1.
Safety and efficacy of erythropoiesis-stimulating agents in critically ill patients admitted to the intensive care unit: a systematic review and meta-analysis
Litton E, Latham P, Inman J, Luo J, Allan P
Intensive care medicine. 2019
Abstract
PURPOSE Severe immune dysregulation is common in patients admitted to the intensive care unit (ICU) and is associated with adverse outcomes. Erythropoietin-stimulating agents (ESAs) have immune-modulating and anti-apoptotic effects. However, their safety and efficacy in critically ill patients remain uncertain. We evaluated whether ESAs, administered to critically unwell adult patients admitted to the ICU, reduced mortality at hospital discharge. METHODS The search strategy was conducted according to a predetermined protocol and included OVID MEDLINE, OVID EMBASE and The Cochrane Central Register of Controlled Trials from inception until 20 May 2019. Publications were eligible for inclusion if they were randomized controlled trials (RCTs) including adult patients admitted to an ICU, that identified and reported a group receiving ESA therapy compared to a group not receiving ESA therapy and reported mortality. There were no language restrictions. RESULTS The systematic review included 21 studies with 5452 participants. In-hospital mortality, reported in 16 studies of which only one was at low risk of bias, was lower in the ESA group (276 of 2187 patients, 12.6%) than the comparator group (339 out of 2204 patients, 15.4%), [relative risk (RR) 0.82, 95% CI 0.71-0.94, P = 0.006, I(2) = 0.0%]. The RR of SAEs and thromboembolic events for the ESA and comparator groups were similar, RR 1.11 (95% CI 0.94-1.31, P = 0.228, I(2) 66%) and 1.22 (95% CI 0.95-1.58, P = 0.086, I(2) 47%), respectively. CONCLUSIONS In heterogenous populations of critically ill adults, evidence from RCTs of mainly low or unclear quality, suggests that ESA therapy may decrease mortality.
2.
Intravenous iron therapy for non-anaemic, iron-deficient adults
Miles LF, Litton E, Imberger G, Story D
The Cochrane database of systematic reviews. 2019;12:Cd013084
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Abstract
BACKGROUND Iron deficiency is one of the most common nutritional deficiencies, and has a number of physiological manifestations. Early, or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity. Oral iron preparations have a high incidence of intolerable side effects, and are ineffective in certain forms of iron deficiency. Consequently, intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency. The newer, more stable iron preparations in particular purport to have a lower incidence of side effects, and are now used across a range of different patient populations. OBJECTIVES To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency. SEARCH METHODS On 18 October 2019 we electronically searched CENTRAL, MEDLINE, Embase, two further databases and two trials registries 2019. We handsearched the references of full-text extracted studies, and contacted relevant study authors for additional data. SELECTION CRITERIA We included randomised controlled trials that compared any intravenous iron preparation to placebo in adults. We excluded other forms of comparison such as oral iron versus placebo, intramuscular iron versus placebo, or intravenous iron studies where other iron preparations were used as the comparator. We also excluded studies involving erythropoietin therapy or obstetric populations. DATA COLLECTION AND ANALYSIS Two review authors screened references for eligibility, extracted data and assessed risk of bias. We resolved differences in opinion through discussion and consensus, and where necessary, involved a third review author to adjudicate disputes. We contacted study authors to request additional data where appropriate. The primary outcome measures were haemoglobin concentration at the end of follow-up, and quality-of-life scores at end of follow-up. Secondary outcome measures were serum ferritin, peak oxygen consumption (as measured by cardiopulmonary exercise testing), adverse effects (graded as mild to moderate and severe) and bacterial infection. We pooled data for continuous outcomes, which we then reported as mean differences (MDs) with 95% confidence intervals (CIs). We reported quality-of-life metrics as standardised mean difference (SMD), and then converted them back into a more familiar measure, the Piper Fatigue Scale. We analysed dichotomous outcomes as risk ratios (RRs). Given an expected degree of heterogeneity, we used a random-effects model for all outcomes. We performed the analysis with the software package Review Manager 5. MAIN RESULTS This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I(2) = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I(2) = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI -0.89 to 6.43; I(2) = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. AUTHORS' CONCLUSIONS Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.
PICO Summary
Population
Adults with non-anaemic iron deficiency, (11 studies, 1074 patients).
Intervention
Intravenous iron therapy.
Comparison
Placebo.
Outcome
Outcome metrics (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L). Quality-of-life scores (Piper Fatigue Scale MD 0.73, and peak oxygen consumption (MD 2.77 mL/kg/min, were associated with very low-quality evidence. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity.
3.
Safety and efficacy of iron therapy on reducing red blood cell transfusion requirements and treating anaemia in critically ill adults: A systematic review with meta-analysis and trial sequential analysis
Shah A, Fisher SA, Wong H, Roy NB, McKechnie S, Doree C, Litton E, Stanworth SJ
Journal of Critical Care. 2018;49:162-171.
Abstract
PURPOSE To evaluate the safety (risk of infection) and efficacy (transfusion requirements, changes in haemoglobin (Hb)) of iron therapy in adult intensive care unit (ICU) patients. MATERIALS AND METHODS We systematically searched seven databases for all relevant studies until January 2018 and included randomized (RCT) studies comparing iron, by any route, with placebo/no iron. RESULTS 805 participants from 6 RCTs were included. Iron therapy, by any route, did not decrease the risk of requirement for a red blood cell (RBC) transfusion (Risk ratio (RR) 0.91, 95% CI 0.80 to 1.04, p=0.15) or mean number of RBCs transfused per participant (mean difference (MD) -0.30, 95% CI -0.68 to 0.07, p=0.15). Iron therapy did increase mean Hb concentration (MD 0.31g/dL, 95% CI 0.04 to 0.59, p=0.03). There was no difference in infection (RR 0.95, 95% CI 0.79 to 1.19, p=0.44). Trial Sequential Analysis suggests that the required participant numbers to detect or reject a clinically important effect of iron therapy on transfusion requirements or infection in ICU patients has not yet been reached. CONCLUSION Iron therapy results in a modest increase in Hb. The current evidence is inadequate to exclude an important effect on transfusion requirements or infection.
4.
Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials
Litton E, Xiao J, Ho KM
Bmj. 2013;347:f4822.
Abstract
OBJECTIVES To evaluate the efficacy and safety of intravenous iron, focusing primarily on its effects on haemoglobin, requirement for transfusion, and risk of infection. DESIGN Systematic review and meta-analysis of randomised controlled trials investigating the safety and efficacy of intravenous iron therapy. DATA SOURCES Randomised controlled trials from Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1966 to June 2013, with no language restrictions. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Eligible trials were randomised controlled trials of intravenous iron compared with either no iron or oral iron. Crossover and observational studies were excluded. MAIN OUTCOME MEASURES Change in haemoglobin concentration and risk of allogeneic red blood cell transfusion (efficacy) and risk of infection (safety). RESULTS Of the 75 trials meeting the inclusion criteria, 72 studies including 10 605 patients provided quantitative outcome data for meta-analysis. Intravenous iron was associated with an increase in haemoglobin concentration (standardised mean difference 6.5 g/L, 95% confidence interval 5.1 g/L to 7.9 g/L) and a reduced risk of requirement for red blood cell transfusion (risk ratio 0.74, 95% confidence interval 0.62 to 0.88), especially when intravenous iron was used with erythroid stimulating agents (ESAs) or in patients with a lower baseline plasma ferritin concentration. There were no significant interactions between the efficacy of intravenous iron and type or dose administered. Intravenous iron was, however, associated with a significant increase in risk of infection (relative risk 1.33, 95% confidence interval 1.10 to 1.64) compared with oral or no iron supplementation. The results remained similar when only high quality trials were analysed. CONCLUSIONS Intravenous iron therapy is effective in increasing haemoglobin concentration and reducing the risk of allogeneic red blood cell transfusion and could have broad applicability to a range of acute care settings. This potential benefit is counterbalanced by a potential increased risk of infection.