Carolyn Doree

Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis

Objective To compare patient outcomes of restrictive versus liberal blood transfusion strategies in patients with cardiovascular disease not undergoing cardiac surgery. Design Systematic review and meta-analysis. Data sources Randomised controlled trials involving a threshold for red blood cell transfusion in hospital. We searched (to 2 November 2015) CENTRAL, Medline, Embase, CINAHL, PubMed, LILACS, NHSBT Transfusion Evidence Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ISRCTN Register, and EU Clinical Trials Register. Authors were contacted for data whenever possible. Trial selection Published and unpublished randomised controlled trials comparing a restrictive with liberal transfusion threshold and that included patients with cardiovascular disease. Data extraction and synthesis Data extraction was completed in duplicate. Risk of bias was assessed using Cochrane methods. Relative risk ratios with 95% confidence intervals were presented in all meta-analyses. Mantel-Haenszel random effects models were used to pool risk ratios. Main outcome measures 30 day mortality, and cardiovascular events. Results 41 trials were identified; of these, seven included data on patients with cardiovascular disease. Data from a further four trials enrolling patients with cardiovascular disease were obtained from the authors. In total, 11 trials enrolling patients with cardiovascular disease (n=3033) were included for meta-analysis (restrictive transfusion, n=1514 patients; liberal transfusion, n=1519). The pooled risk ratio for the association between transfusion thresholds and 30 day mortality was 1.15 (95% confidence interval 0.88 to 1.50, P=0.50), with little heterogeneity (I2=14%). The risk of acute coronary syndrome in patients managed with restrictive compared with liberal transfusion was increased (nine trials; risk ratio 1.78, 95% confidence interval 1.18 to 2.70, P=0.01, I2=0%). Conclusions The results show that it may not be safe to use a restrictive transfusion threshold of less than 80 g/L in patients with ongoing acute coronary syndrome or chronic cardiovascular disease. Effects on mortality and other outcomes are uncertain. These data support the use of a more liberal transfusion threshold (>80 g/L) for patients with both acute and chronic cardiovascular disease until adequately powered high quality randomised trials have been undertaken in patients with cardiovascular disease. Registration PROSPERO CRD42014014251.

Bone Marrow Stem Cell Treatment for Ischemic Heart Disease in Patients with No Option of Revascularization: A Systematic Review and Meta-Analysis.

Objective To evaluate bone marrow stem cell treatment (BMSC) in patients with ischemic heart disease (IHD) and no option of revascularization. Background Autologous BMSC therapy has emerged as a novel approach to treat patients with acute myocardial infarction or chronic ischemia and heart failure following percutaneous or surgical revascularization, respectively. However, the effect of the treatment has not been systematic evaluated in patients who are not eligible for revascularization. Methods MEDLINE (1950–2012), EMBASE (1980–2012), CENTRAL (The Cochrane Library 2012, Issue 8) and ongoing trial databases were searched for relevant randomized controlled trials. Trials where participants were diagnosed with IHD, with no option for revascularization and who received any dose of stem cells by any delivery route were selected for inclusion. Study and participant characteristics, details of the intervention and comparator, and outcomes measured were recorded by two reviewers independently. Primary outcome measures were defined as mortality and measures of angina; secondary outcomes were heart failure, quality of life measures, exercise/performance and left ventricular ejection fraction (LVEF). Results Nine trials were eligible for inclusion. BMSC treatment significantly reduced the risk of mortality (Relative Risk 0.33; 95% Confidence Interval 0.17 to 0.65; Pu200a=u200a0.001). Patients who received BMSC showed a significantly greater improvement in CCS angina class (Mean Difference −0.55; 95% Confidence Interval −1.00 to −0.10; Pu200a=u200a0.02) and significantly fewer angina episodes per week at the end of the trial (Mean Difference −5.21; 95% Confidence Interval −7.35 to −3.07; P<0.00001) than those who received no BMSC. In addition, the treatment significantly improved quality of life, exercise/performance and LVEF in these patients. Conclusions BMSC treatment has significant clinical benefit as stand-alone treatment in patients with IHD and no other treatment option. These results require confirmation in large well-powered trials with long-term follow-up to fully evaluate the clinical efficacy of this treatment.

Long-Term Effects of Autologous Bone Marrow Stem Cell Treatment in Acute Myocardial Infarction: Factors That May Influence Outcomes

Aims To investigate whether there are important sources of heterogeneity between the findings of different clinical trials which administer autologous stem cell treatment for acute myocardial infarction (AMI) and to evaluate what factors may influence the long-term effects of this treatment. Methods and Results MEDLINE (1950-January 2011), EMBASE (1974-January 2011), CENTRAL (The Cochrane Library 2011, Issue 1), CINAHL (1982-January 2011), and ongoing trials registers were searched for randomised trials of bone marrow stem cells as treatment for AMI. Hand-searching was used to screen recent, relevant conference proceedings (2005–2010/11). Meta-analyses were conducted using random-effects models and heterogeneity between subgroups was assessed using chi-squared tests. Planned analyses included length of follow-up, timing of cell infusion and dose, patient selection, small trial size effect, methodological quality, loss of follow-up and date of publication. Thirty-three trials with a total of 1,765 participants were included. There was no evidence of bias due to publication or time-lag, methodological quality of included studies, participant drop-out, duration of follow-up or date of the first disclosure of results. However, in long-term follow-ups the treatment seemed more effective when administered at doses greater than 108 cells and to patients with more severe heart dysfunction. Conclusions Evaluation of heterogeneity between trials has not identified significant sources of bias in this study. However, clinical differences between trials are likely to exist which should be considered when undertaking future trials.

Route of delivery and baseline left ventricular ejection fraction, key factors of bone‐marrow‐derived cell therapy for ischaemic heart disease

Previous evaluation of autologous bone‐marrow stem‐cell (BMSC) therapy following acute myocardial infarction (AMI) suggests that cell dose and timing of stem‐cell administration post‐MI are important factors in the efficacy of cellular therapy. This study aimed to assess whether route of delivery and baseline left ventricular ejection fraction (LVEF) of the participants may also affect the outcome of BMSC treatment in patients with AMI and ischaemic heart disease (IHD).

Quality of life and use of red cell transfusion in patients with myelodysplastic syndromes. A systematic review

The main treatment for many patients with Myelodysplastic Syndromes (MDS) remains red cell transfusion to attenuate the symptoms of chronic anemia. Fatigue can reduce a patients health related quality of life (HRQoL), but there is little understanding of the optimal use of transfusions to improve this. A systematic review was performed to identify and appraise publications reporting the use of HRQoL instruments in patients with MDS. A total of 17 separate studies were identified that used 14 HRQoL instruments, but only one MDS disease specific HRQoL instrument (QOL‐E) was reported. Two well established HRQoL instruments were most often used in MDS research (variants of the Functional Assessment of Cancer Therapy (FACT) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ‐C30)). Several common problems were identified in the published literature including a lack of power calculations to detect clinically relevant changes, small sample sizes and significant attrition rates for completion of HRQoL assessments, all of which limit the strength of any conclusions. There is no consensus on the optimal transfusion regimen to improve HRQoL in transfusion‐dependent MDS. Future research into HRQoL within MDS is a pressing requirement. Studies should focus on the domains that are of most clinical importance to the patient as well as traditional quantitative changes of hemoglobin concentration. Am. J. Hematol., 2009.

The safety and efficacy of red cell transfusions in neonates: a systematic review of randomized controlled trials

Premature neonates commonly receive red blood cell (RBC) transfusions. This study systematically identified and appraised randomized controlled trials (RCTs) where the intervention was ‘transfusion of red blood cells’ from searches of multiple databases. Primary review outcomes were mortality, neurodevelopmental and respiratory endpoints. Two reviewers extracted data and assigned overall quality. Twenty‐seven RCTs were identified and grouped into four predefined categories: trials comparing RBC transfusion versus no transfusion/placebo (n = 3); different thresholds for transfusion (n = 6); differing doses or administration schedule (n = 4), or different types or products of RBC (n = 14). In the threshold group of trials, enrolling 679 neonates, no significant differences in mortality (relative risk 1·22, 95% confidence interval 0·84–1·75) or chronic lung disease were found. Only two trials assessed neurodevelopment outcomes, both within the threshold group, but with differing results. The largest subgroup of RCTs by number evaluated different media for storage of red cells (n = 7), enrolling 221 neonates. The methodological quality of many RCTs was poor. The design of future RCTs can be informed by the lessons from this review. Many trials failed to report on outcomes that would be considered of primary importance to clinicians. Consistent reporting of adverse events is required, and endpoints need to include neurodevelopmental outcomes.

Does bleeding affect patient‐reported outcome measures in patients with myelodysplasia or hematologic malignancies: a systematic review

Relatively minor bleeding (e.g., bruising and/or petechiae) may cause patient distress. This systematic reviews objective was to assess whether bleeding affects health‐related quality of life (HRQoL) or illness perceptions or representations (IPs) in patients with hematologic malignancies or myelodysplasia (MDS).

Increased regulatory T cell graft content is associated with improved outcome in haematopoietic stem cell transplantation: a systematic review.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft‐versus‐host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta‐analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0·42, 95% confidence interval (CI) 0·23–0·74, P = 0·003, 2 studies], with a significant reduction in non‐relapse mortality (HR 0·30, 95% CI 0·14–0·64, P = 0·002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0·59, 95% CI 0·40–0·89, P = 0·01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice.

Current Evidence of the Efficacy of Cell-Based Therapies in Heart Failure

Heart failure (HF) is the major cause of mortality worldwide. For more than a decade, cell-based therapies have been developed as treatment for heart disease as an alternative to current therapies. Trials and systematic reviews have assessed the safety and efficacy of cell therapies in a diverse number of participants and clinical settings. The present study collated and synthesized evidence from all systematic reviews related to cell-based therapies and HF. A total of 11 systematic reviews were identified through searches of electronic databases up to June 2014. We set out to answer 2 key questions on the efficacy of cell therapies in HF: (1) What is the overall effect of cell therapies on primary outcomes such as left ventricular ejection fraction (LVEF) and mortality? (2) How important is it to define the clinical setting and length of follow-up when assessing cell therapies and HF? There seems to be enough evidence to suggest that cell therapies have a moderate, long-lasting effect on LVEF, but the reduction on the risk of mortality observed by some systematic reviews needs to be confirmed in larger, statistically powered clinical trials. Additionally, and in order to strengthen conclusions, it is important to assess clinical evidence for defined clinical settings and to standardize the length of follow-up when comparing outcome data across several trials and systematic reviews.

How to further develop the evidence base for transfusion medicine

Blood transfusion is one of the commonest clinical interventions, but there are considerable data to indicate that much of current transfusion practice is sub-optimal, and varies widely between different hospitals and clinical teams1. Explanations for this variation in practice include that clinicians may not be aware of relevant clinical guidelines or may be reluctant to follow them. Reluctance to implement them may be at least partly due to perceived weaknesses in the evidence base for their recommendations. n nThere are a number of areas of transfusion practice where there are few or no published randomised controlled trials (RCTs) e.g. blood donor screening and selection, and paediatric transfusion. Even for those areas of transfusion medicine in which clinical trials have been carried out, formal assessment has often indicated that the quality of their methodology is poor. A review in the ISBT Science Series in 2008 described the strengths and weaknesses of the evidence base in transfusion medicine and how to develop it2. This review provides an update on those issues.