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A Systematic Review and Meta-analysis of Randomized Controlled Trials Comparing Intraoperative Red Blood Cell Transfusion Strategies
Lenet T, Baker L, Park L, Vered M, Zahrai A, Shorr R, Davis A, McIsaac DI, Tinmouth A, Fergusson DA, et al
Annals of surgery. 2021
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Editor's Choice
Abstract
OBJECTIVE The objective of this work was to carry out a meta-analysis of RCTs comparing intraoperative RBC transfusion strategies to determine their impact on postoperative morbidity, mortality, and blood product use. SUMMARY OF BACKGROUND DATA RBC transfusions are common in surgery and associated with widespread variability despite adjustment for casemix. Evidence-based recommendations guiding RBC transfusion in the operative setting are limited. METHODS The search strategy was adapted from a previous Cochrane Review. Electronic databases were searched from January 2016 to February 2021. Included studies from the previous Cochrane Review were considered for eligibility from before 2016. RCTs comparing intraoperative transfusion strategies were considered for inclusion. Co-primary outcomes were 30-day mortality and morbidity. Secondary outcomes included intraoperative and perioperative RBC transfusion. Meta-analysis was carried out using random-effects models. RESULTS Fourteen trials (8641 patients) were included. One cardiac surgery trial accounted for 56% of patients. There was no difference in 30-day mortality [relative risk (RR) 0.96, 95% confidence interval (CI) 0.71-1.29] and pooled postoperative morbidity among the studied outcomes when comparing restrictive and liberal protocols. Two trials reported worse composite outcomes with restrictive triggers. Intraoperative (RR 0.53, 95% CI 0.43-0.64) and perioperative (RR 0.70, 95% CI 0.62-0.79) blood transfusions were significantly lower in the restrictive group compared to the liberal group. CONCLUSIONS Intraoperative restrictive transfusion strategies decreased perioperative transfusions without added postoperative morbidity and mortality in 12/14 trials. Two trials reported worse outcomes. Given trial design and generalizability limitations, uncertainty remains regarding the safety of broad application of restrictive transfusion triggers in the operating room. Trials specifically designed to address intraoperative transfusions are urgently needed.
PICO Summary
Population
Adult patients undergoing surgery (14 studies, n= 8,641).
Intervention
Restrictive blood transfusion strategy.
Comparison
Liberal blood transfusion strategy.
Outcome
There was no difference in 30-day mortality relative risk (RR) 0.96, and pooled postoperative morbidity among the studied outcomes when comparing restrictive and liberal protocols. Two trials reported worse composite outcomes with restrictive triggers. Intraoperative (RR 0.53) and perioperative (RR 0.70) blood transfusions were significantly lower in the restrictive group compared to the liberal group.
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Phlebotomy resulting in controlled hypovolaemia to prevent blood loss in major hepatic resections (PRICE-1): a pilot randomized clinical trial for feasibility
Martel G, Baker L, Wherrett C, Fergusson DA, Saidenberg E, Workneh A, Saeed S, Gadbois K, Jee R, McVicar J, et al
The British journal of surgery. 2020
Abstract
BACKGROUND Major liver resection is associated with blood loss and transfusion. Observational data suggest that hypovolaemic phlebotomy can reduce these risks. This feasibility RCT compared hypovolaemic phlebotomy with the standard of care, to inform a future multicentre trial. METHODS Patients undergoing major liver resections were enrolled between June 2016 and January 2018. Randomization was done during surgery and the surgeons were blinded to the group allocation. For hypovolaemic phlebotomy, 7-10 ml per kg whole blood was removed, without intravenous fluid replacement. Co-primary outcomes were feasibility and estimated blood loss (EBL). RESULTS A total of 62 patients were randomized to hypovolaemic phlebotomy (31) or standard care (31), at a rate of 3.1 patients per month, thus meeting the co-primary feasibility endpoint. The median EBL difference was -111 ml (P = 0.456). Among patients at high risk of transfusion, the median EBL difference was -448 ml (P = 0.069). Secondary feasibility endpoints were met: enrolment, blinding and target phlebotomy (mean(s.d.) 7.6(1.9) ml per kg). Blinded surgeons perceived that parenchymal resection was easier with hypovolaemic phlebotomy than standard care (16 of 31 versus 10 of 31 respectively), and guessed that hypovolaemic phlebotomy was being used with an accuracy of 65 per cent (20 of 31). There was no significant difference in overall complications (10 of 31 versus 15 of 31 patients), major complications or transfusion. Among those at high risk, transfusion was required in two of 15 versus three of nine patients (P = 0.326). CONCLUSION Endpoints were met successfully, but no difference in EBL was found in this feasibility study. A multicentre trial (PRICE-2) powered to identify a difference in perioperative blood transfusion is justified. Registration number: NCT02548910 ( http://www.clinicaltrials.gov).
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Intraoperative Red Blood Cell Transfusion Decision-Making: A systematic Review of Guidelines
Baker L, Park L, Gilbert R, Ahn H, Martel A, Lenet T, Davis A, McIsaac DI, Tinmouth A, Fergusson DA, et al
Annals of surgery. 2020
Abstract
OBJECTIVES The objective of this work was to carry out a systematic review of clinical practice guidelines (CPGs) pertaining to intraoperative red blood cell (RBC) transfusions, in terms of indications, decision-making, and supporting evidence base. SUMMARY BACKGROUND DATA Red blood cell (RBC) transfusions are common during surgery and there is evidence of wide variability in practice. METHODS Major electronic databases (MEDLINE, EMBASE, and CINAHL), guideline clearinghouses and Google Scholar were systematically searched from inception to January 2019 for CPGs pertaining to indications for intraoperative RBC transfusion. Eligible guidelines were retrieved and their quality assessed using AGREE II. Relevant recommendations were abstracted and synthesized to allow for a comparison between guidelines. RESULTS Ten guidelines published between 1992 and 2018 provided indications for intraoperative transfusions. No guideline addressed intraoperative transfusion decision-making as its primary focus. Six guidelines provided criteria for transfusion based on hemoglobin (range 6.0-10.0 g/dL) or hematocrit (<30%) triggers. In the absence of objective transfusion rules, CPGs recommended considering other parameters such as blood loss (n = 7), signs of end organ ischemia (n = 5), and hemodynamics (n = 4). Evidence supporting intraoperative recommendations was extrapolated primarily from the non-operative setting. There was wide variability in the quality of included guidelines based on AGREE II scores. CONCLUSION This review has identified several clinical practice guidelines providing recommendations for intraoperative transfusion. The existing guidelines were noted to be highly variable in their recommendations and to lack a sufficient evidence base from the intraoperative setting. This represents a major knowledge gap in the literature.
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Efficacy and Safety of Tranexamic Acid in Major Non-Cardiac Surgeries at High Risk for Transfusion: A Systematic Review and Meta-Analysis
Houston BL, Uminski K, Mutter T, Rimmer E, Houston DS, Menard CE, Garland A, Ariano R, Tinmouth A, Abou-Setta AM, et al
Transfusion medicine reviews. 2019
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Editor's Choice
Abstract
Tranexamic acid (TXA) reduces transfusion requirements in cardiac surgery and total hip and knee arthroplasty, where it has become standard of care. Our objective is to determine the efficacy and safety of TXA in other surgeries associated with a high risk for red blood cell (RBC) transfusion. We identified randomized controlled trials in Medline, Embase, CENTRAL, and CAB abstracts from inception to June 2019. We included trials evaluating intraoperative IV TXA in adult patients undergoing a non-cardiac and non-hip and knee arthroplasty surgeries at high-risk for RBC transfusion, defined as a baseline transfusion rate ≥5% in comparator arm. We assessed risk of bias using the Cochrane Risk of Bias tool. We used GRADE methodology to assess certainty of evidence. From 8565 citations identified, we included 69 unique trials, enrolling 6157 patients. TXA reduces both the proportion of patients transfused RBCs (relative risk (RR) 0.59; 95% confidence interval (CI) 0.48 to 0.72; low certainty evidence) and the volume of RBC transfused (MD -0.51 RBC units; 95%CI -0.13 to -0.9 units; low certainty evidence) when compared to placebo or usual care. TXA was not associated with differences in deep vein thrombosis, pulmonary embolism, all-cause mortality, hospital length of stay, need for re-operation due to hemorrhage, myocardial infarction, stroke or seizure. In patients undergoing a broad range of non-cardiac and non-hip and knee arthroplasty surgeries at high risk for RBC transfusion, perioperative TXA reduced exposure to RBC transfusion. No differences in thrombotic outcomes were identified; however, summary effect estimates were limited by lack of systemic screening and short duration of follow-up.
PICO Summary
Population
Adult patients undergoing a non-cardiac and non-hip and knee arthroplasty surgeries at high-risk for RBC transfusion, (69 studies, n=6157).
Intervention
Intraoperative IV tranexamic acid (TXA).
Comparison
Placebo, usual care and active comparators.
Outcome
TXA reduces both the proportion of patients transfused RBCs (relative risk (RR) 0.59 and the volume of RBC transfused (MD -0.51 RBC units) when compared to placebo or usual care. TXA was not associated with differences in deep vein thrombosis, pulmonary embolism, all-cause mortality, hospital length of stay, need for re-operation due to hemorrhage, myocardial infarction, stroke or seizure. In patients undergoing a broad range of non-cardiac and non-hip and knee arthroplasty surgeries at high risk for RBC transfusion, perioperative TXA reduced exposure to RBC transfusion. No differences in thrombotic outcomes were identified; however, summary effect estimates were limited by lack of systemic screening and short duration of follow-up.
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Safety of a Restrictive versus Liberal Approach to Red Blood Cell Transfusion on the Outcome of AKI in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial
Garg AX, Badner N, Bagshaw SM, Cuerden MS, Fergusson DA, Gregory AJ, Hall J, Hare GMT, Khanykin B, McGuinness S, et al
Journal of the American Society of Nephrology : JASN. 2019
Abstract
BACKGROUND Safely reducing red blood cell transfusions can prevent transfusion-related adverse effects, conserve the blood supply, and reduce health care costs. Both anemia and red blood cell transfusion are independently associated with AKI, but observational data are insufficient to determine whether a restrictive approach to transfusion can be used without increasing AKI risk. METHODS In a prespecified kidney substudy of a randomized noninferiority trial, we compared a restrictive threshold for red blood cell transfusion (transfuse if hemoglobin<7.5 g/dl, intraoperatively and postoperatively) with a liberal threshold (transfuse if hemoglobin<9.5 g/dl in the operating room or intensive care unit, or if hemoglobin<8.5 g/dl on the nonintensive care ward). We studied 4531 patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high risk of perioperative death. The substudy's primary outcome was AKI, defined as a postoperative increase in serum creatinine of ≥0.3 mg/dl within 48 hours of surgery, or ≥50% within 7 days of surgery. RESULTS Patients in the restrictive-threshold group received significantly fewer transfusions than patients in the liberal-threshold group (1.8 versus 2.9 on average, or 38% fewer transfusions in the restricted-threshold group compared with the liberal-threshold group; P<0.001). AKI occurred in 27.7% of patients in the restrictive-threshold group (624 of 2251) and in 27.9% of patients in the liberal-threshold group (636 of 2280). Similarly, among patients with preoperative CKD, AKI occurred in 33.6% of patients in the restrictive-threshold group (258 of 767) and in 32.5% of patients in the liberal-threshold group (252 of 775). CONCLUSIONS Among patients undergoing cardiac surgery, a restrictive transfusion approach resulted in fewer red blood cell transfusions without increasing the risk of AKI.
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Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery
Mazer CD, Whitlock RP, Fergusson DA, Belley-Cote E, Connolly K, Khanykin B, Gregory AJ, de Medicis E, Carrier FM, McGuinness S, et al
The New England Journal of Medicine. 2018;379((13):):1224-1233.
Abstract
Background We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. Methods We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. Results At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive-threshold group and in 402 of 2347 patients (17.1%) in the liberal-threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], -1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive-threshold group and 6.4% in the liberal-threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between-group differences in the secondary outcomes. Conclusions In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).
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Restrictive or liberal red-cell transfusion for cardiac surgery
Mazer CD, Whitlock RP, Fergusson DA, Hall J, Belley-Cote E, Connolly K, Khanykin B, Gregory AJ, de Medicis E, McGuinness S, et al
The New England Journal of Medicine. 2017;377((22):):2133-2144
Abstract
Background The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. Methods In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. Results The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. Conclusions In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).
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Transfusion Requirements in Cardiac Surgery III (TRICS III): study design of a randomized controlled trial
Shehata N, Whitlock R, Fergusson DA, Thorpe KE, MacAdams C, Grocott HP, Rubens F, Fremes S, Lellouche F, Bagshaw S, et al
Journal of Cardiothoracic and Vascular Anesthesia. 2017;32((1):):121-129
Abstract
OBJECTIVES To determine if a restrictive transfusion threshold is noninferior to a higher threshold as measured by a composite outcome of mortality and serious morbidity. DESIGN Transfusion Requirements in Cardiac Surgery (TRICS) III was a multicenter, international, open-label randomized controlled trial of two commonly used transfusion strategies in patients having cardiac surgery using a noninferiority trial design (ClinicalTrials.gov number, NCT02042898). SETTING Eligible patients were randomized prior to surgery in a 1:1 ratio. PARTICIPANTS Potential participants were 18 years or older undergoing planned cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. INTERVENTIONS Five thousand patients; those allocated to a restrictive transfusion group received a red blood cell (RBC) transfusion if the hemoglobin concentration (Hb) was less than 7.5 g/dL intraoperatively and/or postoperatively. Patients allocated to a liberal transfusion strategy received RBC transfusion if the Hb was less than 9.5 g/dL intraoperatively or postoperatively in the intensive care unit or less than 8.5 g/dL on the ward. MEASUREMENTS AND MAIN RESULTS The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or new onset renal dysfunction requiring dialysis at hospital discharge or day 28, whichever comes first. The primary outcome was analyzed as a per-protocol analysis. The trial monitored adherence closely as adherence to the transfusion triggers is important in ensuring that measured outcomes reflect the transfusion strategy. CONCLUSION By randomizing prior to surgery, the TRICS III trial captured the most acute reduction in hemoglobin during cardiopulmonary bypass.
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The effects of lysine analogs during pelvic surgery: a systematic review and meta-analysis
Breau RH, Kokolo MB, Punjani N, Cagiannos I, Beck A, NiznickN, Buenaventura C, Cowan J, Knoll G, Momoli F, et al
Transfusion Medicine Reviews. 2014;28((3):):145-55.
Abstract
Pelvic vasculature is complex and inconsistent while pelvic bones impede access to pelvic organs. These anatomical characteristics render pelvic surgery inherently difficult, and some of these procedures are frequently associated with blood loss that necessitates blood transfusion. The aim of this study was to review the literature on the use of lysine analogs to prevent bleeding and blood transfusion during pelvic surgery. The objective of this study was to assess the safety and efficacy of lysine analogs during pelvic surgery. A systematic literature search was performed using Medline, Cochrane Register of Clinical Trials, Embase, and the reference lists of relevant articles. Randomized controlled trials or observational cohort studies comparing a lysine analog to placebo or standard care were included. Outcomes collected were blood transfusion, blood loss, thromboembolic adverse events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), nonthromboembolic adverse events, and death. There were no language limitations. Fifty-six articles reported on 68 comparisons between a lysine analog and an inactive comparator, involving a total of 7244 patients published between 1961 and 2013. Thirty-nine studies evaluated urologic procedures, and 21 evaluated gynecologic procedures. Thirty-six studies (60%) were published before 1980. Of the 43 randomized comparisons, only 30 (44%) had a score of 3 or higher on Jadad's 5-point scale of methodological quality. Among randomized trials, lysine analogs reduced the risk of blood transfusion (pooled odds ratio [OR], 0.47; 95% confidence interval [CI], 0.35-0.64) and blood loss (pooled OR, 0.22; 95% CI, 0.18-0.27). There was a small statistically insignificant increased risk of thromboembolic events (pooled OR, 1.07; 95% CI, 0.72-1.59) and no-thrombotic serious adverse events (pooled OR, 1.11; 95% CI, 0.67-1.83). In the 17 randomized trials published since the year 2000, only 6 thrombotic events were reported, 4 of which occurred in the placebo arm. Lysine analogs did not increase risk of death (pooled OR, 0.91; 95% CI, 0.34-2.48). These results are significant as they indicate that lysine analogs significantly reduce blood loss and blood transfusion during pelvic surgery. Although there does not appear to be a large increase in the risk of thromboembolic and nonthrombotic adverse events, more data are required to definitively assess these outcomes. Based on this review, lysine analogs during pelvic surgery seem to reduce bleeding and blood transfusion requirements. Although there does not seem to be a significant risk of adverse effects, larger studies would help clarify risks, if any, associated with lysine analog use. Copyright © 2014 Elsevier Inc. All rights reserved.
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Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion
Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, Ker K
Cochrane Database of Systematic Reviews. 2011;((3):):CD001886.
Abstract
BACKGROUND Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. In the last few years questions have been raised regarding the comparative performance of the drugs. The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death. OBJECTIVES To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY We searched: the Cochrane Injuries Group's Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2010. SELECTION CRITERIA Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial quality and extracted data. This version of the review includes a sensitivity analysis excluding trials authored by Prof. Joachim Boldt. MAIN RESULTS This review summarises data from 252 RCTs that recruited over 25,000 participants. Data from the head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of reducing perioperative blood loss, but the differences were small. Compared to control, aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.60 to 0.72). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.53 to 0.70) and was 0.81 (95% CI 0.67 to 0.99) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared more effective in reducing the need for RBC transfusion (RR 0.90; 95% CI 0.81 to 0.99).Aprotinin reduced the need for re-operation due to bleeding by a relative 54% (RR 0.46, 95% CI 0.34 to 0.62). This translates into an absolute risk reduction of 2% and a number needed-to-treat (NNT) of 50 (95% CI 33 to 100). A similar trend was seen with EACA (RR 0.32, 95% CI 0.11 to 0.99) but not TXA (RR 0.80, 95% CI 0.55 to 1.17). The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias.When compared with no treatment aprotinin did not increase the risk of myocardial infarction (RR 0.87, 95% CI 0.69 to 1.11), stroke (RR 0.82, 95% CI 0.44 to 1.52), renal dysfunction (RR 1.10, 95% CI 0.79 to 1.54) or overall mortality (RR 0.81, 95% CI 0.63 to 1.06). Similar trends were seen with the lysine analogues, but data were sparse. These data conflict with the results of recently published non-randomised studies, which found increased risk of cardiovascular complications and death with aprotinin. There are concerns about the adequacy of reporting of uncommon events in the small clinical trials included in this review.When aprotinin was compared directly with either, or both, of the two lysine analogues it resulted in a significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89), and a non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 0.82, 1