ARTICLE IN PRESS
Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 1 9
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Journal of Cardiothoracic and Vascular Anesthesia
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Original Article Viscoelastic Blood Tests Use in Adult Cardiac Surgery: Meta-Analysis, Meta-Regression, and Trial Sequential Analysis
Massimo Meco, MD*,2, Andrea Montisci, MDy,z,#, Enrico Giustiniano, MDx,#, Massimiliano Greco, MD, MScx, ,1 Federico Pappalardo, MDk, Liborio Mammana, MD{ , Paolo Panisi, MD*, Claudio Roscitano, MD*, Silvia Cirri, MDy, Francesco Donatelli, MDz,{, Giovanni Albano, MD*
*Anesthesia and Intensive Care Department, Humanitas Gavazzeni Clinic, Bergamo, Italy yDepartment of Anesthesia and Intensive Care, Cardiothoracic Center, Istituto Clinico Sant’Ambrogio, Milano, Italy zChair of Cardiac Surgery, University of Milan, Milano, Italy xDepartment of Anesthesia and Intensive Care, IRCCS Humanitas Clinical and Research Center, Rozzano, Italy kDepartment of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milano, Italy {Department of Cardiac Surgery, Cardiothoracic Center, Istituto Clinico Sant’Ambrogio, Milano, Italy
Objectives: Postoperative hemorrhage in cardiac surgery is a significant cause of morbidity and mortality. Standard laboratory tests fail as pre- dictors for bleeding in the surgical setting. The use of viscoelastic (VE) hemostatic assays thromboelastography (TEG) and rotational thromboe- lastometry (ROTEM) could be an advantage in patients undergoing cardiac surgery. The objective of this meta-analysis was to analyze the effects (benefits and harms) of VE-guided transfusion practice in cardiac surgery patients. Design: A meta-analysis of randomized trials. Setting: For this study, PubMed, EMBASE, Scopus, and the Cochrane Collaboration database were searched, and only randomized controlled trials were included. A systematic review and meta-analysis were performed in accordance with the standards set forth by the Preferred Report- ing Items for Systematic Reviews and Meta-Analyses statement, using a random-effects model. Participants: The study comprised adult cardiac surgery patients. Interventions: VE-hemostatic assays transfusion algorithm compared with transfusion algorithms based on clinicians’ discretion. Measurements and Main Results: Seven comparative randomized controlled trials were considered, including a total of 1,035 patients (522 patients in whom a TEG- or ROTEM-based transfusion algorithm was used). In patients treated according to VE-guided algorithms, red blood cell (odds ratio 0.61; 95% confidence interval [CI]: 0.37-0.99; p: 0.04; I2: 66%) and fresh frozen plasma transfusions (risk difference 0.22; 95% CI: 0.11-0.33; p < 0.0001; I2: 79%) use was reduced; platelets transfusion was not reduced (odds ratio 0.61; 95% CI: 0.32-1.15; p: 0.12; I2 74%). Conclusions: This study demonstrated that the use of VE assays in cardiac surgical patients is effective in reducing allogenic blood products exposure, postoperative bleeding at 12 and 24 hours after surgery, and the need for redo surgery unrelated to surgical bleeding. Ó 2019 Elsevier Inc. All rights reserved.
Key Words: viscoelastic blood test; rotational thromboelastography; adult cardiac surgery; hemorrhage; meta-analysis
1Address reprint requests to Liborio Mammana, MD, Department of Cardiac Surgery, Cardiothoracic Center, Istituto Clinico Sant’Ambrogio, Via Luigi Giu- seppe Faravelli, 16, 20149 Milano, Italy. E-mail address: [email protected] (L. Mammana). 2 M. Meco, A. Montisci, and E. Giustiniano contributed equally to this study. https://doi.org/10.1053/j.jvca.2019.06.030 1053-0770/Ó 2019 Elsevier Inc. All rights reserved. ARTICLE IN PRESS
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CARDIAC SURGERY with cardiopulmonary bypass Study Selection causes severe derangements in the hemostatic system, which contributes to intraoperative and postoperative bleeding and is Once full articles were retrieved, studies were further associated with increased morbidity and mortality.1-4 Transfu- excluded if there was an overlap in patients with another study sion of hemostatic blood products may be guided by clinical within the same analysis (in this case, the larger sample size of judgment, standard laboratory tests, thromboelastography the 2 studies was selected). (TEG) or rotational thromboelastometry (ROTEM), or a com- Two reviewers (MM and AM) evaluated each article sepa- bination of these in a treatment algorithm. None of the stan- rately. Disagreements were resolved by discussion with a third dard laboratory tests (activated partial thromboplastin time, party (GA). prothrombin time, international normalized ratio, platelet The quality of studies was examined using the method rec- count, and plasma fibrinogen) was developed to predict bleed- ommended by a Cochrane Collaboration tool for assessing risk ing or to guide coagulation management in the surgical set- of bias in the included studies. Factors that were assessed are ting.5,6 TEG and ROTEM are viscoelastic (VE) hemostatic as follows: (1) random sequence generation (selection bias), assays7 that provide a graphical evaluation of the kinetics of (2) allocation concealment, (3) blinding of involved personnel, almost all stages of clot formation in the whole blood. (4) blinding of outcome assessment, (5) incomplete outcome The monitoring of the dynamic changes of hemostasis with data, and (6) selective reporting. In the studies reporting only TEG or ROTEM has a pathophysiologic rationale, allowing for median and interquartile range, we interpreted the value of the diagnosis of a specific type of coagulopathy and possibly median as a mean, and standard deviation as interquartile guiding a cause-oriented hemostatic treatment.8 VE tests are not range/1.35.16 as described by Wan (10). Two authors (MM without limitations, which should be considered carefully as and GA) independently extracted the relevant data from they measure coagulation parameters under static rather than articles, and their results were compared to assure accuracy. dynamic conditions9. Moreover, not all stages of coagulation Any disagreement was solved by consensus. can be monitored10 and the assays have a reduced standardisa- tion and validation of reference ranges compared with standard Outcomes laboratory tests.11,12 Moreover, both in cardiac and noncardiac surgical settings, The primary endpoint was the number of patients transfused there is no strong evidence about the efficacy of VE tests in with packed red blood cells, fresh frozen plasma, and platelets. reducing the incidence of strong negative outcomes in patients Secondary endpoints were as follows: (1) total blood loss, (2) receiving VE-guided bleeding management. A recent meta- intensive care unit (ICU) stay, (3) ventilation time, (4) re-ster- analysis of the use of VE hemostatic assays in noncardiac surgi- notomy for bleeding, and (5) mortality. cal settings showed that no definitive evidence can be drawn about the efficacy of these tests due to the high heterogeneity of Selection Criteria the studies considered.13 Similar results in terms of lack of effect on outcomes have been demonstrated by Serraino et al.14 Two authors (MM and AM) screened the literature and In the light of this persistent uncertainty, the authors conducted selected potential relevant articles. Inclusion criteria were the present study to assess the effects of VE-guided manage- established a priori. Inclusion criteria were randomized con- ment of bleeding/coagulopathy in cardiac surgery. trolled trials that studied the effect of VE testing on allogenic blood products exposure in adult cardiac surgery. Material and Methods Moderators (Covariates) Analysis Data Sources and Search Strategy The following covariates (moderators) were considered as A systematic review and meta-analysis were performed in factors that potentially could affect the efficacy of viscoelastic accordance with the standards set forth by the Preferred (VE) tests in reducing patients’ exposure to allogenic blood Reporting Items for Systematic Reviews and Meta-Analyses products: (1) intraoperative routine use of antifibrinolytics, (2) statement.15 PubMed, EMBASE, Web of Science, and the percentage of high-risk interventions in each study, (3) preop- Cochrane Collaboration were searched (see Appendix 1 for erative percentage of patients in antiaggregant therapy, (4) the research strategy used in the study). In addition, referen- quality of transfusion algorithm, (5) type of VE test used ces of retrieved articles were hand-searched, and PubMed’s (TEG or ROTEM), and (6) preoperative anemia. The present related articles featurewasusedtoidentifystudiesnotcap- study tested whether any of these factors explained the hetero- tured by the present study’s primary search strategy. Parallel geneity identified in the results. A detailed moderators analysis group, randomized controlled trials were included. If neces- is reported in Appendix 3. sary, the investigators and authors were contacted in order to retrieve the relevant data. Studies with nonstandard designs, Data Analysis such as crossover trials, were not included. No subgroup of the patient population was excluded. The final search was run Random-effects models were used to determine the effect of on April 22, 2019. VE tests a priori because random-effects models handle ARTICLE IN PRESS
M. Meco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 1 9 3 heterogeneity more precisely.17 For dichotomous outcomes, the those for a single trial, analogous trial sequential monitoring relative effect sizes were calculated as an odds ratio (OR) with boundaries can be applied to a meta-analysis as a trial sequen- 95% confidence interval (CI). For continuous outcomes, esti- tial analysis (TSA). Cumulative meta-analyses of trials are at mates reported as mean difference with 95% CI were pooled. risk of producing random errors because of few data and repet- Heterogeneity was assessed using the I2 statistic. Values itive testing of accumulating data and because the requirement from 50% to 75% were considered to represent substantial het- for the amount of information analogous to the simple size of erogeneity and from 75% to 100% considerable heterogeneity. a single optimally powered clinical trial might not be met. Meta-regression analysis was used to explore whether the The underlying assumption for TSA is that significance test- aforementioned covariates affect the relative effectiveness of ing and CI calculation are performed each time a new trial is VE tests and whether these variables account for part of the published. TSA depends on the quantification of the required heterogeneity observed. The authors expected the inclusion of amount of information. TSA-adjusted CIs are derived consid- covariates to explain some of the between-study heterogeneity. ering the adjusted levels of statistical significance calculated A negative value suggests that covariates predict less heteroge- by sequential monitoring boundaries, thereby taking into neity than what would be expected by chance. account how much information actually has been accrued con- sidering the effect size originally anticipated.19 For the present Publication Bias study, TSA was used to infer whether the cumulative existing evidence is sufficient to draw firm conclusions using 2-sided Small-study effects were explored for both visually by tests with type I error set at 5% and power set at 80%, and drawing a funnel plot and statistically by applying Egger’s TSAs were performed on only blood product exposure. regression test. An asymmetric funnel plot is expected in the Other data were derived from the meta-analyses results as a presence of publication bias. measure of diversity (D2), which is a measure of heterogeneity Normal quantile plots often are used to assess data normal- measuring the proportion of between-trial variance to the sum ity. The normal quantile plot for meta-analysis has each indi- of the between-trial variance and the arithmetic mean of the vidual study’s z score on the y-axis and the normalized within-trial variances from the included trials. For the present quantile of its rank on the x-axis. The plot can be used in meta- study, the authors used as quantification of D2 between analysis to check the normality of the data (dots expected on a included trials in a meta-analysis the relative model variance straight line), to investigate heterogeneity (clustering of dots), reduction when the model of pooling was changed from a ran- and to assess for the presence of publication bias (deviation of dom-effects model into a fixed-effect model.20 The required the tails from the regression line). information size for each meta-analysis was adjusted for D2. The Galbraith plot was used to identify potential outlier studies after which their influence on pooled effects and/or heterogeneity was examined graphically. Outlier analysis was directed at studies Software Used in the overall findings and in the power groups. The L’Abb eplot plots the risks (or odds) in the exposed, or index, group (y-axis) The following software were used for the present study: Review against those of the control group (x-axis) and contains a regres- Manager, version 5.3 (Cochrane, London, United Kingdom) for sion line and a central diagonal line indicating identical risks in the meta-analyses; (2) R (R Project for Statistical Computing) for each group. The sizes of the dots are proportional to the study the meta-regression and publication bias; (3) GRADEpro Guide- weights. This plot was used to view the range of event rates line Development Tool (McMaster University [developed by Evi- among the trials to highlight excessive heterogeneity.18 dence Prime, Inc], Canada) for developing the group reading assessment and diagnostic evaluation; and (4) TSA software, ver- Sensitivity Analysis sion 0.9 beta (Copenhagen Trial Unit, Denmark), for TSAs.
A random-effects model was used for primary analysis and a Results fixed-effects model for sensitivity analysis. The results from the 2 models were compared. If the results between the 2 mod- Characteristics of Included Studies els were similar, the results from the random-effects analysis were reported, and if the results differed substantially, the The study selection process is shown in Figure 1. After authors evaluated for small-study effects. exclusion of duplicate or irrelevant references, 37 potentially relevant articles were retrieved. After detailed evaluation, 8 Trial Sequential Analyses comparative randomized controlled trials21-28 met the inclu- sion criteria and were considered in the present meta-analysis, In a single trial, interim analyses increase the risk of type I including a total of 1,035 patients, 522 patients in whom a error. To avoid an increase in the overall type I error, monitor- TEG- or ROTEM-based transfusion algorithm was used and ing boundaries can be applied to decide whether a single ran- 513 patients with a transfusion algorithm based solely on clin- domized trial could be terminated early because of the p value icians’ discretion. The list of included studies and the quality being sufficiently small. Because no reason exists why the assessment for each study are presented in Table 1. A complete standards for a meta-analysis should be less rigorous then list of excluded studies is reported in Appendix 4. ARTICLE IN PRESS
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size ranged from 26 to 7,402. The trial that enrolled 7,402 patients24 was a multicenter, stepped wedge cluster, random- ized control trial. To adjust for the stepped wedge cluster design, the effective sample size was recalculated according to the recommendation in the Cochrane Handbook, using the intracluster coefficient calculation of 0.095. Five trials evaluated the efficacy of bleeding management algorithms based on TEG results,21,22,23,25,27 and 3 trials evalu- ated the efficacy of bleeding management algorithms based on ROTEM.24,26,28 Bleeding management in control patients was based on standard laboratory tests in combination with clin- icians’ discretion in all included trials. One trial21 randomly assigned patients in the following different groups: in the first group, a multiple electronic aggregometry-based algorithm was used; in the second group, a TEG-based algorithm was used; and in the third group, only clinical judgment was used. For that trial, the authors of the present study analyzed the results by comparing the TEG-based group and patients in whom clinical judgment was used.
Risk of Bias
One trial26 was judged to be at low risk of bias for the recruitment bias, loss of clusters, and incorrect analysis. Ran- dom sequence generation was adequate in 5 trials21-25 and was unclear in 3 trials.26-28 Allocation concealment was unclear in all trials. In all included trials there was unclear evidence of blinding of patients and clinical staff caring for patients. The complete analysis of bias risk is reported in Appendix 3.
Primary Outcomes
Seven RCTs 21 27 reported data on the blood exposition, RBCs transfusion, platelets transfusions. Blood exposition was significantly lower in patients treated with VE tests-guided algorithms (288/511) versus controls (330/499), (OR: 0.85, 95% CI: 0.74-0.97, p: 0.002), but there was a substantial heterogeneity (I2: 58%) (Fig 2, A). RBCs transfusion was reduced in patients treated with VE testing algorithms (OR: 0.55, 95% CI: 0.34-0.88, p: 0.01, I2: 64%) (Fig 2, B). Platelet transfusion was reduced in patients treated with VE testing algorithms (OR: 0.54, 95% CI: 0.30-1, p: 0.05, I2: 73%) (Fig 2, C). The summary effects estimate for VE testing versus control for fresh frozen plasma transfusion was a risk difference of 0.24 (95% CI: 0.12-0.36, p<0.0001, I2: 81%) (Fig 2, D). Three trials21,26,27 reported data on the number of patients receiving cryoprecipitate. The summary effects estimate for VE testing versus controls was OR 0.31 (957% CI: 0.04-2.32, Fig 1. Study selection process. p=0.26, I2: 78%) (Fig 3, A).
Secondary Outcomes Meta-Analyses Results Bleeding and Redo Surgery Of the 8 trials identified, 3 enrolled adults patients undergo- Three studies25-27 reported the effects of VE testing algo- ing coronary artery bypass grafting,21-23 and 5 enrolled adult rithms on bleeding after 12 hours of intervention. The summary patients undergoing mixed cardiac surgery.24-28 The sample effects estimate for VE testing versus control patients was mean ARTICLE IN PRESS
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Table 1 Characteristics of the Included Studies
Number of Type of Inclusion Intervention Reference Patients Study Criteria Test Control Test Outcomes
Karkouti (2016)24 7,402 Mixed cardiac surgery ROTEM Standard laboratory tests Blood products transfusion, bleeding, complications Weber (2012)26 100 RCT Mixed cardiac surgery ROTEM Standard laboratory tests Transfusion, bleeding, complications, mortality Westbrook (2009)27 60 RCT Mixed cardiac surgery TEG Standard laboratory tests Transfusion, bleeding, complications, mortality Ak (2009)22 224 RCT CABG TEG Standard laboratory tests Transfusion, bleeding, complications, mortality Avidan (2004)23 102 RCT CABG TEG Standard laboratory tests Transfusion, bleeding, and redo surgeries Agarwal (2015)21 165 RCT CABG TEG Standard laboratory tests Transfusions, bleeding, redo surgery, intensive care unit stay Shore-Lesserson (1999)25 105 RCT Mixed cardiac surgery TEG Standard laboratory tests Transfusions, bleeding Lehmann (2019)28 26 RCT Mixed cardiac surgery ROTEM Standard laboratory tests Transfusions, bleeding
Abbreviations: CABG, coronary artery bypass grafting; ICU, intensive care unit; RCT, randomized controlled trials; ROTEM, rotational thromboelastometry; TEG, thromboelastography. difference (MD) 178.7 (95% CI: 308.9 to 48.4); p = 0.007; Publication Bias I2 84%, showing that 12-hour bleeding was reduced signifi- A visual inspection of the funnel plot showed asymmetry cantly in VE testing patients (Fig 3, B). Four studies23,25-27 (Fig 5, A). This finding was further evaluated by conducting reported the effects of VE testing algorithms on bleeding after Egger’s test for small-study effects (regression line showing 24 hours from surgery. The summary effects estimate for VE the association between standard error (SE) and effect size testing versus control patients was MD 175.4 (95% CI embedded in the funnel plot), which gave a p value of 0.099 305.78 to 40.9; p = 0.01; I2: 6%), showing that 24-hour when all studies were considered, clearly suggesting the pres- bleeding also was reduced significantly in VE testing patients ence of small-study effects. (Fig 3, C). Use of VE testing resulted in a significant reduction Small-study effects may be caused by publication bias or true in the number of redo surgeries for bleeding (OR: 0.51; 95% differences between small and large studies. By drawing a trim CI: 0.28-0.94; p = 0.03; I2:0%)(Fig 4,A). and fill analysis, the authors found that there were no missing stud- Use of VE testing resulted in a significant reduction in ICU ies, suggesting that the omission of small negative studies may be stay (OR: 4.03; 95% CI: 6.28 to 1.78; p = 0.005; I2: 91%) not the cause for the asymmetry in the funnel plot (Fig 5,E). (Fig 4, C), whereas the summary effects estimate for VE test- In order to investigate the asymmetry of the funnel plot fur- ing versus control patients showed no difference in mortality ther, several regression tests for publication bias were used. between the 2 groups (OR: 0.57; 95% CI: 0.18-1.74; p = 0.38; None of the regression tests showed important publication bias I2: 42%) (Fig 4, D).
Fig 2. Meta-analysis of studies assessing the effect of viscoelastic testing on (A) allogenic blood products transfusions, (B) red blood cell exposition, (C) platelet exposition, (D) fresh frozen plasma transfusion. ARTICLE IN PRESS
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Fig 3. Meta-analysis of studies assessing the effect of viscoelastic testing on (A) cryoprecipitate transfusion, (B) 12-hour postoperative bleeding, (C) 24-hour post- operative bleeding. in the present study, leading the authors to believe that publica- effect size was significantly related to the quality of transfu- tion bias was not a significant problem in the present study. sion algorithm used. The results are presented in Appendix 5. The authors believe that this evidence is able to justify the Meta-Regression Results presence of significant heterogeneity among the trials inserted in this meta-analysis. Meta-regression analyses were performed to explore It should be noted that in applying multiple univariate meta- whether differences in true effect sizes were explained by the regression, the present study ran a high risk of spurious find- following: (1) intraoperative routine use of antifibrinolytics, ings due to an inflated type I error rate, and the possibility of (2) percentage of high-risk surgery (defined according to the confounders cannot be excluded. definition of “high-risk surgery” or “complex surgery” in each study), (3) preoperative percentage of patients in antiaggregant Trial Sequential Analysis therapy, (4) quality of transfusion algorithm used, and (5) VE test type used (TEG or ROTEM). The logarithm of the TSA for blood product exposure was conducted with the fol- observed OR with these covariates was regressed, and the lowing conditions: boundary type was 2-sided, type I error of
Fig 4. Meta-analysis of studies assessing the effect of viscoelastic testing on (A) redo surgery, (B) nonsurgical causes redo sternotomy, (C) intensive care unit stay, (D) mortality. CES, xxx. ARTICLE IN PRESS
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Fig 5. Publication bias. (A) Funnel plot. (B) Galbraith plot. (C) L’Abb e plot. (D) Normal quartile plot. (E) Trim and fill analysis results.
5%, and type II error of 20% (80% power). The TSA was per- bleeding at both 12 hours and 24 hours was observed. The formed using an a priori anticipated intervention effect of 20% meta-analysis also demonstrated a significant decrease in the relative risk reduction (RRR), diversity of 30% in the included incidence of redo sternotomies that were not due to surgical trials, and a control event proportion derived from the accumu- causes in patients treated with VE tests. Furthermore, the use of lated control group of the included trial. TSA confirmed the evidence on the effects of VE tests in reduc- By using these assumptions, the required information size ing the exposure to blood products in general. was 621, being considerably lower under these data-driven Upon analysis of publication bias, asymmetry of the funnel assumptions. The trial sequential monitoring boundaries for plot was observed, indicating the presence of publication bias, benefit were surpassed, the required information size to detect but none of the regression tests showed important publication or reject an RRR of 20% was reached, and the TSA-adjusted bias in the present study. The meta-regression analyses identi- CI was similar to the conventional 95% CI (0.72-0.86) (Fig 6). fied 2 significant associations—the intraoperative use of antifi- brinolytics and the proportion of high-risk interventions in Sensitivity Analysis each study. These modifiers are associated with different degrees of efficacy of VE tests in reducing patients’ exposure Sensitivity analyses for the primary outcomes was per- to blood products. This evidence led the authors to conclude formed by evaluating the difference in the outcome direction, that probably the asymmetry highlighted in the funnel plot, magnitude, and significance when fixed-effect and random- although minimal, still was justifiable by the presence of a effects models were used for the meta-analysis or if studies “clinical” heterogeneity within the studies. that scored “unclear” in more than 3 of the Cochrane risk of The TSA, as described by Kulynskaja,19 was performed bias assessment were removed. No difference in the direction with the sole purpose of clarifying whether this meta-analysis of any outcome variable was found. could provide firm evidence for what concerned the exposure of patients to allogeneic blood products. We have not analyzed Discussion other outcomes as VE tests in cardiac surgery are not intended to reduce the mortality, but to manage in the best possible way By using conventional meta-analysis, the present study dem- the administration of allogeneic blood products. onstrated that the routine use of VE blood tests in adult cardiac A TSA using an anticipated intervention effect derived from surgery patients decreases the number of patients who under- the point estimate of the RRR was evaluated. went transfusions with fresh frozen plasma, platelets, and red The blood product exposition meta-analysis with an antici- blood cells. In addition, a significant reduction in postoperative pated intervention effect of 20% RRR provided TSA analysis ARTICLE IN PRESS
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Fig 6. Trial sequential analysis shows that there was enough information to confirm an relative risk reduction (RRR) of 20% (trial sequential analysis adjusted 95% confidence interval 0.72-0.86). The z curve crosses the boundaries for benefit. with breakthrough of the trial sequential monitoring bound- exposure to allogenic blood products. Choosing an indirect effect aries, confirming the positive results of the primary meta- as a primary outcome is a methodological mistake potentially analysis. compromising all the results of the study. Similarly, to include in In a recent meta-analysis, Serraino et al.29 identified15ran- the meta-analysis unpublished conference abstracts increases the domized controlled trials, of which none was judged to be free risk of bias and altering meta-analysis data. Moreover, Serraino from potential bias. They showed that TEG- or ROTEM-guided et al. included in their meta-analysis studies on the pediatric pop- algorithms for management of coagulopathic hemorrhage ulation with cyanogenic heart disease, which is notoriously reduced the number of patients requiring transfusions but had no accompanied by major specific clotting abnormalities. effect on mortality, stroke, prolonged intubation, emergency Whiting et al.7 in a systematic review concluded that VE tests redo surgery for bleeding, and ICU and hospital length of stay. were likely to be cost-effective. Their analysis, based on histori- The group reading assessment and diagnostic evaluation assess- cal data showing strong associations between red blood cell ment concluded that the quality of evidence was “low” or “very transfusion and adverse clinical outcomes, directly informed low” for all outcomes. It also determined that trials without pro- current National Health Service NICE guidelines, which recom- spective trial registration or availability of trial protocols for ref- mend routine use of VE testing in cardiac surgery. erence should be categorized as having unclear evidence of The strength of this meta-analysis is the construction of a reporting bias. These findings led Serraino et al.29 to hypothesize sound study aimed at obtaining reliable clinical data on the use that VE tests lack clinical effectiveness and to conclude that of VE tests in adult cardiac surgical patients, who represent additional larger trials are unlikely to demonstrate clinical bene- the real world of the authors’ clinical activity. fits for current VE point-of-care tests and that research should The authors of the present study tried to omit from their focus on development of new techniques. In the opinion of the meta-analysis any study that could represent a “confounder” authors of the present study, choosing postoperative mortality as (eg, surgery of cyanogenic defects or surgery in hypothermic a primary outcome is misleading; the main effect of VE tests is circulatory arrest). Moreover, by using TSA, VE tests were to reduce postoperative bleeding and blood product consumption observed to decrease the exposure of patients to allogeneic and possibly reduce mortality as a consequence of minor blood products. This study appears to demonstrate that the use ARTICLE IN PRESS
M. Meco et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 1 9 9 of VE tests in cardiac surgery to guide transfusion strategy is 10 Lanc e MD. A general review of major global coagulation assays: Throm- effective in reducing allogenic blood products exposure and belastography, thrombin generation test and clot waveform analysis. postoperative bleeding at 12 and 24 hours after surgery. Thromb J 2015;13:1. 11 Kitchen DP, Kitchen S, Jennings I, et al. Quality assurance and quality control of thrombelastography and rotational thromboelastometry: The UK Limitations NEQAS for blood coagulation experience. Semin Thromb Hemost 2010;36:757–63. The main limitation was the important heterogeneity present 12 Yeung MCF, Tong SYT, Tong PYW, et al. Use of viscoelastic haemostatic in the conventional meta-analysis. In the authors’ opinion, the assay in emergency and elective surgery. Hong Kong Med J 2015;21:45–51. 13 Franchini M, Mengoli C, Cruciani M, et al. The use of viscoelastic haemo- meta-regression provided valid indications that the majority of static assays in non-cardiac surgical settings: A systematic review and the observed heterogeneity was not a result of selection bias meta-analysis. Blood Transfus 2018;16:235–43. but rather clinical reasons. 14 Serraino GF, Murphy GJ. Effects of cerebral near-infrared spectroscopy on the outcome of patients undergoing cardiac surgery: A systematic review of randomised trials. BMJ Open 2017;7:e016613. Conclusions 15 Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate This study demonstrates that the use of VE-guided manage- health care interventions: Explanation and elaboration. J Clin Epidemiol ment of bleeding/coagulopathy in cardiac surgery is effective 2009;62:e1–34. in reducing allogenic blood products exposure and postopera- 16 Wan X, Wang W, Liu J, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. tive bleeding at 12 and 24 hours after surgery. BMC Med Res Methodol 2014;14:135. 17 Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s Declaration of Competing Interest tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. 18 Bax L, Ikeda N, Fukui N, et al. More than numbers: The power of graphs in meta-analysis. Am J Epidemiol 2008;169:249–55. The authors have no conflicts of interest to disclose. 19 Kulinskaya E, Wood J. Trial sequential methods for meta-analysis. Res Synth Methods 2014;5:212–20. Supplementary materials 20 Pogue JM, Yusuf S. Cumulating evidence from randomized trials: Utiliz- ing sequential monitoring boundaries for cumulative meta-analysis. Con- trol Clin Trials 1997;18:580–93;discussion 661-6. Supplementary material associated with this article can be 21 Agarwal S, Johnson RI, Shaw M. Preoperative point-of-care platelet found in the online version at doi:10.1053/j.jvca.2019.06.030. function testing in cardiac surgery. J Cardiothorac Vasc Anesth 2015;29: 333–41. 22 Ak K, Isbir CS, Tetik S, et al. Thromboelastography-based transfusion References algorithm reduces blood product use after elective CABG: A prospective randomized study. J Card Surg 2009;24:404–10. 1 Hardy J-F, de Moerloose P, Samama CM, et al. Massive transfusion and 23 Avidan MS, Alcock EL, Da Fonseca J, et al. Comparison of structured use coagulopathy: Pathophysiology and implications for clinical management. of routine laboratory tests or near-patient assessment with clinical judge- Can J Anaesth 2006;53:S40–58. ment in the management of bleeding after cardiac surgery. Br J Anaesth 2 Ranucci M, Baryshnikova E, Castelvecchio S, et al. Major bleeding, trans- 2004;92:178–86. fusions, and anemia: The deadly triad of cardiac surgery. Ann Thorac Surg 24 Karkouti K, Callum J, Wijeysundera DN, et al. Point-of-care hemostatic 2013;96:478–85. testing in cardiac surgery: A stepped-wedge clustered randomized con- 3 Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on trolled trial. Circulation 2016;134:1152–62. prognosis in patients with acute coronary syndromes. Circulation 25 Shore-Lesserson L, Manspeizer HE, DePerio M, et al. Thromboelastogra- 2006;114:774–82. phy-guided transfusion algorithm reduces transfusions in complex cardiac 4 Besser MW, Klein AA. The coagulopathy of cardiopulmonary bypass. Crit surgery. Anesth Analg 1999;88:312–9. Rev Clin Lab Sci 2010;47:197–212. 26 Weber CF, Gorlinger€ K, Meininger D, et al. Point-of-care testing: A pro- 5 Luddington RJ. Thrombelastography/thromboelastometry. Clin Lab Hae- spective, randomized clinical trial of efficacy in coagulopathic cardiac sur- matol 2005;27:81–90. gery patients. Anesthesiology 2012;117:531–47. 6 Chee Y-L, Greaves M. Role of coagulation testing in predicting bleeding 27 Westbrook AJ, Olsen J, Bailey M, et al. Protocol based on thromboelasto- risk. Hematol J 2003;4:373–8. graph (TEG) out-performs physician preference using laboratory coagula- 7 Whiting P, Al M, Westwood M, et al. Viscoelastic point-of-care testing to assist tion tests to guide blood replacement during and after cardiac surgery: A with the diagnosis, management and monitoring of haemostasis: A systematic pilot study. Heart Lung Circ 2009;18:277–88. review and cost-effectiveness analysis. Health Technol Assess 2015;19:1–228. 28 Lehmann F, Rau J, Malcolm B, et al. Why does a point of care guided 8 Whitson BA, Huddleston SJ, Savik K, et al. Bloodless cardiac surgery is transfusion algorithm not improve blood loss and transfusion practice in associated with decreased morbidity and mortality. J Card Surg patients undergoing high-risk cardiac surgery? A prospective randomized 2007;22:373–8. controlled pilot study. BMC Anesthesiol 2019;19:24. 9 Biancofiore G. Perioperative coagulation management and point-of-care 29 Serraino GF, Murphy GJ. Routine use of viscoelastic blood tests for diag- monitoring in anesthesia. In: Chiumello D, ed. Practical trends in anesthe- nosis and treatment of coagulopathic bleeding in cardiac surgery: Updated sia and intensive care, New York: Springer; 2018:3–19. systematic review and meta-analysis. Br J Anaesth 2017;118:823–33.