A Systematic Review and Meta-Analysis of Pre-Transfusion Hemoglobin Thresholds for Allogeneic Red Blood Cell Transfusions

Transcription

1 A Systematic Review and Meta-Analysis of Pre-Transfusion Hemoglobin Thresholds for Allogeneic Red Blood Cell Transfusions Authors: Lesley J.J. Soril 1,2, MSc; Laura E. Leggett 1,2, MSc; Joseph Ahn, MSc 3 ; Rebecca Holmes 1, BSc; Tom W. Noseworthy 1,2, MD MSc MPH; Fiona M. Clement 1,2, PhD. Affiliations: 1. Department of Community Health Sciences, Cumming School of Medicine, University of Calgary Teaching Research and Wellness Building 3280 Hospital Drive NW Calgary, Alberta T2N 4N1 2. O Brien Institute for Public Health Teaching Research and Wellness Building 3280 Hospital Drive NW Calgary, Alberta T2N 4N1 3. Department of Medicine Cumming School of Medicine, University of Calgary Health Sciences Centre, Foothills Campus 3330 Hospital Drive NW Calgary, Alberta T2N 4N1

2 Abstract Background: Allogeneic red blood cell transfusions are used to manage anemia among critically ill and surgical patients. Historically a hemoglobin level of 10 grams per deciliter (g/dl) was the accepted trigger at which routine red blood cell transfusion may be initiated. However, there is accumulating evidence to demonstrate that a restrictive transfusion strategy (i.e. pre-transfusion hemoglobin g/dl; transfusion trigger of 7.0 g/dl) may be equally as effective or potentially superior. Objective: This protocol outlines the procedures of a de novo systematic review and metaanalysis on the efficacy of a restrictive transfusion strategy in comparison to a liberal transfusion strategy, for adult patients admitted to hospital. Methods: A systematic review will be completed. Seven multidisciplinary electronic databases will be searched from inception. Abstracts and full-text papers will be screened for inclusion, in duplicate, based on established criteria. Studies will be included if they: report original data from a primary study; use a randomized controlled trial or controlled clinical trial design; adult patient population (including, but not limited to patients admitted to intensive care, emergency department, having cardiovascular surgery); and compare restrictive and liberal transfusion strategies. Each included studies will be assessed in duplicate for quality using the Cochrane Risk of Bias Checklist. Results: Contingent on the number of final studies identified, as well as heterogeneity of the articles and their reported outcomes, a meta-analysis may be conducted to synthesize findings. Should meta-analysis of pooled results be permitted, stratified analysis may be required depending on the heterogeneity between included studies and study populations. If meta-analysis is not possible, a narrative approach to synthesizing results will be used. Conclusions: The findings of this study will provide insight into the best standards for allogeneic red blood cell transfusions. This information will be relevant for both health practitioners and decision-makers to understand the benefits and risks related to the adoption of restrictive transfusion strategies in comparison to standard alternatives across a number of patient populations and clinical settings.

3 Background Allogeneic red blood cell (RBC) transfusions are common medical procedures used to manage anemia among critically ill and surgical patients. 1,2 Historically a hemoglobin level of 10 grams per deciliter (g/dl) and a hematocrit of 30% were the broadly accepted minimum levels at which routine RBC transfusion may be initiated. 3 However, there has been little evidence to substantiate this 10/30 rule or support the notion that routine RBC transfusions would be beneficial to critically ill patients, and it may in fact be associated with worse clinical outcomes. 1,4-6 Evidence from the landmark randomized controlled trial (RCT) conducted by the Canadian Critical Care Trials Group (Transfusion Requirements in Critical Care or TRICC trial) demonstrated that for certain patients in the ICU a restrictive transfusion strategy (i.e. pretransfusion hemoglobin g/dl; transfusion trigger of 7.0 g/dl) was equally effective as and potentially superior than a liberal transfusion strategy (i.e. pre-transfusion hemoglobin g/dl; transfusion trigger of 10 g/dl). 4 Furthermore for younger patients or those less ill (i.e. Acute Physiology and Chronic Health Evaluation [APACHE] II score < 20), there were significantly lower 30-day mortality rates following the restrictive transfusion strategy. 4 Since the TRICC trial, examining the efficacy of a restrictive transfusion strategy in comparison to a liberal transfusion strategy has been of great interest in other patient populations and/or clinical settings. 7-9 A number of clinical practice guidelines and recommendations have also supported the use of restrictive RBC transfusion strategy. 10,11 With this rapidly growing literature base, it is unclear of the current breadth of high-quality studies that have since substantiated (or refuted) this restrictive transfusion strategy across varying patient populations. As such, a more comprehensive, up-to-date synthesis and analysis of the evidence is required. This protocol outlines the procedures of a de novo systematic review and meta-analysis of the literature concerning the efficacy of a restrictive transfusion strategy, in comparison to a liberal transfusion strategy, for adult patients admitted to hospital and in need of a RBC transfusion. Research Question: What are the appropriate pre-transfusion hemoglobin thresholds for initiating a red blood cell transfusion? Using the PICOD methodology, the following details were used to derive the research question for the systematic review and meta-analysis: Population Intervention Comparator Outcome Design Any adult patients Restrictive transfusion (low pre-transfusion hgb level) Liberal transfusion (high pre-transfusion hgb level) Any Randomized controlled trial (RCT), controlled clinical trial For the purposes of our systematic review, the population of interest is defined as: 1. Adult patients (over 18 years of age) admitted to hospital;

4 2. Males or females; 3. With any condition; 4. Who are not experiencing active blood loss prior to the transfusion, chronic anemia, or imminent death; and 5. Are in need of a RBC transfusion. Search Strategy For this systematic review, we will use MEDLINE, PubMed, EMBASE, the Cochrane Central Registry of Controlled Trials, the Cumulative Index to Nursing and Allied Health (CINAHL), the Cochrane Database of Systematic Reviews, and the Health Technology Assessment (HTA) database to conduct our search. The search of the aforementioned databases will include literature of all languages published from journal inception until May The keyword term *blood transfusion will be combined using the Boolean operator or with terms such as criter*, guideline*, policy or policies, threshold* or trigger*. Similarly, these last five terms will be combined using the Boolean operator or. The search will exclude animal studies, case reports, comments, editorials and letters. No other limitations will be applied. Details of the MEDLINE search are provided in Appendix 1. The latter two databases will be specifically searched to identify Health Technology Assessments or systematic reviews of relevance. The reference lists of identified systematic reviews will be hand-searched in duplicate to identify additional articles. Experts in the field will be consulted about other potential ongoing or unpublished studies. Lastly, the clinical trial registry clinical trials.gov will also be searched to identify ongoing trials. Identification of Articles Eligible for Systematic Review: Abstract review will be completed in duplicate. Based on the above PICOD, abstracts will be included for the subsequent full-text review if they report: 1. Original data from a primary study 2. Randomized controlled trial (RCT), controlled clinical trial 3. Restrictive transfusion strategy as the intervention and liberal transfusion strategy as the comparator Abstracts will be excluded if they do not meet the above criteria. No fixed definition of a restrictive or liberal transfusion strategy will be applied; thus any definition used within the included studies will be accepted. Abstracts selected for inclusion by either reviewer will proceed to the full-text review. Abstracts included after the first screen will proceed to full-text review which will also be completed by two reviewers. Full-text articles will be included if they meet the inclusion criteria based on the above PICOD criteria (presented in Table 1). Any disagreement between reviewers will be resolved through discussion and consensus. A kappa statistic for reviewer agreement will be calculated. Table 1: Inclusion and Exclusion Criteria for Review of Full-text Articles

5 Inclusion Criteria Full-text articles Original data Peer-reviewed articles Adult patient populations (e.g. ICU, ED, cardiovascular surgery, arthroplasty, etc) RCT, controlled clinical trial Primary objective: clinical efficacy or effectiveness of pre-transfusion hgb level thresholds Intervention: restrictive or lower pretransfusion hgb level thresholds Comparator: liberal or higher pretransfusion hgb level threshold Any outcome (e.g. mortality, length of stay, etc) Exclusion Criteria Articles not available in full-text Non-original data (e.g. reviews) Pediatric patients Case studies, commentaries, editorials, letters, opinions Animal studies Not focused on primary objective Case control studies, case studies, case series, comments, editorials, letters, opinions Data Extraction: Relevant data from all included full-text articles will be extracted in duplicate using a standardized data extractions form. This data extraction form will be used to compile the detailed data by study design (i.e. RCTs and controlled clinical trials). Any discrepancy in data extraction will be resolved through consensus and discussion. Authors will be contacted if relevant information is not reported or for clarification of resultsdata extraction has been designed to meet the PRISMA checklist standards for reporting of systematic reviews and meta-analyses. 12 Quality Assessment During data extraction, the quality of each included study will be assessed. Quality assessment will be done in duplicate and will consist of a narrative assessment of quality coupled with scores from the Cochrane Risk of Bias Checklist. 13 Data Analysis and Synthesis In the written synthesis, we will summarize the number of articles included and excluded in each step of the review process (abstract review and full-text review). This information will be presented in a flow-chart format, following PRISMA Guidelines. 12 If an article is excluded after undergoing full-text review, justification will be provided for its exclusion. We will present data on the number and characteristics of included studies from the systematic review, as well as the number and characteristics of included studies identified for meta-analysis. All outcomes reported by included studies will be reported narratively and summarized in tables. The way in which the outcomes were recorded or identified in each study (i.e. patient-reported, validated instruments, physician assessment, etc.) will also be collected and described in this review, as the potential for heterogeneity in these methods may lead to heterogeneity in the reported data.

6 Depending on the number of final studies identified, and heterogeneity of included studies, metaanalysis may be conducted. Should meta-analysis of pooled results be permitted, stratified analysis may be required depending on the heterogeneity between included studies and study populations. Significance This proposed de novo systematic review will seek to comprehensively review and meta-analyze the current published literature on the efficacy of a restrictive transfusion strategy relative to a liberal transfusion strategy. This information is particularly relevant for both health practitioners and decision-makers to understand the benefits and risks related to the adoption of restrictive transfusion strategies in comparison to standard alternatives across a number of patient populations and clinical settings.

7 Reference List 1. Thomas J, Jensen L, Nahirniak S, Gibney R. Anemia and blood transfusion practices in the critically ill: a prospective cohort review. Heart & Lung: The Journal of Acute and Critical Care. 2010;39(3): Vincent JL, Baron J-F, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. Jama. 2002;288(12): Adams R, Lundy J. Anesthesia in cases of poor surgical risk: some suggestions for decreasing the risk. Anesthesiology. 1942;3(5): Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. New England Journal of Medicine. 1999;340(6): Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the critically ill Current clinical practice in the United States*. Critical care medicine. 2004;32(1): Corwin HL. CRITICAL CARE ISSUES FOR THE NEPHROLOGIST: Anemia and Red Blood Cell Transfusion in the Critically Ill. Paper presented at: Seminars in dialysis Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. New England Journal of Medicine. 2011;365(26): Lacroix J, Hébert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. New England Journal of Medicine. 2007;356(16): Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. New England Journal of Medicine. 2014;371(15): Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: Red blood cell transfusion in adult trauma and critical care*. Critical care medicine. 2009;37(12): Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012; Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1.

8 Appendix 1 MEDLINE May exp *Blood Transfusion/mt, st [Methods, Standards] 2. ((pretransfus* or pre-transfus*) adj5 (criter* or guideline* or indicator* or policy or policies or protocol* or requirement* or threshold* or trigger* or standard*)).tw. 3. ((H?emoglobin or h?emocrit) adj5 (criter* or guideline* or indicator* or policy or policies or protocol* or requirement* or threshold* or trigger* or standard*)).tw. 4. (transfus* adj5 (criter* or guideline* or indicator* or policy or policies or protocol* or requirement* or threshold* or trigger* or standard*)).tw. 5. ((Red blood cell* or RBC) adj5 (criter* or guideline* or indicator* or policy or policies or protocol* or requirement* or threshold* or trigger* or standard*)).tw or 2 or 3 or 4 or 5 7. limit 6 to animals 8. limit 6 to (animals and humans) 9. 7 not not limit 10 to (case reports or comment or editorial or letter or "review") not ((systematic or critical or scoping) and (review or synthesis)).ti and or (conservative* or liberal* or optimal* or restrict* or trigger or triggers).tw,kw and 16