Restrictive versus liberal blood transfusion for gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials
The Lancet. Gastroenterology & Hepatology. 2017;2((5)):354-360.
BACKGROUND Acute upper gastrointestinal bleeding is a leading indication for red blood cell (RBC) transfusion worldwide, although optimal thresholds for transfusion are debated. METHODS We searched MEDLINE, Embase, CENTRAL, CINAHL, and the Transfusion Evidence Library from inception to Oct 20, 2016, for randomised controlled trials comparing restrictive and liberal RBC transfusion strategies for acute upper gastrointestinal bleeding. Main outcomes were mortality, rebleeding, ischaemic events, and mean RBC transfusion. We computed pooled estimates for each outcome by random effects meta-analysis, and individual participant data for a cluster randomised trial were re-analysed to facilitate meta-analysis. We compared treatment effects between patient subgroups, including patients with liver cirrhosis, patients with non-variceal upper gastrointestinal bleeding, and patients with ischaemic heart disease at baseline. FINDINGS We included four published and one unpublished randomised controlled trial, totalling 1965 participants. The number of RBC units transfused was lower in the restrictive transfusion group than in the liberal transfusion group (mean difference -1.73 units, 95% CI -2.36 to -1.11, p<0.0001). Restrictive transfusion was associated with lower risk of all-cause mortality (relative risk [RR] 0.65, 95% CI 0.44-0.97, p=0.03) and rebleeding overall (0.58, 0.40-0.84, p=0.004). We detected no difference in risk of ischaemic events. There were no statistically significant differences in the subgroups. INTERPRETATION These results support more widespread implementation of restrictive transfusion policies for adults with acute upper gastrointestinal bleeding. FUNDING None.
Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial
BACKGROUND Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=004). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -20 [95% CI -120 to 70]; p=050). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=023), with fewer RBC units transfused (mean 12 [SD 21] vs 19 ; difference -07 [-16 to 03]; p=012), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING NHS Blood and Transplant Research and Development.Copyright © 2015 Elsevier Ltd. All rights reserved.
Restrictive vs liberal transfusion for upper gastrointestinal bleeding: A meta-analysis of randomized controlled trials
World Journal of Gastroenterology. 2013;19((40):):6919-27.
AIM: To compare the outcome of upper gastrointestinal bleeding (UGIB) between patients receiving restrictive and liberal transfusion. METHODS PubMed, EMBASE, and Cochrane Library databases were employed to identify all relevant randomized controlled trials regarding the outcome of UGIB after restrictive or liberal transfusion. Primary outcomes were death and rebleeding. Secondary outcomes were length of hospitalization, amount of blood transfused, and hematocrit and hemoglobin at discharge or after expansion. RESULTS Overall, 4 papers were included in this meta-analysis. The incidence of death was significantly lower in patients receiving restrictive transfusion than those receiving liberal transfusion (OR: 0.52, 95%CI: 0.31-0.87, P = 0.01). The incidence of rebleeding was lower in patients receiving restrictive transfusion than those receiving liberal transfusion, but this difference did not reach any statistical significance (OR: 0.26, 95%CI: 0.03-2.10, P = 0.21). Compared with those receiving liberal transfusion, patients receiving restrictive transfusion had a significantly shorter length of hospitalization (standard mean difference: -0.17, 95%CI: -0.30--0.04, P = 0.009) and a significantly smaller amount of blood transfused (standard mean difference: -0.74, 95%CI: -1.15--0.32, P = 0.0005) with a lower hematocrit and hemoglobin level at discharge or after expansion. CONCLUSION Restrictive transfusion should be employed in patients with UGIB.
Restrictive vs liberal blood transfusion for acute upper gastrointestinal bleeding: rationale and protocol for a cluster randomized feasibility trial
Transfusion Medicine Reviews. 2013;27((3):):146-53.
Acute upper gastrointestinal bleeding (AUGIB) is the commonest reason for hospitalization with hemorrhage in the UK and the leading indication for transfusion of red blood cells (RBCs). Observational studies suggest an association between more liberal RBC transfusion and adverse patient outcomes, and a recent randomised trial reported increased further bleeding and mortality with a liberal transfusion policy. TRIGGER (Transfusion in Gastrointestinal Bleeding) is a pragmatic, cluster randomized trial which aims to evaluate the feasibility and safety of implementing a restrictive versus liberal RBC transfusion policy in adult patients admitted with AUGIB. The trial will take place in 6 UK hospitals, and each centre will be randomly allocated to a transfusion policy. Clinicians throughout each hospital will manage all eligible patients according to the transfusion policy for the 6-month trial recruitment period. In the restrictive centers, patients become eligible for RBC transfusion when their hemoglobin is <8 g/dL. In the liberal centers patients become eligible for transfusion once their hemoglobin is <10 g/dL. All clinicians will have the discretion to transfuse outside of the policy but will be asked to document the reasons for doing so. Feasibility outcome measures include protocol adherence, recruitment rate, and evidence of selection bias. Clinical outcome measures include further bleeding, mortality, thromboembolic events, and infections. Quality of life will be measured using the EuroQol EQ-5D at day 28, and the costs associated with hospitalization for AUGIB in the UK will be estimated. Consent will be sought from participants or their representatives according to patient capacity for use of routine hospital data and day 28 follow up. The study has ethical approval for conduct in England and Scotland. Results will be analysed according to a pre-defined statistical analysis plan and disseminated in peer reviewed publications to relevant stakeholders. The results of this study will inform the feasibility and design of a phase III randomized trial. Copyright 2013 Elsevier Inc. All rights reserved.
Update on the transfusion in gastrointestinal bleeding (TRIGGER) trial: statistical analysis plan for a cluster-randomised feasibility trial
Trials [Electronic Resource]. 2013;14:206
BACKGROUND Previous research has suggested an association between more liberal red blood cell (RBC) transfusion and greater risk of further bleeding and mortality following acute upper gastrointestinal bleeding (AUGIB). METHODS AND DESIGN The Transfusion in Gastrointestinal Bleeding (TRIGGER) trial is a pragmatic cluster-randomised feasibility trial which aims to evaluate the feasibility of implementing a restrictive vs. liberal RBC transfusion policy for adult patients admitted to hospital with AUGIB in the UK. This trial will help to inform the design and methodology of a phase III trial. The protocol for TRIGGER has been published in Transfusion Medicine Reviews. Recruitment began in September 2012 and was completed in March 2013. This update presents the statistical analysis plan, detailing how analysis of the TRIGGER trial will be performed. It is hoped that prospective publication of the full statistical analysis plan will increase transparency and give readers a clear overview of how TRIGGER will be analysed. TRIAL REGISTRATION ISRCTN85757829.
Transfusion strategies for acute upper gastrointestinal bleeding
New England Journal of Medicine. 2013;368((1):):11-21.
BACKGROUND The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. METHODS We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis. RESULTS A total of 225 patients assigned to the restrictive strategy (51%), as compared with 65 assigned to the liberal strategy (15%), did not receive transfusions (P<0.001). The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy. CONCLUSIONS As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundacio Investigacio Sant Pau; ClinicalTrials.gov number, NCT00414713.).
Red cell transfusion for the management of upper gastrointestinal haemorrhage
Cochrane Database of Systematic Reviews. 2010;((9):):CD006613.
BACKGROUND Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year, with a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is unknown. OBJECTIVES To assess the effects of red blood cell (RBC) transfusion in adults with upper gastrointestinal haemorrhage. SEARCH STRATEGY For this update, we re-ran the initial search strategies from the last issue/month searched until March 2010.We previously searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials (RCTs), haematology and gastroenterology conference proceedings, and reference lists of articles. SELECTION CRITERIA Randomised and quasi-randomised studies comparing RBC transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS Three trials involving 126 patients were included, with complete data available for 93 patients. The participants were heterogeneous, none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to RBC transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study fewer than half the participants were included in the final analysis.One RCT of restrictive versus liberal RBC transfusion aims to recruit 860 patients but has yet to be completed. AUTHORS' CONCLUSIONS There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed RCTs of sufficient power are urgently needed.
Acute anemia in high digestive hemorrhage. Margins of security for their handling without transfusion of red globules Spanish
Acta Gastroenterologica Latinoamericana. 1999;29((4):):261-70.
Red cells transfusion in the patient with acute hemorrhage, must be evaluated in a risk/benefit rate context. The present tendencies appoint that the use of the hematocrit "magic" number is unsafe and uncertain to decide a red cell transfusion. We have conducted a prospective randomized and controlled trial in 60 patients with acute digestive hemorrhage without haemodynamic failure. We realized two groups: 1) control group: the target of transfusion in these patients was the hematocrit value of > or = 28%. 2) treatment group: these patients were supported with normovolemic haemodilution with crystalloid solutions until a hematocrit value of 21%. All patients have endoscopic diagnosis and they went evaluated across the study with clinic and laboratory controls. Both groups were significative differences in the hematocrit value. We did not see differences between the groups in the hospital stay neither the rate of organs failure. We find difference between the groups in the amount of red cell units (0.61 +/- 0.87 vs. 2.14 +/- 1.10; treatment and control respectively, P < 0.001). The APACHE score was greater in the treatment group. This supports that the oldest patients, who probably have least physiologic reserve, could be treated without complications. Acute hemorrhage-normovolemic haemodilution-digestive hemorrhage transfusion.
Effect of early blood transfusion on gastrointestinal haemorrhage
British Journal of Surgery. 1986;73((10):):783-5.
The effect of citrated stored blood on coagulation was studied initially in a pilot study where 25 patients with acute severe gastrointestinal haemorrhage had their whole blood coagulation measured using the Biobridge Impedance Clotting Time (ICT). This demonstrated that there is a hypercoagulable response to haemorrhage which was partially reversed by blood transfusion. Similar changes were noted in Kaolin Cephalin Clotting Times (KCCT). A further 50 patients were then randomized to receive, during the 24 h after admission, either at least 2 units of blood or no blood transfusion unless the haemoglobin fell below 8 g/dl or they were shocked. In the transfused group nine patients re-bled compared with only one in the non-transfused group (P less than 0.01, chi 2 with Yates' correction). Early blood transfusion appears to reverse the hypercoagulable response to haemorrhage thereby encouraging re-bleeding and hence the need for an operation.