Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding

Abstract

Background: Severe bleeding and coagulopathy are serious clinical conditions that are associated with high mortality. Thromboelastography (TEG) and thromboelastometry (ROTEM) are increasingly used to guide transfusion strategy but their roles remain disputed. This review was first published in 2011 and updated in January 2016.

Objectives: We assessed the benefits and harms of thromboelastography (TEG)-guided or thromboelastometry (ROTEM)-guided transfusion in adults and children with bleeding. We looked at various outcomes, such as overall mortality and bleeding events, conducted subgroup and sensitivity analyses, examined the role of bias, and applied trial sequential analyses (TSAs) to examine the amount of evidence gathered so far.

Search methods: In this updated review we identified randomized controlled trials (RCTs) from the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1); MEDLINE; Embase; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to 5 January 2016). We contacted trial authors, authors of previous reviews, and manufacturers in the field. The original search was run in October 2010.

Selection criteria: We included all RCTs, irrespective of blinding or language, that compared transfusion guided by TEG or ROTEM to transfusion guided by clinical judgement, guided by standard laboratory tests, or a combination. We also included interventional algorithms including both TEG or ROTEM in combination with standard laboratory tests or other devices. The primary analysis included trials on TEG or ROTEM versus any comparator.

Data collection and analysis: Two review authors independently abstracted data; we resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as risk ratio (RR) with 95% confidence intervals (CIs). Due to skewed data, meta-analysis was not provided for continuous outcome data. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effect based on the presence of coagulopathy of a TEG- or ROTEM-guided algorithm, and in adults and children on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components and the risk of random error through TSA.

Main results: We included eight new studies (617 participants) in this updated review. In total we included 17 studies (1493 participants). A total of 15 trials provided data for the meta-analyses. We judged only two trials as low risk of bias. The majority of studies included participants undergoing cardiac surgery.We found six ongoing trials but were unable to retrieve any data from them. Compared with transfusion guided by any method, TEG or ROTEM seemed to reduce overall mortality (7.4% versus 3.9%; risk ratio (RR) 0.52, 95% CI 0.28 to 0.95; I(2) = 0%, 8 studies, 717 participants, low quality of evidence) but only eight trials provided data on mortality, and two were zero event trials. Our analyses demonstrated a statistically significant effect of TEG or ROTEM compared to any comparison on the proportion of participants transfused with pooled red blood cells (PRBCs) (RR 0.86, 95% CI 0.79 to 0.94; I(2) = 0%, 10 studies, 832 participants, low quality of evidence), fresh frozen plasma (FFP) (RR 0.57, 95% CI 0.33 to 0.96; I(2) = 86%, 8 studies, 761 participants, low quality of evidence), platelets (RR 0.73, 95% CI 0.60 to 0.88; I(2) = 0%, 10 studies, 832 participants, low quality of evidence), and overall haemostatic transfusion with FFP or platelets (low quality of evidence). Meta-analyses also showed fewer participants with dialysis-dependent renal failure.We found no difference in the proportion needing surgical reinterventions (RR 0.75, 95% CI 0.50 to 1.10; I(2) = 0%, 9 studies, 887 participants, low quality of evidence) and excessive bleeding events or massive transfusion (RR 0.38, 95% CI 0.38 to 1.77; I(2) = 34%, 2 studies, 280 participants, low quality of evidence). The planned subgroup analyses failed to show any significant differences.We graded the quality of evidence as low based on the high risk of bias in the studies, large heterogeneity, low number of events, imprecision, and indirectness. TSA indicates that only 54% of required information size has been reached so far in regards to mortality, while there may be evidence of benefit for transfusion outcomes. Overall, evaluated outcomes were consistent with a benefit in favour of a TEG- or ROTEM-guided transfusion in bleeding patients.

Authors' conclusions: There is growing evidence that application of TEG- or ROTEM-guided transfusion strategies may reduce the need for blood products, and improve morbidity in patients with bleeding. However, these results are primarily based on trials of elective cardiac surgery involving cardiopulmonary bypass, and the level of evidence remains low. Further evaluation of TEG- or ROTEM-guided transfusion in acute settings and other patient categories in low risk of bias studies is needed.

Conflict of interest statement

Anne Wikkelsø: Declares to have received thromboelastography (TEG) assays from Haemonetics Corp. but no financial support for a randomized controlled trial (RCT) investigating fibrinogen concentrate in postpartum haemorrhage with TEG used as haemostatic monitoring (trial not part of this review).

Arash Afshari: Declares to have received TEG assays from Haemonetics Corp. but no financial support for an RCT investigating fibrinogen concentrate in postpartum haemorrhage with TEG used as haemostatic monitoring (trial not part of this review).

Ann Merete Møller: Declares to have received TEG assays from Haemonetics Corp. but no financial support for an RCT investigating fibrinogen concentrate in postpartum haemorrhage with TEG used as haemostatic monitoring (trial not part of this review).

Jørn Wetterslev: Declares that he is a member of Trial Sequential Analysis (TSA) at Copenhagen Trial Unit developing and programming TSA.

Figures

1

Trial sequential analysis (TSA) of mortality shows that only 54% of the required information size (717 of 1325) for a 49% relative risk reduction (RRR) has been reached in a fixed‐effect model with continuity adjustment for zero event trials (0.001 in each arm) resulting in a TSA alfa‐boundary adjusted RR of 0.51 (95% CI 0.21 to 1.26, Diversity (D2) = 0%, I2 = 0%, fixed‐effect model) with a control event proportion of 7.4%. Cumulative Z‐curve does not cross the monitoring boundary constructed for a required information size of 1325 participants corresponding to a RRR of 49% with 80% power and alpha of 0.05. However, only two trials had low risk of bias, with insufficient event rate to carry out a separate meta‐analysis for low risk of bias trials. When carrying out the TSA by using random‐effects model instead of fixed‐effect model, the RR is 0.59 (95% CI 0.23 to 1.54, Diversity (D2) = 0%, I2 = 0%).

2

Trial Sequential Analysis (TSA) of all trials on the effect of haemostatic transfusion guided by TEG or ROTEM on the need for PRBCs resulted in a TSA alfa‐spending boundary adjusted RR of 0.86 (95% CI 0.79 to 0.95, D2= 0%, I2= 0%, fixed‐effect model) with a control event proportion of 93.3% with continuity adjustment for zero event trials (0.001 in each arm). Cumulative Z‐curve in blue crosses the monitoring boundary constructed for an adjusted information size of 507 participants corresponding to a RRR of 14% with 80% power and alpha of 0.05.

3

TSA of the effect of haemostatic transfusion guided by TEG or ROTEM on proportion of patients in need of FFP resulted in a TSA alfa‐spending boundary adjusted RR of 0.6 (95% CI 0.55 to 0.65) with the cumulative Z‐curve crossing the boundary constructed for an information size of 372 in the meta‐analysis with a RRR of 40% (alfa = 0.05) and a power of 80% (beta = 0.20) in a random‐effects model with high heterogeneity (I2 = 73%) and diversity (D2= 88%) and control group event rate of 47.1% with continuity adjustment for zero event trials (0.001 in each arm). However, one has to exert caution when interpreting indications of firm evidence for this outcome, since only two trials had low risk of bias (Nakayama 2015; Shore‐Lesserson 1999) and the required information size based on these two trials is 2921 and the cumulative Z‐curve does not cross the boundary.

4

TSA of all trials for the effect of haemostatic transfusion guided by TEG or ROTEM on the need for platelets indicates firm evidence and resulted in a TSA alfa‐spending boundary adjusted RR of 0.73 (95% CI 0.70 to 0.76, Diversity (D2) = 0%, I2 = 0%, fixed‐effect model) with a control event proportion of 34.4% and with continuity adjustment for zero event trials (0.001 in each arm). Cumulative Z‐curve crosses the monitoring boundary constructed for an adjusted information size of 177 participants corresponding to a RRR of 27% with 90% power and alpha of 0.05. However, as with previous analysis, only two trials had low risk of bias (Nakayama 2015; Shore‐Lesserson 1999) and the low‐risk of bias adjusted required information size is 1090 participants.

5

TSA of all trials for the effect of haemostatic transfusion guided by TEG or ROTEM on the need for re operations results in a TSA alfa‐spending boundary adjusted RR of 0.74 (CI 0.63 to 0.86, D2= 0%, I2 = 0%, fixed‐effect model) but the cumulative Z‐curve does not cross the monitoring boundary constructed for an adjusted information size of 516 participants corresponding to a RRR of 26% with 80% power and alpha of 0.05 and a control event proportion of 10.8% with continuity adjustment for zero event trials (0.001 in each arm). However, only trial was with low risk of bias.

6

Updated flow diagram for selection of randomized controlled trials up to 5 January 2016.

7

Updated flow diagram for selection of randomized controlled trials from 31 October 2010 to 5 January 5 2016.

8

Flow diagram for selection of randomized controlled trials up to 31 October 31 according to last published version of this review (Afshari 2011).

9

Updated risk of bias summary: review authors' judgements about each risk of bias item for each included study.

10

Updated risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

1.1. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 1 Mortality; grouped by TEG or ROTEM.

1.2. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 2 Mortality; grouped by coagulopathy or severe postoperative bleeding status.

1.3. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 3 Patients receiving PRBCs; grouped by TEG or ROTEM.

1.4. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 4 Patients receiving PRBCs; grouped by adult or paediatric patients.

1.5. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 5 Patients receiving PRBCs; grouped by coagulopathy or severe postoperative bleeding status.

1.6. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 6 Patients receiving FFP; grouped by TEG or ROTEM.

1.7. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 7 Patients receiving FFP; grouped by coagulopathy or severe postoperative bleeding status.

1.8. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 8 Patients receiving platelets; grouped by TEG or ROTEM.

1.9. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 9 Patients receiving platelets; grouped by adult or paediatric patients.

1.10. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 10 Patients receiving platelets; grouped by coagulopathy or severe postoperative bleeding status.

1.11. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 11 Transfusion of FFP & platelets.

1.12. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 12 Patients receiving fibrinogen concentrate.

1.13. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 13 Patients receiving prothrombin complex concentrate (PCC).

1.14. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 14 Patients receiving factor VIIa.

1.15. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 15 Surgical reintervention; grouped by coagulopathy or severe postoperative bleeding status.

1.16. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 16 Surgical reintervention; grouped by TEG or ROTEM.

1.17. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 17 Dialysis‐dependent renal failure.

1.18. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 18 Thrombotic events.

1.19. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 19 Surgical source of re‐bleeding.

1.20. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 20 Excessive bleeding events and massive transfusion.

1.21. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 21 Post hoc: mortality; grouped by comparison.

1.22. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 22 Post hoc: patients receiving PRBCs; grouped by comparisons.

1.23. Analysis

Comparison 1 TEG or ROTEM versus any comparison, Outcome 23 Post hoc: patients receiving FFP; grouped by comparison.

2.1. Analysis

Comparison 2 TEG or ROTEM versus clinical judgement or usual care, Outcome 1 Mortality.

2.2. Analysis

Comparison 2 TEG or ROTEM versus clinical judgement or usual care, Outcome 2 Patients receiving PRBCs.

2.3. Analysis

Comparison 2 TEG or ROTEM versus clinical judgement or usual care, Outcome 3 Patients receiving FFP.

2.4. Analysis

Comparison 2 TEG or ROTEM versus clinical judgement or usual care, Outcome 4 Patients receiving platelets.

2.5. Analysis

Comparison 2 TEG or ROTEM versus clinical judgement or usual care, Outcome 5 Surgical reintervention.

3.1. Analysis

Comparison 3 TEG or ROTEM versus SLT‐guided transfusion, Outcome 1 Mortality.

3.2. Analysis

Comparison 3 TEG or ROTEM versus SLT‐guided transfusion, Outcome 2 Patients receiving PRBCs.

3.3. Analysis

Comparison 3 TEG or ROTEM versus SLT‐guided transfusion, Outcome 3 Patients receiving FFP.

3.4. Analysis

Comparison 3 TEG or ROTEM versus SLT‐guided transfusion, Outcome 4 Patients receiving platelets.

3.5. Analysis

Comparison 3 TEG or ROTEM versus SLT‐guided transfusion, Outcome 5 Surgical reintervention.

4.1. Analysis

Comparison 4 TEG or ROTEM in combination with SLT or other devices versus clinical judgement or usual care, Outcome 1 Mortality.

4.2. Analysis

Comparison 4 TEG or ROTEM in combination with SLT or other devices versus clinical judgement or usual care, Outcome 2 Patients receiving PRBCs.

4.3. Analysis

Comparison 4 TEG or ROTEM in combination with SLT or other devices versus clinical judgement or usual care, Outcome 3 Patients receiving FFP.

4.4. Analysis

Comparison 4 TEG or ROTEM in combination with SLT or other devices versus clinical judgement or usual care, Outcome 4 Patients receiving platelets.

4.5. Analysis

Comparison 4 TEG or ROTEM in combination with SLT or other devices versus clinical judgement or usual care, Outcome 5 Surgical reintervention.