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J Thorac Cardiovasc Surg 2006;132:475-480
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

A randomized trial of tranexamic acid in combination with cell salvage plus a meta-analysis of randomized trials evaluating tranexamic acid in off-pump coronary artery bypass grafting

^a Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom
^b Department of Cardiac Surgery, Clinica Montevergine, Mercogliano, Avellino, Italy.

Received for publication October 21, 2005; revisions received January 6, 2006; accepted for publication January 17, 2006.

^_* Address for reprints: G. D. Angelini, MD, FRCS, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom (Email: G.D.Angelini{at}bristol.ac.uk).

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

 
OBJECTIVES: We sought to evaluate the effectiveness of tranexamic acid in off-pump coronary artery bypass grafting surgery, either when used in combination with mechanical cell salvage or when used alone.

METHODS: One hundred patients were randomized to either 2 g of tranexamic acid as an intravenous bolus before sternotomy or to placebo. Intraoperative and postoperative cell salvage was used in all patients. The primary end point was early postoperative blood loss (within 4 hours). To evaluate the efficacy of tranexamic acid in isolation, we also performed a meta-analysis of 4 randomized trials identified from a systematic literature search. The primary end point of the meta-analysis was red cell transfusion.

RESULTS: In our randomized trial patients in the tranexamic acid group had a significant reduction in early postoperative blood loss, (median difference, 50 mL; 95% confidence interval, 15-100 mL; P < .01); however, there was no reduction in the frequency of blood component transfusion. Patients in the placebo group received a significantly larger volume of autotransfused red cells (median difference, 120 mL; 95% confidence interval, 0-220 mL; P = .02). The meta-analysis demonstrated a significant reduction in red cell transfusions in patients receiving tranexamic acid compared with those receiving placebo (risk ratio, 0.48; 95% confidence interval, 0.24-0.97; P = .041). There was also a reduction in the frequency of any allogeneic blood component transfusion, as well as a highly significant reduction in postoperative blood loss, in patients receiving tranexamic acid (P < .001).

CONCLUSIONS: Tranexamic acid reduces blood loss and transfusion requirements in off-pump coronary artery bypass grafting surgery. A reduction in allogeneic blood transfusion was not evident in the presence of perioperative cell salvage. These data support the routine use of tranexamic acid in off-pump coronary artery bypass grafting surgery.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

 
The evidence base for the development of multimodality blood conservation protocols that minimize transfusion risk is incomplete. Transfusion of blood components increase health care costs both directly through the use of an increasingly scarce commodity and indirectly because of transfusion-associated morbidity attributed to immunosuppression, end-organ dysfunction, and the better-known but rare complications, such as viral transmission.^1–3 Off-pump coronary artery bypass grafting (OPCAB) surgery has been shown in a meta-analysis of randomized trials⁴ to reduce the need for allogeneic blood component transfusion compared with conventional coronary artery bypass grafting (CABG); however, up to a quarter of patients in OPCAB studies^5–7 still receive a transfusion. We have previously demonstrated that mechanical cell salvage and autotransfusion reduces allogeneic blood transfusion rates in OPCAB surgery.⁸ There is also evidence from several small randomized trials that tranexamic acid might reduce postoperative blood loss in OPCAB surgery.^9–12 The aim of the present randomized trial was to assess whether the combination of perioperative mechanical cell salvage plus the antifibrinolytic agent tranexamic acid results primarily in a significant reduction in postoperative blood loss and secondarily in a reduction in transfusion requirements compared with perioperative cell salvage plus placebo in patients undergoing OPCAB surgery. We also sought to establish whether the observed reductions in blood loss associated with tranexamic acid use translates into a reduction in red cell transfusions in a larger cohort by performing a meta-analysis of randomized trials that evaluated the efficacy of tranexamic acid alone versus placebo in OPCAB surgery.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

 
Study Population and Patient Allocation
Of 153 consecutive patients undergoing isolated OPCAB surgery at the Clinica Montevergine, Mercogliano, Avellino, Italy, over a 6-month period, 100 patients consented to enrollment in the study, 26 refused consent, and a further 27 were judged unsuitable according to the inclusion-exclusion criteria. Inclusion criteria were any male or female patients aged 18 years or older who were undergoing nonemergency first-time OPCAB surgery. Exclusion criteria included advanced chronic renal insufficiency (creatinine >2 mg/dL, n = 12), active chronic hepatitis or cirrhosis (n = 8), neurologic dysfunction (n = 4), and hematologic disorders (n = 1). Patients treated with aspirin or heparin, but not clopidogrel (n = 5), before the operation were enrolled (some patients met more than one exclusion criteria). The study received local ethics committee approval. Patients were assigned in a 1:1 ratio in a double-blind fashion to one of 2 randomized groups: a treatment group (50 patients) who received tranexamic acid as a bolus of 2 g over 20 minutes after the induction of anesthesia but before skin incision and a placebo control group (50 patients) who received a bolus of saline. Allocations were generated by a card system and concealed in sealed opaque envelopes. Both the staff of the operating room and that of the intensive care unit (ICU) were blinded regarding the treatment by the use of identical unmarked syringes for drug or placebo administration. The primary end point for the study was early postoperative blood loss (within 4 hours postoperatively). Given that mean blood loss 4 hours after OPCAB surgery is approximately 250 mL (standard deviation, 120 mL),^9–12 this study was powered to detect a 30% reduction in early blood loss (ie, a mean difference of 75 mL) with an value of .05 and a power of 0.8. Secondary end points included total blood loss defined as blood loss at the time of drain removal, frequency of red cell transfusion, and frequency of any blood component transfusion. This, as well as clinical outcome data, were collected prospectively on preprinted leaflets and transferred to a computerized database (Microsoft Access 2003; Microsoft Corp, Seattle, Wash).

Operative Technique
The anesthetic technique, including heparin dose (150 IU/kg), target activated clotting time of greater than 300 seconds, and protamine dose (1:1 ratio), was standardized for all patients and has been reported previously.¹³ The method of exposure and stabilization used to perform the anastomoses has been described previously.¹⁴ The target vessel was snared proximally before arteriotomy, and an intracoronary shunt (Anastoflo Intravascular Shunt; Research Medical Inc, Midvale, Utah) was used to perform each anastomosis to reduce blood loss.¹⁴ No patient had predonated autologous blood for use perioperatively. All patients underwent perioperative cell salvage (Fresenius C.A.T.S Continuous AutoTransfusion System; Fresenius Kabi Ltd, Warrington, United Kingdom) with autotransfusion of washed salvaged red cells at the completion of the operative procedure. After closure of the sternum, postoperative mediastinal drainage was achieved with 28F single-lumen rigid sump drains (1-3 in number) to a 1000-mL sterile collection chamber connected to 20 cm H₂O wall suction through an underwater seal, from which subsequent shed mediastinal fluid loss was then recorded. In accordance with unit protocols, where sufficient mediastinal loss occurred in any patient (>400 mL), the shed fluid was processed and washed, and shed cells were autotransfused at 6 hours postoperatively or sooner in the event of heavier blood loss. Chest drains were removed when bleeding was less than 100 mL in the preceding 4 hours.

Allogeneic Blood Component Transfusion
Perioperatively, all patients were administered homologous packed red cells as blood replacement therapy, according to predefined unit protocols. The threshold for transfusion of homologous blood was a hemoglobin concentration of less than 8.5 g/dL or a hematocrit value of less than 0.25. As part of routine postoperative care, haemoglobin concentration and hematocrit value were measured on arrival in the ICU and then at 2-hour intervals or as clinically indicated through the indwelling arterial cannula. In patients with excessive blood loss and cardiovascular instability, packed red cells were given at the discretion of anesthetic or ICU staff. Clotting products and platelets were administered at the discretion of the ICU staff in response to bleeding in the presence of coagulopathy or diminished platelet count. We also performed a comparison of hematologic and clotting pathway parameters in the postoperative period (Appendix E1).

Meta-analysis
The MEDLINE and PubMed databases (1966 through November 2004) were searched by using the medical subject headings for "Coronary artery bypass" or the text words "OPCAB" or "off pump" or "beating heart" or "randomized controlled trial" or "coronary arteriosclerosis" or "myocardial revascularization" combined with the text words "tranexamic acid" or "hemostatics" or "antifibrinolytic agents." In addition, the reference lists from relevant articles, abstracts, and reviews were also searched for additional trials. Study selection was as described in Figure E1. ^9–12 Studies were assessed and selected by a single observer (GJM) if they met the following criteria: (1) comparison of tranexamic acid with placebo; (2) patients undergoing OPCAB surgery; (3) prospective randomized controlled methodology; and (4) reporting of postoperative transfusion rates and postoperative blood loss. This identified 3 studies.^9–11 The primary end point for analysis was the frequency of red cell transfusion. Where these data were missing,¹¹ authors of the study were contacted individually to provide missing data (Table E1). This correspondence also resulted in the identification of a further randomized trial before its publication. This has subsequently been published.¹² A scoring system was not used, and all 4 studies were entered into the meta-analysis. Secondary end points included frequency of any blood component transfusion (early and total blood loss [reported in milliliters]) and the frequency of thromboembolic complications (venous thrombosis, thromboembolism, myocardial infarction, or stroke). In one study⁹ data on the total number of patients receiving any blood product were missing, and in this case the figures for the total number of patients receiving red cells were used in the meta-analysis. In 2 of the randomized trials^9,12 data were extracted from studies in which tranexamic acid versus placebo in OPCAB surgery comprised 2 of a total of 3¹² or 4⁹ randomized groups, respectively. The thresholds for allogeneic blood transfusion were broadly similar in all of the studies (hemoglobin, 8-8.5 g/dL), and the dose of tranexamic acid administered was the same, a 1-g bolus at anesthetic induction followed by a continuous infusion of 400 mg/h. Data from the present randomized trial were not included because of the significant differences in methodology, such as the use of cell salvage, that were likely to interact with the primary outcome.

View larger version (16K): [in this window] [in a new window]   Figure E1. Systematic literature search and study selection for meta-analysis. OPCAB, Off-pump coronary artery bypass grafting.

Meta-analysis was used to combine results from trials examining the effect of tranexamic acid on outcome. A fixed-effects model was chosen because only 4 trials were found. Study results were combined by using the Mantel-Haenszel method (transfusion requirement) or the inverse variance method (blood loss). Blood loss followed a skewed distribution and was transformed to the logarithmic scale for analysis. Results are presented as a risk ratio (transfusion requirement) or as a standardized mean difference (ln[blood loss]). Heterogeneity between studies was assessed by using the ² test. Data analysis was performed with SPSS for Windows, Version 9.0 (Chicago, Ill) and SAS version 8.2 (SAS Institute, Inc, Cary, NC; mixed regression models) and Stata, Version 8.2 (Stata Corporation, College Station, Tex) (meta-analysis) software packages. No correction was made for the number of outcomes compared. Our interpretation of the findings is based on the consistency of the findings and their magnitude, as well as their statistical significance.

	Results

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

 
Randomized Trial of Tranexamic Acid Versus Placebo in OPCAB Surgery
Preoperative and operative characteristics are shown in Table E2. The 2 groups were balanced preoperatively with respect to demographics and comorbidity, except for a higher proportion of triple-vessel disease in the tranexamic acid group (82% vs 62%, P = .026), although the number of grafts performed was similar. EuroSCOREs were similar for the 2 groups (P = .20, Table E2). Intraoperative characteristics were also well matched, apart from a longer median operation time in the placebo group (median, 240 [interquartile range, 205-270] vs 210 [interquartile range, 180-240]; P = .002). No patients were withdrawn from the study, and there was no crossover between the groups.

View larger version (8K): [in this window] [in a new window]   Figure 1. Effect of tranexamic acid on red cell transfusion after OPCAB surgery. Tranexamic acid significantly reduced red cell transfusion. There was no evidence of heterogeneity between the studies (heterogeneity test, 0.61; P = .90). 95% CI, 95% confidence interval.

View larger version (8K): [in this window] [in a new window]   Figure E2. Effect of tranexamic acid on the frequency of any blood component transfusion after off-pump coronary artery bypass grafting surgery. Tranexamic acid significantly reduced exposure to any allogeneic blood product (heterogeneity test, 0.61; P = .895). CI, Confidence interval.

View larger version (9K): [in this window] [in a new window]   Figure E3. Effect of tranexamic acid on 4-hour blood loss after off-pump coronary artery bypass grafting surgery. Distributions for blood loss followed a skewed distribution and were transformed to the logarithmic scale for meta-analysis. Values represent the standardized mean difference (ln[blood loss]) for tranexamic acid versus placebo. There was evidence to suggest heterogeneity between studies (heterogeneity test, 8.23; P = .041). CI, Confidence interval.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

Several observations should be considered when reviewing these results; first, in the randomized trial there was a longer operation time in the placebo group, despite similar numbers of bypass grafts between the groups. Prolonged operating times in CABG surgery are associated with greater blood loss and subsequently with blood transfusion.¹⁵ We also cannot discount that this time difference could have been attributable to more bleeding from the operative field, with longer closing times in the placebo group. The magnitude of the time difference was small, however, and there was no difference between the groups with regard to the decrease in hematocrit values between preoperative and immediate postoperative values. We therefore consider it unlikely that this affected our results. Second, median reduction in blood loss in the tranexamic acid group was 50 mL, which suggests a small treatment effect. When one also considers that the median difference in autotransfusion volumes was 120 mL, or approximately half a unit of packed leukodepleted red cells, (patients with only small volume losses over 6 hours were not autotransfused), one can surmise that the treatment effect might be more clinically significant than this figure suggests, however. By extrapolating from pharmacokinetic studies in patients undergoing conventional CABG,¹⁶ this 2-g bolus dose, approximately 25 mg/kg per patient, should be sufficient to inhibit fibrinolysis in vitro; however, when one considers that the effective half-life of tranexamic acid in patients with normal renal function is approximately 2 hours,¹⁷ this effect might not be sustained.¹⁶ It is noteworthy that total blood loss was not different between treatment and placebo in the current study, unlike those studies cited in the meta-analysis,^9–12 in which an infusion was maintained intraoperatively. Although our data suggest that that higher blood loss in the placebo group was counterbalanced by larger autotransfusions, resulting in equivalent rates of allogeneic transfusion, we cannot exclude the possibility that a larger tranexamic acid dose or an intraoperative infusion might have produced a different result. Third, the randomized study presented here excluded many high-risk patients and is not absolutely representative of the patient population at this institution. Similar criticisms can be made of the studies incorporated into the meta-analysis, where the cohorts recruited appeared to have generally low transfusion risks (few female subjects, relatively high mean body mass, and young patients with good ventricles undergoing nonemergency operations). Whether the observations made either in our randomized trial or in the meta-analysis would also apply in higher-risk cases cannot be extrapolated from these data. Another limitation of the meta-analysis is the small sample size. As well as limiting the power of our observations, it also prevents us from commenting on the safety of tranexamic acid in this setting, given the relative rarity of thromboembolic complications. We have previously calculated that any clinical study powered to detect a significant reduction (10%) in the frequency of allogeneic blood exposure in our OPCAB practice (overall allogeneic transfusion rate, 23%; power, 0.9; value, 0.05) would require more than 600 patients.⁸ This meta-analysis therefore represents the best available evidence to date supporting the efficacy of tranexamic acid in OPCAB surgery. Finally, in the meta-analysis there was heterogeneity between the studies for postoperative blood loss. This can be attributed to different transfusion risks among cohorts in different trials. For example preoperative aspirin within 5 days of the operation, a recognized risk factor for postoperative bleeding and blood transfusion,¹⁸ varied from approximately 25% in one study to 47% in another.^9,11 That this did not translate into heterogeneity between the trials for blood transfusion rates presumably reflects the large differences in blood loss required to alter transfusion rates.

In conclusion, we have previously demonstrated a reduction in postoperative blood loss with the use of mechanical cell salvage in OPCAB surgery. The meta-analysis presented here demonstrates a significant reduction in blood transfusion rates when tranexamic acid is used in isolation. Our randomized trial suggests that tranexamic acid reduces blood loss when combined with perioperative cell salvage; however, there is no reduction in the frequency of allogeneic transfusion. Larger trials are required to confirm these findings and develop more comprehensive multimodality protocols for reducing exposure to allogeneic blood products.

	Appendix E1

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

 
Laboratory Measurements of Clotting Pathway Function
Measurement of hematocrit values, platelet counts, clotting pathway function (prothrombin time and international normalized ratio of the prothrombin time, measurement of the extrinsic and common clotting pathways, and measurement of activated partial thromboplastin time expressed as the activated partial thromboplastin time ratio to a normalized control value, a measure of the intrinsic and common clotting pathways), and serum fibrinogen levels were performed preoperatively, immediately postoperatively on admission to the ICU, and then at 24 and 48 hours postoperatively.

Statistical Analysis
Postoperative measurements of hematocrit values, platelet count, clotting parameters, and renal function were compared by using a mixed regression model, with adjustment for preoperative readings. A variety of models describing the correlation between repeated measurements on the same patient were examined, and the structure leading to the lowest value for the Schwarz's Bayesian information criterion was chosen in each case. Creatinine measurements followed a skewed distribution and were transformed to the logarithmic scale for analysis. Changes in treatment effect over time were assessed by using the F test, and if statistically significant at the 10% level, the treatment difference is reported separately at each time point; otherwise, an overall effect of treatment is given (estimate of common difference). Results are presented as least squares means and as difference between means with 95% confidence intervals. Creatinine results are presented as geometric means and as a ratio of geometric means.

	Acknowledgments

 
We thank Dr Tomas Vanek and Dr Martin Jares, Department of Cardiac Surgery, 3rd Medical School of Charles University, Prague, Czech Republic, for their helpful contributions to this study. We also thank Lucy Culliford for designing the trial database.

	References

Top Abstract Introduction Patients and Methods Results Discussion Appendix E1 References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Gavin J. Murphy Vincenzo Lucchetti Francesco Battaglia Gianni D. Angelini Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murphy, G. J. Articles by Angelini, G. D. Search for Related Content PubMed PubMed Citation Articles by Murphy, G. J. Articles by Angelini, G. D. Related Collections Cardiac - other Coronary disease Minimally invasive surgery