5 Outcomes

The Diagnostics Advisory Committee (section 11) considered evidence from several sources (section 12).

How outcomes were assessed

5.1 The assessment was performed by an External Assessment Group and consisted of a systematic review and development of a decision analytical model for viscoelastometric point‑of‑care testing to help detect, manage and monitor haemostasis.

5.2 The systematic review was carried out to provide evidence on the clinical effectiveness, and the decision analytical model was developed to assess the cost effectiveness.

Clinical effectiveness

5.3 The purpose of the review was to find out how clinical outcomes differ among people who are tested with viscoelastometric devices during or after surgery compared with those who are tested with standard laboratory tests alone. Cardiac surgery, trauma and management of postpartum haemorrhage were included in the assessment. When there were no data on a viscoelastometric device, the accuracy of the device in predicting relevant clinical outcomes (for example, need for transfusion) during or after surgery was evaluated.

5.4 In total, 39 publications of 33 studies were included in the systematic review: 11 randomised controlled trials (RCTs; 14 publications) evaluating ROTEM and TEG and 3 prediction studies that evaluated Sonoclot (because no RCTs evaluating Sonoclot were identified) in cardiac surgery patients; 1 ongoing RCT, 1 controlled clinical trial and 15 prediction studies (18 publications) in trauma patients; and 2 prediction studies (1 publication) in women with postpartum haemorrhage.

Cardiac surgery

5.5 The External Assessment Group included 11 RCTs (n=1089, range 22 to 228; 14 publications) for the assessment of viscoelastometric devices in patients having cardiac surgery. Of these RCTs, 6 assessed TEG, 4 assessed ROTEM and 1 assessed ROTEG (an early version of ROTEM). Information on 2 RCTs was only available as abstracts. The RCTs were conducted in Australia, Austria, Germany, Spain, Turkey, the UK and the USA. Most included patients having surgery irrespective of whether or not they had a bleeding event; 2 RCTs assessing ROTEM were restricted to patients who had experienced bleeding above a certain level. A further RCT of TEG was restricted to patients at moderate to high risk of transfusion procedures. One RCT was restricted to patients having aortic surgery, 2 included patients having coronary artery bypass graft and the remainder included patients having mixed cardiac surgery.

5.6 Mean or median age, when reported, ranged from 53 to 72 years and the proportion of men ranged from 56–90%. Most studies did not place any restriction on entry based on anticoagulation use, but 1 study excluded patients who had used low molecular weight heparin up to the day of operation. The ROTEM/TEG algorithms varied across studies. Six studies used an algorithm based on TEG or ROTEM alone, 2 combined TEG with standard laboratory tests, 2 combined ROTEM with platelet function testing (point‑of‑care in 1), and 1 combined ROTEM with clinical evaluation. The timing of the viscoelastometric test varied across studies.

5.7 All studies except 1, which performed TEG on arrival at the intensive care unit, administered multiple viscoelastometric tests. Timing included baseline or before bypass or anaesthesia, after cardiopulmonary bypass, after protamine administration, on admission to intensive care unit and up to 24 hours post‑cardio‑pulmonary bypass in 1 study. Four studies only performed viscoelastometric testing after surgery in patients who were continuing to bleed. Four studies used an algorithm based on standard laboratory tests in the control group; all other studies stated that control groups included combinations of clinical judgement and standard laboratory tests.

5.8 There were a number of methodological issues with the RCTs included in this assessment. Only 3 of the 11 RCTs were rated as 'low' risk of bias with respect to their randomisation procedures. The trials were generally poorly reported; all were rated as 'unclear' or at 'high' risk of bias on at least 50% of the assessed criteria.

5.9 The External Assessment Group included 3 prediction studies conducted in Switzerland and the USA, which evaluated Sonoclot, because no RCTs were available. Two of these also evaluated TEG and so provided a direct comparison between the 2 devices. Mean or median age, when reported, ranged from 63 to 65 years and the proportion of men ranged from 61–69%. All of the studies included patients having mixed cardiac surgery irrespective of whether or not they had a bleeding event. Patients with a known coagulopathy were excluded in 1 study and another study excluded patients with abnormal preoperative coagulation. Both studies excluded patients receiving anticoagulants and 1 also excluded patients on antiplatelet treatment. None of the 3 studies reported follow‑up of patients to assess the potential effects of different testing regimens on longer‑term transfusion‑related complications and mortality.

5.10 The External Assessment Group assessed the risk of bias and the applicability of the 3 studies. The main areas of concern were the patient selection process, which was unclear in all cases, and whether the way in which viscoelastometric testing was applied was applicable to the objectives of the assessment. Two of the studies were rated as having 'high' applicability concerns for the intervention because they assessed the predictive ability of selected individual parameters of viscoelastometric testing, rather than the device as a whole, or reporting data for all assays and parameters measured by the device.

Evidence on outcomes

Red blood cell transfusion

5.11 Eight RCTs evaluated red blood cell transfusion within 24 to 48 hours as a continuous outcome. All 8 RCTs reported lower volume of red blood cell transfusion in the viscoelastometric algorithm group compared with the control group but this was only statistically significant in 3 RCTs (2 of ROTEM and 1 of TEG). One RCT, which assessed ROTEM, did not report on the statistical significance of the difference. Six RCTs provided dichotomous data (having 2 possible values) on the number of patients who received red blood cell transfusion in each intervention group. The summary relative risk was 0.88 (95% confidence interval [CI] 0.80 to 0.96) suggesting a significant beneficial effect of the viscoelastometric testing algorithm in reducing the number of patients who received red blood cell transfusion. There was no evidence of heterogeneity across studies (I2=0%). Summary estimates were similar when stratified according to viscoelastometric device: relative risk 0.86 (95% CI 0.72 to 1.02) for the 3 RCTs that evaluated TEG and 0.88 (95% CI 0.78 to 1.00) for the 3 RCTs that evaluated ROTEM and ROTEG.

Any blood transfusion

5.12 Three RCTs evaluated any blood product transfusion as a continuous outcome. All 3 reported lower volume of any blood product transfusion in the viscoelastometric algorithm group compared with the control group. This was statistically significant in 2 (1 ROTEM and 1 TEG), while the third did not report on the statistical significance of the difference. Two RCTs provided dichotomous data on the number of patients who received any blood product transfusion in each intervention group. One assessed ROTEM (relative risk 0.89, 95% CI 0.78 to 1.02) and the other assessed TEG (relative risk 0.63, 95% CI 0.44 to 0.92). The summary relative risk was 0.79 (95% CI 0.57 to 1.08) suggesting a beneficial effect of the viscoelastometric testing algorithm in reducing the number of patients who received any blood product transfusion. However, this effect did not reach statistical significance. There was some evidence of heterogeneity across studies (I2=64%).

Factor VIIa transfusion

5.13 Two RCTs that assessed ROTEM provided dichotomous data on the number of patients who received a factor VIIa transfusion in each intervention group. The summary relative risk was 0.19 (95% CI 0.03 to 1.17) suggesting a beneficial effect of the ROTEM testing algorithm. However, this difference did not reach statistical significance. There was no evidence of heterogeneity across studies (I2=0%).

Fresh frozen plasma transfusion

5.14 All the included RCTs evaluated fresh frozen plasma transfusion either as a continuous or dichotomous outcome. Fresh frozen plasma transfusion within 24 to 48 hours was evaluated as a continuous outcome in 10 RCTs. All but 2 RCTs reported lower volume of fresh frozen plasma transfusion in the viscoelastometric algorithm group compared with the control group. This was statistically significant in 6 RCTs (2 of ROTEM and 4 of TEG); 3 did not report on the statistical significance of the difference. Dichotomous data on the number of patients who received fresh frozen plasma transfusion in each intervention group were reported in 5 RCTs. The summary relative risk was 0.47 (95% CI 0.35 to 0.65), suggesting a significant beneficial effect of the viscoelastometric testing algorithm in reducing the number of patients who received a fresh frozen plasma transfusion. There was no evidence of heterogeneity across studies (I2=0%). Summary estimates were similar when stratified according to viscoelastometric device; relative risk 0.52 (95% CI 0.20 to 1.35) for the 3 RCTs that evaluated TEG and 0.46 (95% CI 0.34 to 0.63) for the 2 RCTs that evaluated ROTEM.

Fibrinogen concentrate transfusion

5.15 Fibrinogen concentrate transfusion was evaluated as a continuous outcome in 3 RCTs which used ROTEM as the intervention. All 3 reported no difference in the volume of fibrinogen concentrate transfused between the viscoelastometric algorithm group and the control group. Dichotomous data on the number of patients who received a fibrinogen concentrate transfusion in the intervention group were also provided in 2 RCTs. The summary relative risk was 0.94 (95% CI 0.77 to 1.14) suggesting no difference between the treatment groups.

Platelet transfusion

5.16 All the included RCTs evaluated platelet transfusion as either a continuous or dichotomous outcome. Platelet transfusion within 24 to 48 hours was evaluated as a continuous outcome in 8 RCTs (4 used TEG and 4 used ROTEM as the intervention). All reported lower volume of platelet transfusion in the viscoelastometric algorithm group compared with the control group but this was only statistically significant in 5 (2 of ROTEM and 3 of TEG). Statistical significance of the difference was not reported in 2 RCTs. Dichotomous data on the number of patients who received a platelet transfusion in each intervention group were reported in 6 RCTs (3 used TEG and 3 used ROTEM as the intervention). The summary relative risk was 0.72 (95% CI 0.58 to 0.89) suggesting a significant beneficial effect of the viscoelastometric testing algorithm in reducing the number of patients who received a platelet transfusion. There was no evidence of heterogeneity across studies (I2=0%). Summary estimates were similar when stratified according to viscoelastometric device; relative risk 0.56 (95% CI 0.36 to 0.86) for the 3 RCTs that evaluated TEG and 0.78 (95% CI 0.60 to 1.00) for the 3 RCTs that evaluated ROTEM and ROTEG.

Prothrombin complex concentrate transfusion

5.17 Prothrombin complex concentrate transfusion was evaluated as a continuous outcome in 3 RCTs. All 3 reported lower volume of prothrombin complex concentrate transfusion in the viscoelastometric algorithm group compared with the control group but this was only statistically significant in 1 RCT while a second did not report on the statistical significance of the difference. Dichotomous data on the number of patients who received a prothrombin complex concentrate transfusion in each intervention group were reported in 2 of the 3 RCTs. The summary relative risk was 0.39 (95% CI 0.08 to 1.95) suggesting no difference between the treatment groups.

Bleeding

5.18 Bleeding was evaluated as a continuous outcome in 9 RCTs. Most reported less bleeding in the viscoelastometric intervention group; however, only 2 reported a statistically significant difference in bleeding between the 2 groups.

5.19 The 3 predictive studies that evaluated Sonoclot provided data which allowed calculation of odds ratios for predicting bleeding in patients who tested positive on a particular test or test parameter (Sonoclot, TEG or standard laboratory tests) compared with those who tested negative. Positive results on standard laboratory tests, TEG and Sonoclot were all associated with an increased risk of bleeding with no clear differences according to test. One study evaluated individual components of each of the tests separately and found that all the parameters investigated, with the exception of 1 TEG and 1 Sonoclot parameter, were associated with a statistically significant increased risk of bleeding. Two of the standard laboratory tests (prothrombin time and activated partial thromboplastin time) showed higher odds ratios than other parameters, but confidence intervals overlapped with other standard laboratory tests and TEG and Sonoclot parameters.

5.20 Another study evaluated each test class as a whole (that is, it evaluated a positive TEG result rather than the results for individual parameters of TEG). This study reported that a positive TEG or Sonoclot result were both highly predictive of bleeding. However, this study, performed in 1989, was very small and confidence intervals were wide. The limited data suggested that TEG results were more predictive than Sonoclot, but confidence intervals overlapped. The standard laboratory tests performed less well and were not predictive of bleeding.

Reoperation

5.21 Dichotomous data on the number of patients who needed reoperation to investigate bleeding in each intervention group were reported in 7 RCTs. The summary relative risk was 0.72 (95% CI 0.41 to 1.26), suggesting a beneficial effect of the viscoelastometric testing algorithm in reducing the number of patients needing reoperation. However, this difference was not statistically significant. There was no evidence of heterogeneity across studies (I2=0%). Summary estimates were similar when stratified according to viscoelastometric device; relative risk 0.75 (95% CI 0.31 to 1.83) for the 5 RCTs that evaluated TEG and 0.69 (95% CI 0.33 to 1.44) for the 2 RCTs that evaluated ROTEM.

Surgical source of bleeding identified on reoperation

5.22 Dichotomous data on the number of patients in whom a surgical source of bleeding was identified on reoperation was reported in 4 RCTs. The summary relative risk was 1.04 (95% CI 0.42 to 2.57) suggesting no difference between the groups. There was very little evidence of heterogeneity across studies (I2=3%). One RCT assessed ROTEM and reported a relative risk of 0.86 (95% CI 0.26 to 2.87). The summary estimate for the 3 RCTs assessing TEG was similar at 0.99 (95% CI 0.18 to 5.36).

Length of intensive care unit stay

5.23 The length of intensive care unit stay was evaluated as a continuous outcome in 4 RCTs. All reported shorter stays in the viscoelastometric group compared with the control group but this difference was only statistically significant in 1 study.

Length of hospital stay

5.24 The length of hospital stay was evaluated as a continuous outcome in 4 RCTs. All reported similar durations of stay in the viscoelastometric and standard laboratory test groups.

Mortality

5.25 Dichotomous data on the number of deaths (within 24 hours, 48 hours, in hospital or 'early mortality') in each intervention group were reported in 4 RCTs. The summary relative risk was 0.87 (95% CI 0.35 to 2.18) suggesting no difference between the intervention groups. There was no evidence of heterogeneity across studies (I2=0%). One RCT assessed ROTEM and reported a relative risk of 0.86 (95% CI 0.26 to 2.87) and the summary estimate for the 3 RCTs assessing TEG was similar at 0.88 (95% CI 0.21 to 3.66). An additional RCT provided data on 6‑month mortality. This study reported statistically significantly reduced mortality in the viscoelastometric testing group at 6 months compared with the standard laboratory test group (relative risk 0.20, 95% CI 0.05 to 0.87).

Trauma

5.26 The External Assessment Group identified 1 ongoing RCT that is comparing the TEG (rapid assay) with standard laboratory testing (international normalised ratio, fibrinogen, D‑dimer) in adults with blunt or penetrating trauma who are likely to need a transfusion of red blood cells within 6 hours from admission as indicated by clinical assessment. The study authors provided the External Assessment Group with additional information on the trial (in the form of a study protocol). The outcomes being evaluated in this study include quality and quantity of blood products transfused, patterns of transfusion ratios of red blood cell, fresh frozen plasma, bleeding‑related deaths classified as very early mortality (less than 2 hours post‑injury),early mortality and late mortality, cessation of coagulopathic bleeding and multiple organ failure. Results from this study are not yet available.

5.27 Because no other RCTs were identified, the External Assessment Group considered lower levels of evidence. One controlled clinical trial reported as an abstract was included. This study compared a rapid‑TEG guided protocol with a standard transfusion protocol in adult trauma patients needing massive transfusion (defined as more than 12 red blood cell units in 24 hours, or more than 4 red blood cell units in 4 hours). Although the study did not report numerical or statistical outcome data, it stated that there were no statistically significant differences between groups for death, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ failure, sepsis, deep vein thrombosis, stroke, acute coronary syndrome, or days to discharge. There was a statistically non‑significant trend towards reduced pneumonia, days on the ventilator and intensive care unit days, and a statistically significant trend towards increasing platelet use in the group tested with TEG. No other studies with a concurrent control group were identified for the trauma population.

5.28 There were insufficient data from studies that evaluated differences in clinical outcomes between viscoelastometric‑tested and untested populations, and the External Assessment Group therefore included lower levels of evidence. Fifteen prediction studies (18 publications; n=4217) were included. Nine studies evaluated TEG of which 4 also evaluated standard laboratory tests. The other 6 studies evaluated ROTEM of which 4 also evaluated standard laboratory tests. No studies of Sonoclot were identified. None of the studies evaluated both TEG and ROTEM in the same patients.

5.29 The prediction studies in trauma patients were conducted in the UK, the USA, Switzerland, Netherlands, Denmark and Austria. Most included mixed trauma patients but 3 were restricted to patients with blunt trauma and 2 were restricted to patients with traumatic brain injury. One study excluded patients with traumatic brain injury, and 1 excluded patients with isolated head injury. None of the studies restricted inclusion based on bleeding. One study excluded patients who had previously taken anticoagulants and another excluded patients who had recently taken clopidogrel or warfarin. The mean or median age, when reported, ranged from 33 to 49 years. The proportion of men ranged from 59–82%. Mean injury severity score, reported in 11 studies, ranged from 12 to 34. Mean Glasgow Coma Scale scores ranged from 11 to 14 but were only reported in 6 studies.

5.30 Outcomes assessed in the studies included any blood product transfusion, fresh frozen plasma transfusion, massive transfusion, massive transfusion of cryoprecipitate, massive transfusion of plasma, massive transfusion of platelets, plasma transfusion, platelet transfusion, red blood cell transfusion, bleeding, neurosurgical intervention and death. Six studies used multiple logistic regression models to estimate odds ratios for the association of individual TEG or ROTEM parameters or standard laboratory tests with the outcomes of interest controlled for various factors such as red blood cell transfusion, age, sex, mechanism of injury, trauma or injury severity, haemoglobin levels and race.

5.31 The main areas of concern with regard to these studies were the process of patient selection and whether the way in which viscoelastometric testing was applied was applicable to the objectives of the assessment. With 2 exceptions, all studies were rated as being at 'high' or 'unclear' risk of bias in the patient selection process. Ten of the 15 studies were rated as having 'high' applicability concerns for the index test because they assessed the predictive ability of selected individual components of viscoelastometric testing, rather than assessing the device as a whole, or reporting data for all assays and parameters measured by the device. Two further studies were rated as having 'unclear' applicability because no details of the assay(s) used or parameters measured were reported. Ten studies were rated as having 'high' applicability concerns with respect to the reference standard, when the reference standard was 1 or more measure(s) of transfusion requirements, because it was unclear whether or not the decision to transfuse was informed by viscoelastometric testing results. This also resulted in an 'unclear' risk of bias rating with respect to the reference standard. The remaining 5 studies were rated as 'low' applicability concerns because they reported objective reference standards (for example mortality).

Evidence on outcomes

Red blood cell transfusion

5.32 The ability of viscoelastometric devices to predict red blood cell transfusion was evaluated in 3 studies (2 of TEG, 1 of ROTEM and standard laboratory tests). One study used an end point of any red blood cell transfusion within 12 hours, 1 used an end point of transfusion within 6 hours and 1 did not specify the time point. A positive result (indicating a need for red blood cell transfusion) on each of the parameters assessed, with the exception of CT on ROTEM, was associated with an increased risk of red blood cell transfusion. There were no clear differences between ROTEM parameters or ROTEM and standard laboratory tests in the 1 study that reported multiple evaluations.

Any blood transfusion

5.33 The ability of viscoelastometric devices to predict any blood product transfusion was evaluated in 3 studies (2 of TEG, 1 of ROTEM and standard laboratory tests). One of the studies of TEG also evaluated standard laboratory tests. A positive result on each of the parameters assessed was associated with an increased risk of any blood product transfusion. An overall TEG result suggesting that the patient's blood was hypercoagulable was associated with a decreased risk of transfusion (odds ratio 0.14, 95% CI 0.03 to 0.76). There were insufficient data to calculate confidence intervals in 1 of the studies so the significance of the odds ratios from this study could not be assessed. The other 2 studies both reported statistically significant associations for all parameters assessed. An overall TEG result indicating that the patient's blood was hypocoagulable was found to be associated with the greatest increased risk of transfusion, but confidence intervals were very wide (odds ratio 180.00, 95% CI 14.15 to 2289.13). Odds ratios for individual TEG, ROTEM or standard laboratory tests were much smaller, ranging from 2.50 to 15.26.

Massive transfusion

5.34 The ability of viscoelastometric devices to predict massive red blood cell transfusion was evaluated in 6 studies (3 of TEG and 3 of ROTEM). All but 1 also evaluated standard laboratory tests. All used a threshold of 10 units or more of red blood cells transfused to define massive transfusion but the time frame within which this had to occur ranged from 6 to 24 hours. Three studies provided data as adjusted odds ratios for at least 1 of the viscoelastometric test components. A further study provided data that permitted calculation of odds ratios. The other 2 studies only provided data on area under the curve together with 95% confidence intervals. A positive result on each of the parameters assessed was associated with an increased risk of massive transfusion. However, this difference was not statistically significant for some of the ROTEM parameters and standard laboratory tests. There were no clear differences between ROTEM, TEG or standard laboratory tests, or individual test parameters, in terms of ability to predict massive transfusion. Areas under the curve, when reported, were between 0.70 and 0.92 with no clear differences between ROTEM, TEG or standard laboratory tests.

Mortality

5.35 The association of viscoelastometric devices with mortality was evaluated in 7 studies (5 evaluated TEG, 2 evaluated ROTEM and 3 also evaluated standard laboratory tests). Two studies provided data as adjusted odds ratios and 3 further studies provided data that permitted calculation of odds ratios and associated confidence intervals. The other 2 studies only provided data on area under the curve with 95% confidence intervals. These data were also reported in 1 of the studies that reported adjusted odds ratios. A positive result was associated with a statistically significant increased risk of death for most parameters assessed. The only exceptions were 2 parameters that were associated with a decreased risk of death, although this difference was not statistically significant: the presence of moderate hyperfibrinolysis (0.76, 95% CI 0.09 to 6.20) and an overall TEG result suggesting that a patient's blood was hypocoagulable (odds ratio 0.23, 95% CI 0.03 to 1.91). Three studies that evaluated a ROTEM or TEG result indicating the presence of hyperfibrinolysis showed the strongest association with death with odds ratios ranging from 25 to 147, although confidence intervals were wide. Areas under the curve were between 0.63 and 0.93 with no clear differences between ROTEM, TEG or standard laboratory tests.

Management of postpartum haemorrhage

5.36 No studies were identified that compared clinical outcomes among patients with postpartum haemorrhage who were tested with viscoelastometric devices compared with those who were not tested.

5.37 Because no studies evaluated differences in clinical outcomes between viscoelastometric‑tested and untested populations, the External Assessment Group included lower levels of evidence. Two prediction studies, reported only as abstracts, were included in the review (n=245). Both studies were conducted in the UK. The outcomes evaluated in the studies varied: 1 assessed the prediction of coagulopathy needing treatment, fresh frozen plasma transfusion and platelet transfusion; the other assessed the prediction of red blood cell transfusion and invasive procedures. One included women with postpartum haemorrhage defined as more than or equal to 1000 ml blood loss, and the other included women with major obstetric haemorrhage defined as equal to or more than 1500 ml blood loss.

5.38 The main area of concern with regard to the 2 prediction studies conducted in patients with postpartum haemorrhage was whether the way in which viscoelastometric testing was applied was applicable to the objectives of the assessment.

5.39 Both studies provided data that allowed calculation of odds ratios for predicting outcomes in patients who tested positive on ROTEM compared with those who tested negative. The study that evaluated ROTEM and standard laboratory tests only reported data in a format that allowed calculation of odds ratios for the ROTEM parameter (maximum clot firmness based on FIBTEM analysis) for the prediction of red blood cell transfusion of at least 4 units. There was a strong positive relationship between this parameter and red blood cell transfusion (odds ratio 41.54, 95% CI 9.01 to 191.59).

5.40 The other study reported that a positive ROTEM result was associated with coagulopathy needing treatment (odds ratio 168.0, 95% CI 15.6 to 1814.7). This study also evaluated fresh frozen plasma transfusion and platelet transfusion. Data were available to calculate odds ratios for these outcomes but not associated confidence intervals. The ROTEM results were also predictive of both these outcomes but the significance of the association was unclear. The size of the odds ratio was smaller than for the association with coagulopathy needing treatment ( 76 for fresh frozen plasma transfusion and 19 for platelet transfusion).

Cost effectiveness

5.41 The aim of the External Assessment Group's economic analysis was to identify the cost‑effectiveness of ROTEM, TEG and Sonoclot compared with standard laboratory tests to help detect, manage and monitor haemostasis in patients having cardiac surgery and trauma surgery who have suspected coagulopathy. The cost‑effectiveness of viscoelastometric devices was not assessed in the management of postpartum haemorrhage because of the lack of evidence in the clinical effectiveness review.

Review of existing economic analyses

5.42 Searches were carried out to identify cost‑effectiveness studies of viscoelastometric point‑of‑care testing. The searches identified 331 records of which 5 studies fulfilled the inclusion criteria. Two were only available as conference abstracts; 3 were conducted in cardiac patients, 1 in patients having liver transplant and 1 in both cardiac and liver transplant patients.

5.43 One study was a formal cost‑effectiveness analysis of viscoelastometric devices in cardiac and liver transplant patients. This study was conducted for the Scottish NHS.

5.44 The other 4 studies were cost‑minimisation studies performed alongside a retrospective before and after study. All 4 studies compared the volume and costs of blood transfused before and after the introduction of a viscoelastometric device. Three studies evaluated ROTEM and 1 evaluated TEG. All 4 found that costs were reduced as a result of the introduction of a viscoelastometric device. Only 1 of the 4 studies reported a detailed breakdown of cost savings. It showed that, after the introduction of ROTEM, the cumulative average monthly costs of all blood products decreased by 32%).

Cost‑effectiveness model

5.45 For both the cardiac and trauma models, the External Assessment Group adopted the model structure used in the Health Technology Assessment carried out for NHS Scotland in 2008. This was largely based on a cost‑effectiveness study of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion by Davies et al (2006). However, the External Assessment Group used more recent data sources whenever possible to update the input parameters of the model.

5.46 The models were based on a decision tree that started with the choice of strategy to be followed, that is, viscoelastometric device (ROTEM, TEG or Sonoclot) or standard laboratory tests. Within each strategy, patients then either did or did not receive a transfusion. Transfusion, when it occurs, may be associated with adverse events or complications. Complications were categorised as being related to surgery and/or transfusion, or related to transfusion alone.

5.47 Complications related to surgery and/or transfusions included in the model were: renal dysfunction, myocardial infarction, stroke, thrombosis, excessive bleeding needing reoperation, wound complications and septicaemia. Transfusion‑related complications included transfusion‑associated graft‑versus‑host disease, complications related to the administration of an incorrect blood component, haemolytic transfusion reactions (acute or delayed), post‑transfusion purpura, transfusion‑related acute lung injury and febrile reaction.

5.48 In addition, the External Assessment Group assumed that patients may also experience transfusion‑transmitted infections. Transfusion‑transmitted infections include bacterial contamination, variant Creutzfeldt–Jakob disease, malaria, human T‑cell lymphotropic virus, HIV and hepatitis A, B and C.

5.49 The models' time horizons were set to 1 month and 1 year because the benefits of a reduction in red blood cell transfusion were considered to have occurred within this time frame. At 1 month, the models reflect the period of hospitalisation and accordingly capture the impact of complications related to surgery and blood loss, transfusion‑related complications and infection caused by bacterial contamination. It should be noted that, as in Davies et al. (2006), bacterial contamination is the only transfusion‑transmitted infection that was assumed to occur during the hospitalisation period. For other transfusion‑transmitted infections included in the models, a time horizon of 1 year was considered more appropriate, because these infections do not usually appear immediately.

5.50 Costs were estimated from the perspective of the NHS and personal social services. Consequences were expressed in life years gained and quality‑adjusted life years (QALYs). QALY weights (utilities) were assigned to adverse events to express their consequences. Discounting was not necessary since the longest time horizon was set at 1 year.

Model inputs (cardiac and trauma models)

Red blood cell transfusion

5.51 For the cardiac model, the baseline risk of having a transfusion was estimated based on the number of red blood cell transfusions in the standard laboratory tests group in 4 of the cardiac surgery trials included in the effectiveness review. Since the effectiveness review did not find evidence of a difference in the relative risk of red blood cell transfusion between studies that assessed ROTEM and those that assessed TEG, the External Assessment Group applied the summary relative risk for red blood cell transfusion estimated for all studies for the ROTEM and TEG models. Limited data suggested that the accuracy of Sonoclot in predicting clinical outcomes may be similar to that of TEG. The External Assessment Group therefore assumed that this summary relative risk could be applied in the Sonoclot model. A beta and a normal distribution were assigned for the probabilistic sensitivity analyses.

5.52 For the trauma model, the baseline risk of red blood cell transfusion for the standard laboratory tests group was also estimated using data from those studies that reported data on the proportion of patients who received red blood cell transfusion. A random effects model was used to estimate the mean proportion of patients who received red blood cell transfusion. As there were no data comparing the proportion of transfused patients in a trauma population who received viscoelastometric testing with those who received standard laboratory tests, the External Assessment Group applied the same relative risk as in the cardiac surgery population.

Complications related to surgery

5.53 Reoperation to investigate bleeding is the only complication among those included in the model that was evaluated by the RCTs included in the effectiveness review. Data on the other complications were limited so the External Assessment Group assumed that there was no difference in the direct risk of having a complication between those tested with viscoelastometric devices and those tested with standard laboratory tests. The same assumption was made in Davies et al. (2006). The risk of complications in each testing strategy was influenced indirectly by the different red blood cell transfusion rates associated with each strategy. The probability of experiencing septicaemia was obtained from 1 study. However, the population in this study was not representative of the population in the assessment because it only included patients who received 4 or more units of red blood cell within 1 day of surgery (that is, patients with massive bleed). The External Assessment Group judged this estimate to be too high and reduced the estimate by an arbitrary factor of 0.5.

5.54 For the trauma model, 2 complications were included: acute respiratory distress syndrome and multiple organ failure. Estimates for the incidence of acute respiratory distress syndrome were obtained from a study of 14,070 trauma patients conducted in the USA, which reported an overall incidence of 4.6%. The same study was used to calculate the proportion of patients with acute respiratory distress syndrome among those who received a transfusion as 15.5%. For multiple organ failure, no studies were found that either provided estimates or allowed direct calculation of incidence for those transfused. However, based on the overall incidence of multiple organ failure being 3 to 5 times higher than that of acute respiratory distress syndrome, the External Assessment Group considered that a multiple organ failure incidence rate of 30% was a realistic assumption.

Transfusion‑related complications

5.55 The trials included in the clinical effectiveness review did not report data on transfusion‑related complications. Therefore, data on the probabilities of experiencing transfusion‑related complications were based on a UK Serious Hazards of Transfusion report, which collects and analyses anonymised information on adverse events and reactions in blood transfusions from all relevant healthcare organisations in the UK. The observations from the report were corrected for participation in the UK Serious Hazards of Transfusion survey (98%). The External Assessment Group assumed that the total number of transfused patients per year is around 800,000.

5.56 For the trauma model, the probability of transfusion‑related complications was assumed to be the same as that for the cardiac surgery patients. The External Assessment Group considered this likely to be an underestimation given that people with trauma on average receive more units of blood than cardiac surgery patients, which increases the exposure to various donors.

Transfusion‑transmitted infections

5.57 The probabilities of experiencing transfusion‑transmitted infections were also taken from the UK Serious Hazards of Transfusion report, using the same method of calculation as for transfusion‑related complications. These were also reported as the risk per patient transfused.

5.58 For the trauma population, the probability of transfusion‑transmitted infections was assumed to be the same as that for the cardiac surgery population. The External Assessment Group acknowledged that this is likely to be an underestimation, because patients with trauma receive on average more units of blood than cardiac surgery patients, which increases the exposure to various donors.

Mortality

5.59 For the cardiac model, the estimated risk of mortality in the standard laboratory tests group at 1 month was estimated based on the number of deaths reported in 1 study. This study was based on a large sample (n=8598) of a population that matched the target population for the assessment. It reported a 1–month mortality of 0.4% for non‑transfused patients and 4.3% for transfused patients. Using the transfusion percentage applied in the current model (59.2%), this gave an overall 1–month mortality of 2.7%.

5.60 Even though mortality may vary by complication, it was assumed that the mortality of all transfused patients (essentially the sum of mortalities due to each complication and no complication) was fixed at 4.3%. Therefore, in order to obtain a 4.3% mortality in the transfused group, the External Assessment Group used a calibration procedure, meaning that when reliable estimates were available, a specific mortality estimate was applied to each complication. For the rest, and for no complications, the mortality value was calculated so that the total mortality added up to 4.3%. This mortality value was calculated to be 4.28%. For the transfusion‑transmitted infections (except bacterial contamination), 1–month mortality was assumed to be zero because it was assumed that these infections appeared after the hospitalisation period. Mortality for various transfusion‑related complications and bacterial contamination were derived from the UK serious hazards of transfusion survey, unless they were lower than the calibrated mortality value. Those complications with mortality lower than 4.3% were included in the calibration procedure.

5.61 In order to estimate the mortality associated with the use of viscoelastometric testing, the External Assessment Group assumed that any mortality benefit from viscoelastometric testing resulted from fewer patients receiving a transfusion. This meant that the 1–month mortality for each group (not transfused, transfused without complications, and transfused with complications) in the viscoelastometric group was assumed to be the same as in the standard laboratory tests group.

5.62 At 1 year, the mortality in the standard laboratory tests group was estimated using data from a study which reported 1–year mortality of 1.2% for non‑transfused patients and 7.8% for transfused patients. For the non‑transfused patients, 0.4% mortality at 1 month and 1.2% mortality at 1 year gave a mortality of 0.8% for between 1 and 12 months. Similarly, for the transfused patients, mortality for between 1 and 12 months was calculated as 3.66%. The 1–year mortality for each subgroup of patients in the viscoelastometric group was assumed to be the same as in the standard laboratory tests group.

5.63 For the trauma population, the External Assessment Group used a random effects model to estimate mortality at 1 month based on the studies included in the effectiveness review. In the standard laboratory tests group, the mean 1‑month mortality was 15.7% (95% CI 11.7% to 20.1%). The External Assessment Group assigned 1‑month mortality to transfused and non‑transfused patients, such that the overall mortality would be equal to 15.7%. One study was retrieved that showed that mortality was 3.3 times higher among patients who received a transfusion. Therefore, the goal was to estimate mortality such that the weighted average of these gave an overall mortality of 15.7%, the mean mortality in the standard laboratory tests group derived from the systematic review. From this it follows that mortality was 9.1% in patients who did not receive a transfusion and 29.8% in those who did.

5.64 Mortality for the 2 trauma and/or transfusion‑related complications acute respiratory distress syndrome and multiple organ failure were estimated from other sources. The probability of mortality was estimated from a trial in acute respiratory distress syndrome patients that reported a mortality of 83/385 (21.6%). Data from 2 studies were pooled to estimate the mortality in patients with multiple organ failure, giving an overall mortality of 26.2%.

5.65 One‑month mortality rates for transfusion‑related complications and transfusion‑transmitted infections were derived when possible from the Serious Hazards of Transfusion survey, and, as in the cardiac surgery population, it was assumed that all infections apart from bacterial contamination would only appear after 1 month, implying zero mortality in the first month. As in the cardiac population, the 1‑month mortality for each subgroup of patients in the viscoelastometric group was assumed to be the same as in the standard laboratory tests group, implying that any mortality benefit in the viscoelastometric group was due to fewer patients being transfused.

5.66 Few data were available for mortality between 1 and 12 months after trauma. One study was identified, which reported 3% mortality for this period, but no information was identified on how this mortality was distributed over transfused and non‑transfused patients. The External Assessment Group therefore applied the same ratio as for 1–month mortality (3.3). This gave a mortality of 1.7% in non‑transfused patients and 5.7% in transfused patients. These values were assumed to apply to both the standard laboratory tests and the viscoelastometric group.

Health benefits

5.67 Health benefits were expressed in terms of life years and QALYs gained at 1 month and 1 year. For the calculation of the life years, patients were assumed to die in the middle of the period where death occurred. Life years were then valued with different utilities depending on the health state of the patient. Except for stroke, the External Assessment Group used utility values from the 1996 Health Survey for England.

5.68 For the trauma model, the External Assessment Group identified a study that collected EQ‑5D utilities 12 to 18 months after trauma. This study included patients with severe trauma and reported a mean utility of 0.69 (standard error 0.016) 12 to 18 months after the trauma. No studies reporting utilities for the period of hospitalisation and shortly afterwards were identified. The External Assessment Group therefore assumed the same utility for the period of hospitalisation as for the cardiac population during hospitalisation.

5.69 For patients with acute respiratory distress syndrome, the External Assessment Group used the results of a prospective cohort study that measured quality‑adjusted survival in 200 patients in the first year after acute respiratory distress syndrome. This study reported utilities of 0.60 (standard error 0.01) and 0.64 (standard error 0.01) at 6 months and 1 year after onset of acute respiratory distress syndrome respectively. The External Assessment Group applied a value of 0.60 to the period of 1 month, and 0.64 to the period between months 1 and 12. Similar data were unavailable for patients with multiple organ failure, so the External Assessment Group applied the same utilities as for patients with acute respiratory distress syndrome based on the assumption that both complications are similar in severity. For patients with transfusion‑related complications, the External Assessment Group assumed that after discharge, as in the cardiac population, the utility would be equivalent to patients without complications.

Costs (cardiac and trauma models)

5.70 Short‑term (1 month) and long‑term (1 year) costs were considered in both the cardiac and trauma models. Preoperative and perioperative costs of transfusion were taken from Davies et al. (2006) and inflated to 2013 costs.

5.71 Three types of blood products were included in the model. The respective prices for standard red blood cells, adult platelets and clinical fresh frozen plasma were £122.09, £208.09, and £27.98, as obtained from the NHS blood and Transplant price list 2013/14. Data on units of blood transfused were obtained from 1 study. In the trauma population, data from 2 trauma studies included in the effectiveness review, that reported volumes of blood products used, were used to estimate the average number of units transfused per patient needing a transfusion.

5.72 The total cost of the different viscoelastometric devices consisted of the costs of the devices themselves, the costs of extra items (only those that were available and comparable for the 3 devices) and after‑care and training costs. The differences in costs in terms of device, between the cardiac and trauma models, were in the types of assays used to define a basic test and in the number of tests run.

5.73 The External Assessment Group assumed that cardiac surgery patients will be tested 3 times. Therefore, for ROTEM a basic test would consist of INTEM, EXTEM, FIBTEM and HEPTEM; for TEG a basic kaolin and heparinise test; and for Sonoclot, gbACT and kACT. The External Assessment Group assumed that trauma patients would not be tested using the heparin assays. Therefore, for ROTEM a basic test would consist of INTEM, EXTEM and FIBTEM; for TEG the regular kaolin test would be replaced by the rapid TEG and Sonoclot patients would just receive an H‑gbACT+ test. Each patient was assumed to be tested 5 times.

5.74 The total cost per set of standard laboratory tests inflated to 2013 prices was taken from the Scottish health technology assessment and was equal to £26 for fibrinogen concentration, prothrombin time, activated clotting/coagulation time and activated partial thromboplastin time combined. This cost was applied to both the cardiac and trauma models.

5.75 The average length of hospital stay for the cardiac model was sourced from the Hospital Episode Statistics 2012/13, which reports a mean stay of 10.53 days per patient having cardiac surgery. The cost per day (inflated to 2013 prices) was £198 for patients without complication, according to Davies et al. (2006). None of the studies included in the effectiveness review reported statistically significant differences between viscoelastometric and standard laboratory test groups in terms of length of hospital stay, so the External Assessment Group assumed equal average length of hospital stay for each of the different strategies. Costs of intensive care unit stay were not considered.

5.76 For the trauma model, data on length of hospital stay were taken from the only 2 trauma studies included in the effectiveness review that reported on this parameter. The average length of stay in hospital was 10.55 days, 4.9 of which were spent in the intensive care unit. Based on the National Schedule of Reference Costs, intensive care unit stay was valued at £1173 per day. For hospital stay after intensive care unit, the External Assessment Group was unable to define a cost per day because of the wide variability in trauma injuries, and assumed the same per‑day costs as for the cardiac surgery model.

5.77 The External Assessment Group used the following estimated lengths of stay for the different complications, based on the available evidence:

  • For acute respiratory distress syndrome, the External Assessment Group used data from a study that reported an intensive care unit length of stay of 18.8 days and hospital length of stay of 26.8 days.

  • For multiple organ failure, a study reported an intensive care unit length of stay of 19.1 days. However, there were no data for overall stay so the External Assessment Group assumed that amount of time spent in hospital after intensive care unit discharge is equal to the time spent by people with acute respiratory distress syndrome (8 days).

  • For patients without acute respiratory distress syndrome or multiple organ failure, the lengths of intensive care unit and hospital stay were estimated to be 2.2 days and 7.4 days respectively, in order to achieve the averages of 10.55 days and 4.9 days for all patients.

  • For people with transfusion‑related complications and bacterial infection, the External Assessment Group assumed the same length of stay as for cardiac surgery patients and the same unit costs per day. While patients stayed in the intensive care unit, no additional hospital costs were applied for complications because the External Assessment Group assumed that the level of care was already such that the marginal resource use due to complications was relatively small. Once patients were out of the intensive care unit, the same per‑day costs applied for the cardiac model were applied.

5.78 Long‑term costs (costs between hospital discharge and 1 year after surgery) included those related to the other transfusion‑transmitted infections, specifically variant Creutzfeldt‑Jakob disease, malaria, human T‑cell lymphotropic virus, HIV, hepatitis A, B and C.

Base‑case results (cardiac and trauma models)

5.79 For the cardiac model, all the viscoelastometric devices dominated (that is, were more effective and less costly than) standard laboratory tests. The External Assessment Group assumed the same treatment effects for each viscoelastometric testing device (QALY=0.8773). The cost of Sonoclot was lower than that of ROTEM and TEG, and the device was associated with greater cost savings (£132) than either TEG (£79) or ROTEM (£43).

5.80 For the trauma model, all the viscoelastometric technologies dominated standard laboratory tests. The effectiveness of the devices was the same (QALY=0.5713). The cost of Sonoclot was lower than that of ROTEM or TEG and so this device was associated with greater cost savings (£818) than TEG (£721) or ROTEM (£688).

5.81 The results of other outputs from both the cardiac and trauma models showed that, compared with standard laboratory tests, the use of viscoelastometric devices is associated with lower mortality, a reduced probability of experiencing complications, and lower transfusion and hospitalisation costs. The probability of experiencing transfusion‑transmitted infections was very low (almost zero) in both groups but lower in the viscoelastometric group.

Probabilistic analysis results (cardiac and trauma models)

5.82 The impact of statistical uncertainties regarding the models input parameters was explored through probabilistic sensitivity analysis.

5.83 For the cardiac model, the scatter plot of the probabilistic sensitivity analysis outcomes in the cost‑effectiveness plane was not very informative because the model only assumed a difference in costs between the technologies. The probabilistic sensitivity analysis confirmed that using standard laboratory tests is the strategy with the lowest probability of being cost effective. If the maximum acceptable incremental cost‑effectiveness ratio (ICER) was £30,000 per QALY gained, the probability of cost effectiveness for each of the 3 viscoelastometric technologies compared with standard laboratory tests was 0.79 for ROTEM, 0.82 for TEG and 0.87 for Sonoclot. When the maximum acceptable ICER was higher than £30,000 per QALY gained, the cost‑effectiveness probabilities converged to around 0.80 for all technologies.

5.84 Probabilistic sensitivity analysis results for the trauma model were similar to the cardiac model. The analysis confirmed that using standard laboratory tests was the strategy with the lowest probability of being cost effective. A comparison of ROTEM with standard laboratory tests found a cost‑effectiveness probability equal to 0.96 for ROTEM for a ceiling ratio equal to £0. As the ceiling ratio increased, the cost‑effectiveness acceptability curve for ROTEM converged to 0.87. A similar pattern was observed for TEG and Sonoclot.

Scenario analysis results

5.85 For the cardiac model, all scenario analyses suggested that ROTEM remained cost saving. The only exception was the number of tests run on each device per year. If the number of tests run on each device were reduced to 200, ROTEM no longer dominated standard laboratory tests, and ICER was £16,487 per QALY gained. The External Assessment Group estimated, using iterative analysis, that if all other parameters in the model remained unchanged, the costs of ROTEM and standard laboratory tests would be equal if 326 tests were run on ROTEM each year. At this level the ICER would be £0 per QALY gained. If the number of tests per year were reduced to 152, the ICER would be around £30,000 per QALY gained.

5.86 Additional scenario analyses for cardiac surgery suggested that when viscoelastometric testing is carried out in conjunction with standard laboratory testing, TEG was more effective and less costly (−£1) than standard laboratory testing alone and that the ICER for ROTEM and standard laboratory testing alone was £7487 per QALY gained. When the number of tests and type of assays used were varied, viscoelastometric testing dominated standard laboratory testing alone.

5.87 For the trauma model, all scenario analyses suggested that ROTEM remained cost saving. The iterative analysis performed to estimate the number of tests per year such that ROTEM would still be cost saving suggested a break‑even value of 81 tests per year; at this level the ICER was £0 per QALY gained. When the number of tests per year was reduced to 65, the ICER was approximately £30,000 per QALY gained.

5.88 Additional scenario analyses for trauma surgery suggested that when viscoelastometric testing is carried out in conjunction with standard laboratory testing, ROTEM and TEG dominated (−£558 and −£591 respectively) standard laboratory testing alone. When the number of tests and type of assays used were varied, viscoelastometric testing dominated standard laboratory testing alone.

5.89 For the trauma model, threshold analysis on the combined effect of a reduction in the percentage of patients transfused and the blood volumes transfused (assuming that equal volumes of blood were transfused in the viscoelastometric testing and standard laboratory test groups) showed that, at a relative risk of transfusion of 0.9822 or more, ROTEM was no longer cost saving (with an ICER of £0 per QALY gained). When the relative risk of transfusion increased to 0.9874, the ICER of ROTEM compared with standard laboratory tests was £30,000 per QALY gained.

5.90 Reducing baseline transfusion risk in the standard laboratory test group (assuming that equal volumes of blood were transfused in the viscoelastometric testing and standard laboratory test groups) showed that ROTEM was no longer cost saving at a transfusion rate of 5%, and that the ICER was £30,000 per QALY gained for a transfusion rate of 4%. This compares with a transfusion rate of 32% used in the base‑case analysis. When the analysis was repeated with an increased relative risk of red blood cell transfusion (from 0.88 to 0.95), the ICER was above £30,000 per QALY gained for a transfusion rate of 8% or less. After reducing the probability of complications related to trauma and/or transfusion, transfusion‑related complications and transfusion‑related infection to zero, ROTEM remained cost saving with a reduction in costs of £372.

  • National Institute for Health and Care Excellence (NICE)