The efficacy of intravenous iron for treatment of anemia before cardiac surgery: An updated systematic review and meta-analysis with trial sequential analysis
Journal of Cardiothoracic Surgery. 2023;18(1):16
BACKGROUND Preoperative anemia is common in patients undergoing cardiac surgery with various etiologies, among which iron deficiency is the leading cause. However, the benefit of intravenous (IV) iron for the treatment of anemia before cardiac surgery is uncertain. This updated meta-analysis aimed to evaluate the efficacy of IV iron in adult cardiac surgery patients with preoperative anemia. METHODS This review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched Embase, PubMed and the Cochrane Central Register of Controlled Trials to identify eligible randomized controlled trials (RCTs) and observational studies. Quality was assessed using the Cochrane Collaboration risk of bias tool and Newcastle-Ottawa scale, and the strength of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. Trial sequential analysis was performed on the primary outcome (transfusion rate) to confirm whether firm evidence was reached. RESULTS Six RCTs (936 patients) and 5 observational studies (1350 patients) were included in this meta-analysis. The IV iron group and the control group were comparable in terms of transfusion rate [55.1% vs 60.9%, risk ratio (RR) = 0.91, 95% confidence interval (CI) 0.81-1.03, P = 0.13, low quality]. There were no significant differences in units transfused per patient, ICU stay and hospital length of stay between the two groups. And pooled data showed a benefit of IV iron compared to the control group on mortality (2.76% vs 3.75%, RR = 0.58, 95% CI 0.36-0.95, P = 0.03, moderate quality) and no mortality reduction existed when including only RCTs. CONCLUSIONS This meta-analysis suggested that IV iron treatment for patients with anemia before cardiac surgery did not reduce the transfusion requirement (low quality), but it was associated with decreased mortality (moderate quality). More large-scale, high-quality randomized clinical trials are warranted to confirm or refute our findings. PROSPERO registry reference: CRD42022331875.
Interventions for reducing red blood cell transfusion in adults undergoing hip fracture surgery: an overview of systematic reviews
The Cochrane database of systematic reviews. 2023;6(6):Cd013737
BACKGROUND Following hip fracture, people sustain an acute blood loss caused by the injury and subsequent surgery. Because the majority of hip fractures occur in older adults, blood loss may be compounded by pre-existing anaemia. Allogenic blood transfusions (ABT) may be given before, during, and after surgery to correct chronic anaemia or acute blood loss. However, there is uncertainty about the benefit-risk ratio for ABT. This is a potentially scarce resource, with availability of blood products sometimes uncertain. Other strategies from Patient Blood Management may prevent or minimise blood loss and avoid administration of ABT. OBJECTIVES To summarise the evidence from Cochrane Reviews and other systematic reviews of randomised or quasi-randomised trials evaluating the effects of pharmacological and non-pharmacological interventions, administered perioperatively, on reducing blood loss, anaemia, and the need for ABT in adults undergoing hip fracture surgery. METHODS In January 2022, we searched the Cochrane Library, MEDLINE, Embase, and five other databases for systematic reviews of randomised controlled trials (RCTs) of interventions given to prevent or minimise blood loss, treat the effects of anaemia, and reduce the need for ABT, in adults undergoing hip fracture surgery. We searched for pharmacological interventions (fibrinogen, factor VIIa and factor XIII, desmopressin, antifibrinolytics, fibrin and non-fibrin sealants and glue, agents to reverse the effects of anticoagulants, erythropoiesis agents, iron, vitamin B12, and folate replacement therapy) and non-pharmacological interventions (surgical approaches to reduce or manage blood loss, intraoperative cell salvage and autologous blood transfusion, temperature management, and oxygen therapy). We used Cochrane methodology, and assessed the methodological quality of included reviews using AMSTAR 2. We assessed the degree of overlap of RCTs between reviews. Because overlap was very high, we used a hierarchical approach to select reviews from which to report data; we compared the findings of selected reviews with findings from the other reviews. Outcomes were: number of people requiring ABT, volume of transfused blood (measured as units of packed red blood cells (PRC)), postoperative delirium, adverse events, activities of daily living (ADL), health-related quality of life (HRQoL), and mortality. MAIN RESULTS We found 26 systematic reviews including 36 RCTs (3923 participants), which only evaluated tranexamic acid and iron. We found no reviews of other pharmacological interventions or any non-pharmacological interventions. Tranexamic acid (17 reviews, 29 eligible RCTs) We selected reviews with the most recent search date, and which included data for the most outcomes. The methodological quality of these reviews was low. However, the findings were largely consistent across reviews. One review included 24 RCTs, with participants who had internal fixation or arthroplasty for different types of hip fracture. Tranexamic acid was given intravenously or topically during the perioperative period. In this review, based on a control group risk of 451 people per 1000, 194 fewer people per 1000 probably require ABT after receiving tranexamic acid (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.46 to 0.68; 21 studies, 2148 participants; moderate-certainty evidence). We downgraded the certainty for possible publication bias. Review authors found that there was probably little or no difference in the risks of adverse events, reported as deep vein thrombosis (RR 1.16, 95% CI 0.74 to 1.81; 22 studies), pulmonary embolism (RR 1.01, 95% CI 0.36 to 2.86; 9 studies), myocardial infarction (RR 1.00, 95% CI 0.23 to 4.33; 8 studies), cerebrovascular accident (RR 1.45, 95% CI 0.56 to 3.70; 8 studies), or death (RR 1.01, 95% CI 0.70 to 1.46; 10 studies). We judged evidence from these outcomes to be moderate certainty, downgraded for imprecision. Another review, with a similarly broad inclusion criteria, included 10 studies, and found that tranexamic acid probably reduces the volume of transfused PRC (0.53 fewer units, 95% CI 0.27 to 0.80; 7 studies, 813 participants; moderate-certainty evidence). We downgraded the certainty because of unexplained high levels of statistical heterogeneity. No reviews reported outcomes of postoperative delirium, ADL, or HRQoL. Iron (9 reviews, 7 eligible RCTs) Whilst all reviews included studies in hip fracture populations, most also included other surgical populations. The most current, direct evidence was reported in two RCTs, with 403 participants with hip fracture; iron was given intravenously, starting preoperatively. This review did not include evidence for iron with erythropoietin. The methodological quality of this review was low. In this review, there was low-certainty evidence from two studies (403 participants) that there may be little or no difference according to whether intravenous iron was given in: the number of people who required ABT (RR 0.90, 95% CI 0.73 to 1.11), the volume of transfused blood (MD -0.07 units of PRC, 95% CI -0.31 to 0.17), infection (RR 0.99, 95% CI 0.55 to 1.80), or mortality within 30 days (RR 1.06, 95% CI 0.53 to 2.13). There may be little or no difference in delirium (25 events in the iron group compared to 26 events in control group; 1 study, 303 participants; low-certainty evidence). We are very unsure whether there was any difference in HRQoL, since it was reported without an effect estimate. The findings were largely consistent across reviews. We downgraded the evidence for imprecision, because studies included few participants, and the wide CIs indicated possible benefit and harm. No reviews reported outcomes of cognitive dysfunction, ADL, or HRQoL. AUTHORS' CONCLUSIONS Tranexamic acid probably reduces the need for ABT in adults undergoing hip fracture surgery, and there is probably little or no difference in adverse events. For iron, there may be little or no difference in overall clinical effects, but this finding is limited by evidence from only a few small studies. Reviews of these treatments did not adequately include patient-reported outcome measures (PROMS), and evidence for their effectiveness remains incomplete. We were unable to effectively explore the impact of timing and route of administration between reviews. A lack of systematic reviews for other types of pharmacological or any non-pharmacological interventions to reduce the need for ABT indicates a need for further evidence syntheses to explore this. Methodologically sound evidence syntheses should include PROMS within four months of surgery.
Adults undergoing hip fracture surgery (26 systematic reviews, n= 3,923).
Pharmacological and non-pharmacological interventions to prevent or minimise blood loss, treat the effects of anaemia, and reduce the need for allogenic blood transfusions (ABT).
Between and within categories of intervention, standard of care or placebo.
17 reviews were found about tranexamic acid, 9 reviews about iron, and none for any other types of treatment. The three reviews providing the most relevant information were: A review about tranexamic acid including 24 studies with 2,148 people with a broken hip; a review about tranexamic acid including 10 studies with 1,123 people; and a review about iron including 2 studies with 403 people. The authors concluded that tranexamic acid probably reduces the need for ABT in adults undergoing hip fracture surgery, and there is probably little or no difference in adverse events. For iron, there may be little or no difference in overall clinical effects, but this finding is limited by evidence from only a few small studies. Reviews of these treatments did not adequately include patient-reported outcome measures, and evidence for their effectiveness remains incomplete.
Effect of Intravenous Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation (EFFECT-KTx): rationale and study protocol for a double-blind, randomised, placebo-controlled trial
BMJ open. 2023;13(3):e065423
INTRODUCTION Iron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs. METHODS AND ANALYSIS The Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin <100 µg/L or plasma ferritin 100-299 µg/L with transferrin saturation <20%. Patients are randomised to receive 10 mL of ferric carboxymaltose (50 mg Fe(3+)/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function. ETHICS AND DISSEMINATION The protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER NCT03769441.
Effect of erythropoietin on perioperative blood transfusions in primary total hip arthroplasty: A systematic review
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103718
BACKGROUND Primary total hip arthroplasty (THA) often requires blood transfusion. Transfusions are undesirable due to risks of infectious and noninfectious complications. This systematic review therefore studied the effectiveness of erythropoietin (EPO) in reducing allogeneic transfusion rate during THA. METHODS Using the MESH terms "Erythropoietin" AND "Total Hip" with restrictions to 'Randomized Controlled Trial', 'Clinical Trial', 'Humans', and 'English', a literature search was performed in PubMed and CINAHL. Articles were scanned by both authors and retained for further review if eligibility was met according to the inclusion criteria defined by the PICOS (population, intervention, comparator, outcomes, study design) configuration. Risk of bias was assessed using the Cochrane risk of bias criteria. Data extracted include patient demographics, intervention versus comparator arm, outcomes, laboratory data, and individual study characteristics. The primary outcome of focus was rate or amount of allogeneic blood transfusions intra- or postoperatively. In 6/8 studies, data permitted calculations of absolute risk reduction (ARR) in transfusion rate (%) and number needed to treat (NNT) to evade transfusions. RESULTS A total of 8 studies met all eligibility criteria and were retained for data extraction; risk of bias was low-moderate in 7/8 and high in 1/8. Allogeneic transfusion exposure was lowered by the intervention in 7/8 studies with ARR from 9.6% to 33.5% and NNT from 4 to 10. CONCLUSIONS In the blood conservation systems described, the addition of EPO was effective in reducing allogeneic transfusions. The studies included spanned a nearly 30-year period. Earlier studies incorporated preoperative autologous donation, a now outdated modality.
Intravenous iron and erythropoietin therapy for postoperative anemia among orthopedic surgery patients
Journal of orthopaedic surgery and research. 2023;18(1):510
BACKGROUND Postoperative anemia is a risk factor for adverse surgical outcomes. Our study aimed to assess the role of intravenous iron and erythropoietin therapy for the rapid correction of anemia following orthopedic surgery. METHODS Patients undergoing elective orthopedic surgery were prospectively enrolled and randomly divided into three groups: Control (placebo), Group 1 (IV iron monotherapy), and Group 2 [combined IV iron and recombinant human erythropoietin (rHuEPO) therapy]. Blood tests were performed preoperative (baseline) and on postoperative days (PODs) 1, 3, and 7. RESULTS All groups demonstrated significantly lower hemoglobin (Hb) concentrations compared to baseline, with no significant inter-group differences in postoperative Hb concentrations (p > 0.05). Serum erythropoietin, ferritin, and vitamin B(12) levels, and reticulocyte count increased beyond normal ranges in all groups. Significantly lower serum iron levels were observed postoperatively in all groups (p < 0.05). No significant inter-group differences in hepcidin level were observed (p > 0.05). CONCLUSION Postoperative treatment with combined intravenous iron and rHuEPO was ineffective in correcting postoperative anemia among orthopedic surgery patients, besides achieving higher reticulocyte counts in the first week of surgery. No improvement in mobilization of storage iron was achieved with rHuEPO. We further suggest against vitamin B(12) administration during the early postoperative period.
Effect of Preoperative Administration of Intravenous Ferric Carboxymaltose in Patients with Iron Deficiency Anemia after Off-Pump Coronary Artery Bypass Grafting: A Randomized Controlled Trial
Journal of clinical medicine. 2023;12(5)
Patients scheduled for cardiac surgery often have anemia and iron deficiency. We investigated the effect of the preoperative administration of intravenous ferric carboxymaltose (IVFC) in patients with iron deficiency anemia (IDA) who were due to undergo off-pump coronary artery bypass grafting (OPCAB). Patients who were due to undergo elective OPCAB between February 2019 and March 2022 who had IDA (n = 86) were included in this single center, randomized, parallel-group controlled study. The participants were randomly assigned (1:1) to receive either IVFC or placebo treatment. Postoperative hematologic parameters [hemoglobin (Hb), hematocrit, serum iron concentration, total iron-binding capacity, transferrin saturation, transferrin concentration, and ferritin concentration] and the changes in these parameters during the follow-up period were the primary and secondary outcomes, respectively. The tertiary endpoints were early clinical outcomes, such as the volume of mediastinal drainage and the need for blood transfusions. IVFC treatment significantly reduced the need for red blood cell (RBC) and platelet transfusions. Despite receiving fewer RBC transfusions, patients in the treatment group had higher levels of Hb, hematocrit, and serum iron and ferritin concentrations during weeks 1 and 12 after surgery. No serious adverse events occurred during the study period. Preoperative IVFC treatment in patients with IDA undergoing OPCAB improved the values of the hematologic parameters and iron bioavailability. Therefore, is a useful strategy for stabilizing patients prior to OPCAB.
Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for TAVI Results of the IIISAS randomised trial
European journal of heart failure. 2022
AIMS: The aim of this trial was to evaluate whether intravenous iron could provide benefit beyond transcatheter aortic valve implantation (TAVI) in iron deficient patients with severe aortic stenosis. METHODS AND RESULTS In this randomised, placebo-controlled, double-blinded, single-centre trial, we enrolled patients with severe aortic stenosis and iron deficiency (defined as ferritin < 100 μg/L, or 100-299 μg/L with a transferrin saturation < 20 %) who were evaluated for TAVI. Patients were randomly assigned (1:1) to receive i.v. ferric derisomaltose or placebo approximately three months before TAVI. The primary endpoint was the between-group, baseline-adjusted six-minute walk distance measured three months after TAVI. Secondary outcomes included quality of life, iron stores, handgrip strength, NYHA class, and safety. Between January 2020 and September 2021, we randomised 74 patients to ferric derisomaltose and 75 patients to placebo. The modified intention-to-treat population comprised the 104 patients who completed the six-minute walk test at baseline and three months after successful TAVI. Iron stores were restored in 76 % of the patients allocated to iron and 13 % of the patients allocated to placebo (p < 0.001). There was no difference in the baseline-adjusted six-minute walk distance between the two treatment arms (p = 0.82). The number of serious adverse events, quality of life, handgrip strength, and NYHA class did not differ between the treatment arms. CONCLUSION Treatment with intravenous iron did not provide clinical benefit beyond TAVI in iron deficient patients with severe aortic stenosis.
Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery
Obesity surgery. 2022
PURPOSE Iron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery. MATERIALS AND METHODS Data were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia. RESULTS The analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed. CONCLUSIONS In patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated.
Benefits of pre-operative oral Sucrosomial(®) iron supplementation in cardiac surgery: influence of patient's baseline hemoglobin and gender
Blood transfusion = Trasfusione del sangue. 2022
BACKGROUND The prevalence of low pre-operative hemoglobin (Hb) among cardiac surgery patients is high. As iron homeostasis is often impaired in these patients, restoration of iron availability might over-ride iron-restricted erythropoiesis. This post-hoc analysis of a previously published, large, randomized clinical trial (ClincalTrials.gov NCT03560687; n=1,000) assesses which sub-cohort of patients benefits the most from pre-operative Hb optimization with oral Sucrosomial(®) iron. MATERIALS AND METHODS Patients without baseline Hb (n=349) or receiving >5 red blood cell units (n=57) were excluded from the study. Data from the remaining 594 were reanalyzed according to treatment, baseline anemia (Hb <13 g/dL) or gender. Patients (pt) received a one-month course of 60 mg/day Sucrosomial(®) iron (Iron group, n=309) or routine care (Control group, n=285) prior to elective cardiac surgery. Main end-point variables were increase in Hb from randomization to hospital admission, transfusion requirements, and cost-effectiveness of Sucrosomial(®) iron administration. RESULTS At hospital admission, Hb had increased 0.7 g/dL and 0.1 g/dL, for Iron and Control groups, respectively (p<0.001), with no gender-related differences, leading to a decrease in transfusion rate (30 vs 59%, respectively; p<0.001) and transfusion index (0.5 units/patient vs 1.2 units/pt, respectively; p<0.001). Sucrosomial(®) iron administration was well-tolerated, and yielded cost-savings of €92/pt (p<0.001), particularly in those presenting with baseline Hb <13 g/dL. CONCLUSIONS This post-hoc analysis confirms pre-operative Sucrosomial(®) iron administration is a safe and cost-effective strategy to increase preoperative Hb and decrease transfusion requirements in elective cardiac surgery, especially in those anemic at baseline.
Cardiac surgery patients (n= 594).
Sucrosomial® iron prior to elective cardiac surgery (Iron group, n= 309).
Routine care (Control group, n= 285).
This post-hoc analysis of a large, randomized clinical trial (n= 1,000) reanalyzed data according to treatment, baseline anemia (Hb <13 g/dL) or gender. At hospital admission, haemoglobin (Hb) had increased 0.7 g/dL and 0.1 g/dL, for Iron and Control groups, respectively, with no gender-related differences, leading to a decrease in transfusion rate (30 vs. 59%, respectively) and transfusion index (0.5 units/patient vs. 1.2 units/pt, respectively). Sucrosomial® iron administration was well-tolerated, and yielded cost-savings of €92/pt, particularly in those presenting with baseline Hb <13 g/dL.
Adverse events of iron and/or erythropoiesis-stimulating agent therapy in preoperatively anemic elective surgery patients: a systematic review
Systematic Reviews. 2022;11(1):224
BACKGROUND Iron supplementation and erythropoiesis-stimulating agent (ESA) administration represent the hallmark therapies in preoperative anemia treatment, as reflected in a set of evidence-based treatment recommendations made during the 2018 International Consensus Conference on Patient Blood Management. However, little is known about the safety of these therapies. This systematic review investigated the occurrence of adverse events (AEs) during or after treatment with iron and/or ESAs. METHODS Five databases (The Cochrane Library, MEDLINE, Embase, Transfusion Evidence Library, Web of Science) and two trial registries (ClinicalTrials.gov, WHO ICTRP) were searched until 23 May 2022. Randomized controlled trials (RCTs), cohort, and case-control studies investigating any AE during or after iron and/or ESA administration in adult elective surgery patients with preoperative anemia were eligible for inclusion and judged using the Cochrane Risk of Bias tools. The GRADE approach was used to assess the overall certainty of evidence. RESULTS Data from 26 RCTs and 16 cohort studies involving a total of 6062 patients were extracted, on 6 treatment comparisons: (1) intravenous (IV) versus oral iron, (2) IV iron versus usual care/no iron, (3) IV ferric carboxymaltose versus IV iron sucrose, (4) ESA+iron versus control (placebo and/or iron, no treatment), (5) ESA+IV iron versus ESA+oral iron, and (6) ESA+IV iron versus ESA+IV iron (different ESA dosing regimens). Most AE data concerned mortality/survival (n=24 studies), thromboembolic (n=22), infectious (n=20), cardiovascular (n=19) and gastrointestinal (n=14) AEs. Very low certainty evidence was assigned to all but one outcome category. This uncertainty results from both the low quantity and quality of AE data due to the high risk of bias caused by limitations in the study design, data collection, and reporting. CONCLUSIONS It remains unclear if ESA and/or iron therapy is associated with AEs in preoperatively anemic elective surgery patients. Future trial investigators should pay more attention to the systematic collection, measurement, documentation, and reporting of AE data.