Susan J Brunskill

Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review.

AIMS To provide systematic assessment of the safety and efficacy of autologous bone marrow-derived stem cell (BMSC) transplantation in acute myocardial infarction (AMI) based on clinical evidence. METHODS AND RESULTS The search strategy included MEDLINE, EMBASE, the Cochrane Library, and Current Controlled Trials Register through to August 2007 for randomized controlled trials of BMSC treatment for AMI. Thirteen trials (14 comparisons) with a total of 811 participants were included. Data were analysed using a random effects model. Overall, stem cell therapy improved left ventricular ejection fraction (LVEF) by 2.99% [95% confidence interval (CI), 1.26-4.72%, P = 0.0007], significantly reduced left ventricular end-systolic volume (LVESV) by 4.74 mL (95% CI, -7.84 to -1.64 mL, P = 0.003), and myocardial lesion area by 3.51% (95% CI, -5.91 to -1.11%, P = 0.004) compared with controls. Subgroup analysis revealed that there was statistical significant difference in LEVF in favour of BMSCs when cells were infused within 7 days following AMI and when the BMSC dose administered was higher than 10(8) BMSCs. In addition, there were trends in favour of benefit for most clinical outcomes examined, although it should be acknowledged that the 95%CI included no significant difference. CONCLUSION Stem cell treatment for AMI still holds promise. Clinically, these data suggest that improvement over conventional therapy can be achieved. Further, adequately powered trials using optimal dosing, longer term outcome assessments, more reliable, and more patient-centred outcomes are required.

Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials

Randomized controlled trials of good quality are a recognized means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomized trials involving fresh frozen plasma (FFP) has been undertaken in parallel to the drafting of the updated British Committee for Standards in Haematology guidelines on the use of FFP. A total of 57 trials met the criteria for inclusion in the review. Most clinical uses of FFP, currently recommended by practice guidelines, are not supported by evidence from randomized trials. In particular, there is little evidence for the effectiveness of the prophylactic use of FFP. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias. No studies have taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. There is a need to consider how best to develop new trials to determine the efficacy of FFP in different clinical scenarios to provide the evidence base to support national guidelines for transfusion practice. Trials of modified FFP (e.g. pathogen inactivated) are of questionable value when there is little evidence that the standard product is an effective treatment.

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; P = 0.001). 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; P = 0.02) 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).

Platelet transfusion prophylaxis for patients with haematological malignancies: where to now?

National guidelines for platelet transfusion in many countries recommend that the general platelet transfusion trigger for prophylaxis is 10 × 109/l. This annotation reviews the evidence for this threshold level and discusses other current unresolved issues relevant to platelet transfusion practice such as the optimal dose and the clinical benefit of a strategy for the prophylactic use of platelet transfusions when the platelet count falls below a given threshold.

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 Impact of Electronic Decision Support on Transfusion Practice: A Systematic Review

Decision support systems (DSSs) provide clinicians with tailored treatment recommendations by combining individual patient information and local guidelines. The objective of this systematic review was to assess the effects of electronic DSS on blood product ordering practices. Eligible studies were identified from searches of MEDLINE, Embase, CINAHL, The Cochrane Library, PubMed, and the Transfusion Evidence Library from January 2000 to April 2014. Of these, 23 articles were eligible, resulting in the inclusion of 20 independent studies in this systematic review. There was a significant variation in study population, the type of DSS used, and outcome reporting. All but one study used a before-after design without any element of randomization. Overall, there is good evidence that implementation of a DSS improves red blood cell usage. The effect of a DSS on plasma, platelets, and cryoprecipitate usage is less clear probably because fewer studies have been conducted focusing on these products. In addition, the introduction of a DSS resulted in cost savings in the 7 studies that reported financial outcomes. Patient outcomes were generally not studied in detail, and there were few data on the sustainability of the effect of DSS. Further data are needed to assess the effect of a DSS on blood products other than red blood cell, and future studies should standardize reporting of outcomes.

The clinical effects of red blood cell transfusions: an overview of the randomized controlled trials evidence base.

No up-to-date overview of randomized controlled trials (RCTs) in red blood cell (RBC) transfusion exists. This systematic review examines the quantity and quality of the evidence for the clinical effects of RBC transfusion. One hundred forty-two eligible RCTs were identified through searches of The Cochrane Library (issue 4, 2009), MEDLINE (1950 to November 2009), EMBASE (1974 to November 2009), and other relevant sources. After data extraction and methodological quality assessment, trials were grouped by clinical specialty and type of RBC transfusion. Data analysis was predominantly descriptive. The 142 RCTs covered 11 specialties and 10 types of RBC transfusion. The number of included patients varied widely across the RCTs (median, 57; IQ range, 27-167). Most trials were single center comparing 2 parallel study arms. Overall, the reporting of methodological assessment was poor, although it improved markedly from 2001. Clinical areas with few trials are highlighted. Comparison with a study of RBC use in clinical practice highlighted a lack of correlation between the size of the evidence base for a given clinical specialty and the proportion of total RBC use by that clinical specialty. The gaps in the evidence base and the poor methodology of trials particularly in the past do not provide a strong evidence base for the use of RBC transfusions, but they indicate important targets for future research.