The use of viscoelastic haemostatic assays in goal-directing treatment with allogeneic blood products – A systematic review and meta-analysis

Background Management of the critically bleeding patient can be encountered in many medical and surgical settings. Common for these patients is a high risk of dying from exsanguination secondary to developing coagulopathy. The purpose of this meta-analysis was to systematically review and assess randomised controlled trials (RCTs) performed on patients in acute need for blood transfusions due to bleeding to evaluate the effect of viscoelastic haemostatic assay (VHA) guidance on bleeding, transfusion requirements and mortality. Methods PubMed and EMBASE were searched for RCTs that 1) randomised patients into receiving transfusions based on either a VHA-guided (thromboelastography [TEG] or rotational thromboelastometry [ROTEM]) algorithm (intervention group) or at the clinician’s discretion and/or based on conventional coagulation tests (control group) and 2) adequately reported on the outcomes bleeding and/or transfusions and/or mortality. Data on bleeding, transfusions and mortality were extracted from each trial and included in a meta-analysis. Results Fifteen RCTs (n = 1238 patients) were included. Nine trials referred to cardiothoracic patients, one to liver transplantation, one to surgical excision of burn wounds and one to trauma. One trial was conducted with cirrhotic patients, one with patients undergoing scoliosis surgery while one trial randomised treatment in post-partum females presenting with bleeding. The amount of transfused red blood cells (RBCs), fresh frozen plasma (FFP) and bleeding volume was found to be significantly reduced in the VHA-guided groups, whereas no significant difference was found for platelet transfusion requirements or mortality.


Background
Haemorrhage remains a major cause of potentially preventable deaths worldwide. Trauma and massive transfusion is associated with coagulopathy secondary to tissue injury, hypoperfusion, dilution and consumption of clotting factors and platelets [1][2][3][4][5][6][7][8][9]. Patients undergoing cardiac surgery accompanied by cardiopulmonary bypass (CPB) stand a high risk of dying due to microvascular bleeding and 11% have excessive bleeding after CPBin most cases found to be nonsurgical [10,11]. The non-surgical bleeding risk in these patients originates in coagulopathy arisen from distortion of the haemostatic system [12,13]. Concepts of damage control surgery in trauma have evolved, prioritizing early control of the cause of bleeding by non-definitive means, while haemostatic resuscitation seeks early control of coagulopathy [14,15]. Haemostatic resuscitation provides transfusions with fresh frozen plasma (FFP) and platelets in addition to red blood cells (RBCs) in an immediate and sustained manner as part of the transfusion protocol for critically bleeding patients. Transfusion of RBCs, FFP and platelets in a similar proportion as in whole blood prevents both hypovolemia and coagulopathy [16,17]. Although an early and effective reversal of coagulopathy is documented [16,18], the most effective means of preventing coagulopathy of massive transfusion remains debated. Results from recent before-and-after studies in massively bleeding patients and one randomised clinical trial (RCT) indicate that trauma exsanguination protocols involving the early administration of plasma and platelets are associated with improved survival [19][20][21][22]. Furthermore, viscoelastic haemostatic assays (VHAs), such as thrombelastography (TEG)/rotational thromboelastometry (ROTEM), appear advantageous for identifying coagulopathy in patients with severe haemorrhage, as opposed to conventional coagulation tests (CCTs) [23][24][25]. Current views recommend that patients with uncontrolled bleeding, regardless of its cause, should be treated with goal-directed haemostatic resuscitation involving the early administration of plasma and platelets and the use of VHAs should be considered. The aim of goal-directed therapy should be to maintain a normal haemostatic competence until surgical haemostasis is achieved, as this appears to be associated with reduced mortality [4,6,12,20].
The aim of the present study was to perform a systematic review and meta-analysis of all published RCTs comparing the effect of VHAs versus CCTs on blood loss, transfusion requirements and mortality.

Materials and methods
An electronic search was conducted by one of the authors (MF) in the PubMed and EMBASE database using the following search strategy: (Thrombelastography OR Thromb?elastograph* OR thromboelastograph OR ROTEM OR TEG OR ROTEG OR Thromboelastometry OR (algorithm AND bleeding)) AND ((randomized controlled trial OR controlled clinical trial) OR (randomized OR placebo OR trial)), to identify all RCTs done on bleeding patients using treatment algorithms based on results from either TEG or ROTEM. The search identified 1245 references in PubMed and 1835 references in EMBASE. 222 duplicate findings were discarded, leaving a total of 2858 references for further assessment. References were assessed by one of the authors (MF) and discussed and consensus reached with all authors in doubt cases. Only published RCTs were eligible for this analysis. Inclusion criteria were 1) trial designs in which patients were randomly allocated to receive transfusions based on either a VHA-guided (TEG or ROTEM) algorithm (intervention group) or at the clinician's discretion and/or based on laboratory coagulation tests (control group) and 2) references had to adequately report the outcomes bleeding and/or transfusions and/or mortality. Studies written in other languages than English were also eligible for inclusion. Trials were excluded immediately based on title or abstract, if they did not meet the inclusion criteria. Moreover, trials that were not performed on humans and paediatric studies were also excluded. The remaining studies were evaluated and assessed for relevance by all authors. Reference lists of the included studies were searched for subsequent relevant studies not identified by search engines. Corresponding authors were contacted to retrieve inadequately reported or missing data. Primary outcomes for data extraction were all-cause mortality, total amount of bleeding expressed either as bleeding at 12 h, 24 h or perioperative amount of bleeding and amount of total RBC transfusions, FFP transfusions and platelet transfusions. When amount of blood transfusions was given in mL, calculations of the corresponding number of units were done using the conversion factors illustrated in table 1. The volume per unit was an estimate of the standard volume of the given allogeneic blood product over the last years in the Capital Region Blood Bank, Rigshospitalet, Copenhagen. The latest follow up data on mortality were used in the analysis of all-cause mortality.

Statistics
Statistical meta-analyses were conducted using Review Manager (RevMan) Version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Pooled estimates and their 95% confidence intervals (CI) were calculated using the inverse variance method. The randomeffects model was used in anticipation of significant heterogeneity [26]. Statistical heterogeneity was explored using the inconsistency (I 2 ) measure [27]. For all calculations, two-tailed P values of less than 0.05 were considered statistically significant.

Meta-analyses
All-cause mortality Six trials were included in the meta-analysis of all-cause mortality with a total of 579 patients of whom 291 patients were allocated to the intervention. Three trials concerned patients undergoing cardiothoracic surgery [28,30,34] one trial concerned orthotopic liver transplantation [37], one studied cirrhotic liver patients [39] and one studied trauma patients [22]. The meta-analysis demonstrated no difference in survival between the groups with an OR of 0.60 (95% CI 0.34 to 1.07; p = 0.08) (figure 2a).

Discussion
We found the total bleeding volume and the amount of transfused RBCs and FFP to be significantly reduced in the VHA-guided intervention groups compared to CCTguided control groups. Considering that most trials used the same transfusion trigger for RBCs in both groups, the difference in RBC requirements may be explained by a better haemostatic competence in TEG/ROTEM-guided groups accomplished through timely administration of plasma and platelets, further supported by the reduction of bleeding in the VHA-guided group of patients. In our meta-analysis no statistically significant difference was found between groups regarding all cause-mortality and required amounts of platelets. The sizes of the respective trial populations were small and a lack of cohesion in permission of platelet inhibitors, anticoagulants, antifibrinolytics and triggers used to guide resuscitation with blood products was observed. The control groups were managed either by clinical judgement combined with CCTs or by the sole use of algorithms applying only CCT-triggers for transfusion. The decision to transfuse potentially encompasses a bias to a greater number of transfusions between clinicians with a different background and clinical practice, in alignment with Avidan et al. [29] finding a reduction in transfusions administered with CTT-algorithm     guided perioperative management versus transfusion guidance based only on the physician's discretion. Although only a difference in amount of FFP and no statistical difference in the amount of platelets transfused between groups was detected, the timing of these transfusions may differ with VHA-analyses having shorter turn-around time than conventional coagulation tests [43]. This accentuates the importance of early administration of the appropriate blood products as also emphasized by Cotton et al. [20] who found reduced odds of mortality (74%) and transfusions in a group of trauma patients managed with early and aggressive resuscitation on admittance to the emergency department. Although 24-h transfusion requirements were reduced in patients treated according to the exsanguination protocol, amounts of intraoperative transfusions were found to be larger in this cohort in comparison with the conventionally treated controls, illustrating the importance of early resuscitation with blood products. Also Johansson et al. [21] found similar results in patients undergoing surgery for ruptured abdominal aortic aneurysm (rAAA) with a proactive intraoperative administration of platelets and FFP yielding an increase in survival in massively bleeding rAAA patients. They found a significant reduction in postoperative transfusions, indicating that early blood product administration plays a pivotal role in improving haemostasis in massive bleeders. Gonzalez et al. [22] have conducted the first RCT to evaluate VHA-guided transfusion therapy in trauma. They found a survival benefit in the TEG-guided group especially with regards to less haemorrhagic and early deaths. Additionally, they argued that the administration of more platelets and FFP does not necessarily increase survival chances but highlight the  effect of the appropriate treatment being given at the optimal time rather than the amount of blood product administered. Moreover, in patients undergoing surgery with extracorporeal circulation, the use of TEG/ROTEM heparinase analyses, where coagulopathy can be identified despite patient being heparinized, may provide an even earlier assessment of coagulation status and thereby enable an earlier correction of coagulopathies, exemplified by Royston et al. [32] and Girdauskas et al. [30]. Weber et al. [34] report a notably higher mortality among their patients than usually seen in cardiac surgery. Despite this, we did not find a significant difference in mortality in the VHA-guided groups compared to conventionally treated groups. However, our metaanalysis suggested clinical difference in survival in patients having treatment based on VHA-results, in congruence with a before-and after study conducted on trauma patients by Johansson et al., showing a reduction in mortality of approximately 30% in a group resuscitated using TEG results in patients requiring massive transfusions [19]. Furthermore, a Cochrane review from Wikkelsø et al. [44] found the use of TEG or ROTEM in guiding resuscitation of bleeding patients to reduce allcause mortality and the number of patients transfused with blood products, although no difference was found with regard to excessive bleeding events and proportion of massively transfused, in agreement with our results. Also, NICE-report done by Whiting et al. [45] finds a tendency to fewer transfusions of allogeneic blood products being administered in cardiac surgery patients treated according to VHA-results when comparing to patients managed with CCT-results, while no difference was found with regard to trauma patients and postpartum bleeding. The discrepancies in study selection with the review from Whiting et al. [45] are explained in table 5.

Limitations
A limited number of adequately reported trials were eligible for our meta-analyses. Out of the 15 included trials in this analysis, five did not report sufficient information to be included in any of the meta-analyses performed [29,31,32,35,36]. This meta-analysis has an overweight of trials concerning cardio-thoracic patients, while other patient groups are only represented by a single RCT each, limiting comparability of results. Furthermore, the studies included present patients with bleeding originating from different aetiologies. This can potentially be problematic in that the severity of bleeding may vary.

Conclusions
In conclusion, the performed meta-analyses demonstrated trends towards the superiority of treating haemorrhaging patients under the guidance of VHAalgorithms. There is, however, a need for larger RCTs, such as the ongoing trials "implementing Treatment Algorithms for the Correction of Trauma Induced Coagulopathy (iTACTIC)" NCT02593877.