing network. Furthermore, for the first time it will become possible to analyse in detail the molecular biomarkers of TIC and to couple this to results from functional viscoelastical haemostatic assays. Consequently, we have already developed novel haemostatic resuscitation algorithms (WP4-WP6) that will be evaluated in the first randomized clinical trial (RCT) addressing this topic (WP8). Already, we have extremely detailed data at the biomarker level that are linked to patient management and outcome and we are currently developing several important scientific manuscripts addressing TIC and its management soon to be published in open access journals to the scientific community. Also, importantly, we have calculated the health-economic costs, at the different partner sites, of the existing therapies. Thus, together with similar data from the RCT also the economic consequence of novel resuscitation strategies will be provided at an individual, hospital and societal level to inform both clinicians and health policy developers (WP3). Also, in WP7 we focus on improving the clinical utility of using existing VHA by developing a novel software especially designed for trauma patients in collaboration with our commercial partners Haemonetics Corp. and TEM. This has resulted in a prototype that will be tested among the partners and further developed using data from the RCT and this will be an important tool for effective international implementation of best practice guidelines that will be the result of the TACTIC project.

The main objectives for the first reporting period (01.11.2013 - 30.04.2015) were in work package one (WP1) to ensure the timely and complete delivery of the TACTIC program, according to legal and ethical requirements, as well as those of the FP7 Health program.  In WP2 the main objectives were to establish a sustainable infrastructure to ensure the standardized collection, consolidation, and distribution of the Consortium’s clinical samples and associated trauma patient data. In WP3 the overall aim was to compare trauma patient coagulation, outcomes and costs in response to different existing transfusion strategies and in WP4 to determine trauma patient biomarker profiles of coagulation, endothelial damage and shock. In WP5 we should define Viscoelastic Haemostatic Assay (VHA) diagnostic criteria of ‘normal’ and ‘coagulopathic’ patients and also map biomarker signatures to the VHA profiles. In WP6 the objectives were to define the functional and molecular changes due to the existing therapy, and to deliver patient-matched treatment algorithms to be used in WP8. WP7 should determine barriers to the acceptance of VHA by trauma clinicians to develop a “trauma” display. WP8 should the set-up a clinical trial comparing the effect of VHA treatment algorithm versus local empiric treatment on patient outcome. WP9 should disseminate information and results generated within the project to relevant parties.  

 

TACTIC workflow between and from the work packages

 


 

The management of TACTIC (WP1) is coordinated by Partner 1 who has efficiently administered this task including implementing an organizational structure encompassing a project steering committee, executive committee and a management steering group. Kick-off meeting in Brussels was organized as well as project steering group meetings in Frankfurt and London 2014, two scientific meetings in Copenhagen & London and a project meeting in Amsterdam in May 2015. The coordinator advises and supports the other Partners in all aspects concerning fulfilling the administrative requirements of the TACTIC project.                                                                                                                                           

WP2 has established centralised resources for the consolidation of data from over 3,300 international study patients, and over 5,300 subject-linked tissue samples from this cohort. The TACTIC research Database (London) and Biobank (Copenhagen) enables coordinated research that involves the biochemical analysis of patient blood defining key aspects of its molecular composition and of its overall functional clotting state pivotal for other TACTIC WPs. Furthermore, WP2 plays an integral role in the collection, processing, storage and analysis of study patient data and tissues from the randomized clinical trial to be conducted in WP8.

In WP3, site-specific massive transfusion protocols and management practice algorithms were obtained to demonstrate differences in transfusion regimes in regard to the use of pre-hospital blood products and viscoelastic testing for detecting and guiding haemostatic therapies between the Partners. Legacy outcome and resource use data from each partner were synthesised to generate a dataset of 2,172 patients.  These data were analysed for the cohort as a whole and also according to scores for mortality (RISC) and critical bleeding (TASH). The resource use data were used to estimate the costs associated with each Partner’s massive transfusion protocols and practices. To inform the design of the randomized controlled trial relevant patient outcome measures were identified such as transfusion of blood products at specific time points, time spent in coagulopathy, the proportion of coagulopathic patients at 24 hours, change in haemostatic competence and survival, mortality including proportion of patients exsanguinating, and patient health-related quality of life.

 

 

In WP4 more than 4,000 blood samples from ~1,600 trauma patients admitted to Trauma Centers at six different Partner sites were analysed. Partner 5 measured 25 biomarkers of bleeding coagulopathy at baseline and during resuscitation (after 4, 8 and 12 units packed red blood cells (RBC)). Partner 1 measured 6 biomarkers of vasculopathic coagulopathy in blood sampled at baseline, during resuscitation (after 4, 8 and 12U RBC) and after 24 and 72 hours follow-up. Also, Partner 1 purified genomic DNA from 1,812 baseline buffy coat samples. Comprehensive data analysis is underway and the biomarker results are centrally available for WP5 and WP6 to further classify TIC using demographic and clinical data and to further define the molecular changes that occur in response to treatment and their association with outcome. The impact of this is a knowledge platform allows development of improved resuscitation strategies of bleeding trauma patients.

In WP5 the TACTIC project is aiming at describing TIC based on two Viscoelastic Haemostatic Assays, Thrombelastograph (TEG®) and Rotational Thrombelastometry (ROTEM®), in order to define VHA diagnostic criteria of ‘normal’ and ‘coagulopathic’ patients. The identified TIC patient patterns will be characterized according to their linkage with functional coagulation profiles and biomarker signatures, and their association with haemorrhage, transfusion, morbidity, and mortality. The data of 2,287 patients (enrolled 2008-2013) in the TACTIC centralized Trauma Registry from six different Trauma Centres have been analyzed and out of the 2,287 patients analyzed, 1,032 (45%) were severely injured with injury severety score (ISS)>15 and 138 (13%) were hypocoagulable with INR >1.2.

A total of 2,015 patients had complete ROTEM® data sets and the analyses included EXTEM and FIBTEM traces. Regardless if we defined coagulopathy by INR >1.2 or a fibrinogen threshold of 1, 1.5 or 2g/dL, or transfusion requirements above a certain number of red blood cells (RBCs), CA5 and maximal clot firmness (MCF) consistently were the most significant contributors to coagulopathy in the statistical models employed. Similarly a total of 963 patients had complete TEG® data sets and the analyses comprised kaolin TEG®, rapid TEG® and TEG® Functional Fibrinogen. The maximal amplitude (MA) reflecting maximal clot strength value was the variable that most significantly correlated to coagulopathy in the statistical models employed, together with the alpha angle, reflecting clot strength build-up.

We used univariate and multivariate statistical modelling with receiver operating characteristic (ROC) curves in order to define test performance and relevant VHA parameters to include, with their corresponding cut-off values (most sensitive and specific values defined using the Youden Index) in relation to coagulopathy and clinical outcomes. These thresholds are used in the development of the treatment algorithms for the planned RCT – iTACTIC. In parallel to this work a risk stratification score is being developed – TASH neo, a novel prognostic score including a viscoelastic test parameter for prognostication, which will be validated using the TACTIC database.

In WP6 the viscoelastical haemostatic response as evaluated by ROTEM to therapy of patients who have received any transfusion and were alive at 24 hours showed that EXTEM values indicate reversing hypocoagulopathy in patients receiving high ratio of FFP to RBC, whereas EXTEM and FIBTEM values indicate reversing hypocoagulopathy in those receiving low ratio of platelets to RBC. 72 hours after trauma, all ROTEM parameters progressed towards a hypercoagulable state. Similar findings were observed for TEG. The transfusion strategy associated with best outcome (‘correction of INR ≤ 1.2 at 24 hours’, ‘mortality’ or ‘alive after 24 hours and free of massive transfusion’) was determined according to transfusion ratios (RBC:plasma ≤ 1:1 vs RBC:plasma >1:1 and RBC:platelets ≤1:1 vs RBC:platelets >1:1). After multiple imputations, statistical analysis was performed with univariate and multivariate logistic regression models. The final model was adjusted for age, trauma mechanism, ISS, SBP, GCS, Hb, platelet count, INR, fibrinogen, BE, fluids, site, and procedure. This model shows that tranexamic acid reduces mortality and increases the number of patients alive and free from massive transfusion. Analyses for the effect of different ratios of blood products are ongoing.

Also, subgroup analyses stratified for presence of shock, age and need for massive transfusion are ongoing. Regarding the response of biomarkers to transfusion, a high FFP to RBC, and a high platelet to RBC ratio is associated with increased shedding of syndecan-1, VE cadherin, E selectin, all indicators of a stressed endothelium. A low FFP to RBC ratio is associated with reduced fibrinolysis and increased thrombomodulin levels.

WP7 unites the clinical expertise of Partners 1-6 with the industry Partners 7 (Haemonetics Corp.) & 8 (TEM Innovations GmbH) to determine barriers to the acceptance of VHA by trauma clinicians and to develop a bespoke VHA trauma display for both their diagnostic platforms. The overall aim is to facilitate the uptake of VHA in the management of coagulopathic, bleeding trauma patients if proven to be a cost-effective means of treatment. Independent information has been gathered concerning “Code Red” practice (i.e. local trauma team activation and unguided/protocolised delivery of massive transfusion) at Partners 1-6. Applying this knowledge, an initial mock VHA interface has now been developed that enables the fixing of thresholds currently considered relevant to trigger actions in trauma care (e.g. replenishment of depleted coagulation factors). The next round of display mock-up prototypes will be made more realistic and are configurable, in that they can thereby incorporate TACTIC-derived threshold parameters as triggers for the treatment algorithm (WP6). This will enable their use in the randomised controlled trial to assess the benefit of VHA-guided therapy versus current, empiric transfusion using pre-assembled transfusion packs (WP8). In parallel we shall test the trauma VHA interface in the wider (i.e. non-TACTIC) trauma setting to pre-empt barriers to EU-wide deployment should the results of WP8 demonstrate a clear and cost-effective benefit to its use for clinical decision making during the management of coagulopathic, trauma haemorrhage.

In WP8 the trial, implementing TACTIC (iTACTIC) is designed as a randomized controlled trial, with the aim of including 200 bleeding trauma patients per study arm. Haemostatic resuscitation in the active arm based on an optimized Massive Transfusion Protocol (MTP) and Viscoelastic Haemostatic Assays (VHAs) guiding further resuscitation with blood products and procoagulant factors. In the control arm the haemostatic resuscitation also is based on an optimized MTP and conventional coagulation tests (CCTs) to guide further resuscitation with blood products and procoagulant factors.  The primary endpoint of the trial will address survival free of massive transfusion at 24 hours. Secondary endpoints include other relevant outcome measures.

The protocol for the RCT is currently being finalized. The algorithms and optimized MTP are being developed based on WP5 and WP6 results, and the CRF is being adapted to the centralized electronic database. Consent forms and protocols for waiver of consent are being developed. The protocol will shortly be submitted for ethics approval.

In WP9 the TACTIC dissemination plan was presented at the Kick-off meeting in Brussels, Nov 2013. By implementing 1-month (or longer) exchange placements, individuals are able to undertake standardised patient recruitment (e.g. WP8) and specific TACTIC aligned-research at other research centres thereby promoting wider individual experience and the exchange of knowledge and ideas between Partners. In order to formalize the scientific dissemination, a publication and authorship agreement was drafted and signed by all Partners (August 2014). The Partners have actively engaged in publicizing the TACTIC project, its findings to date and its future objectives in the wider context of dissemination at scientific meetings including: 15th Annual NATA Symposium; Porto, April 2014, Traumatic Hemostasis and Oxygenation Research (THOR) Network Symposium; Bergen, June 2014, European Congress Trauma and Emergency Surgery (ECTES); Amsterdam, May 2015.  

 

November 2013

Current treatment of bleeding and coagulopathy is based on empirical “blind” administration of blood products, with large variations in practice between trauma centres. Starting in November 2013, TACTIC will see the INTRN partners continue to work alongside the key industry leads in coagulation diagnostics field to recruit patients across a consortium of trauma centres (in Amsterdam, Cologne, Copenhagen, London, Oslo and Oxford) to:

1. Compare patient coagulation and outcomes in response to different existing transfusion strategies
2. Specify different disease profiles underlying Trauma Induced Coagulopathy
3. Develop personalised strategies for targeted transfusion
4. Compare existing practices with personalised, targeted treatment of Trauma Induced Coagulopathy
5. Deliver guidelines and support for the clinical management of coagulopathic bleeding

 

The Health theme is a major theme of the Cooperation programme of FP7, with the aim to improve the health of European citizens and boost the competitiveness of health-related industries and businesses, as well as address global health issues. Coordinated by Prof. Pär I Johansson of Rigshospitalet in Copenhagen, Denmark, TACTIC will conduct the first multicentre randomised controlled trial against existing, empiric transfusion practice in trauma and resolve barriers to the subsequent continental implementation of patient-matched targeted transfusion policy.

 

Links to press releases:

 

http://rh-intranet.regionh.dk/topmenu/Nyheder/Intranet+nyheder/2013/09/5_9+mio+euro+45+mio+kr+til+forskning+i+bloedningsforstyrrelser+hos+traumepatienter.htm

 

http://www.qmul.ac.uk/media/news/items/smd/116150.html

European Commission
Blod og væv Region Hovedstaden
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The TACTIC project is co-funded by the European Commission under the HEALTH-Contract No. F3-2013-602771
 

Section of Transfusion Medicine Capital Region Blood Bank & Department of Clinical Immunology
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