Preoperative IV iron and postoperative blood transfusion reduction in non-anaemic patients undergoing cardiac surgery: a systematic review and meta-analysis of RCTs

Abstract

Background

Preoperative intravenous iron has become increasingly popular as a strategy to optimize hemoglobin before major surgery. However, its potential benefit in non-anaemic patients undergoing cardiac surgery remains unclear. To address this uncertainty, we conducted a systematic review and meta-analysis to investigate whether preoperative IV iron reduces red blood cell transfusion requirements and improves hematologic and clinical outcomes in adults with normal baseline hemoglobin undergoing cardiac surgery.

Methods

We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library until October 2025 for randomized controlled trials. Eligible studies compared preoperative IV iron to a control (placebo, saline, or standard care) in non-anaemic (per WHO definition) adult patients (≥ 18 years) undergoing cardiac surgery. The primary outcomes were the incidence of postoperative RBC transfusion and the number of units transfused. Secondary outcomes included postoperative hemoglobin level, Postoperative iron indices, length of ICU stay, length of hospital stay (LOS), overall postoperative infection, All-cause mortality, and adverse events possibly related to IV iron (hypersensitivity, anaphylaxis). We used the Cochrane ROB 2 tool for bias assessment and for evidence certainty. Pooled Risk ratios, odds ratios, mean difference, and standardized mean difference with 95% confidence intervals were calculated using random-effects models, with the fixed-effects model applied when heterogeneity was absent or low (I² < 10%).

Results

From 529 initial records, 3 RCTs met the inclusion criteria, encompassing 338 patients. The overall risk of bias was low to moderate. Preoperative IV iron significantly reduced the incidence of postoperative RBC transfusion compared to the control group (Risk Ratio [RR] = 0.62; 95% CI 0.43–0.88; p = 0.008; I² = 0%), representing a 38% relative risk reduction. Furthermore, IV iron significantly decreased the mean number of RBC units transfused (Mean Difference [MD] = − 1.08 units; 95% CI − 1.61 to − 0.54; I² = 0%). While no significant difference was observed in hemoglobin levels at 48 h or one week postoperatively, the IV iron group showed significantly higher hemoglobin at 4–6 weeks (MD = 0.84 g/dL; 95% CI 0.41–1.26; p = 0.0001). IV iron also significantly increased postoperative serum ferritin and transferrin saturation. There were no statistically significant differences in overall postoperative infection rates (RR = 1.16; 95% CI 0.64–2.08) or all-cause mortality (Risk Difference = − 0.00; 95% CI − 0.03 to 0.03). The GRADE certainty of evidence for the primary outcome was moderate.

Conclusion

In non-anaemic adult patients undergoing cardiac surgery, preoperative IV iron administration significantly reduces the incidence of postoperative RBC transfusion and the total volume of blood transfused. This intervention also improves hemoglobin levels during the 4–6 week recovery period without an increased risk of infection or mortality. The moderate-certainty evidence suggests this is a beneficial strategy, though further adequately powered RCTs are warranted to strengthen these findings.

PROSPERO registry reference

CRD420251161421.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13019-026-04309-0.

Background

Cardiac surgery is frequently associated with substantial blood loss and remains one of the procedures with the highest risk of postoperative complications, including increased morbidity and mortality [1]. In routine practice, allogeneic red blood cell transfusion is commonly used to manage postoperative anemia [2, 3]. However, transfusion exposure is not benign. A large body of evidence has repeatedly linked RBC transfusion with septicemia, wound infection, prolonged intensive care unit stay, and increased mortality [4–6]. In addition to these clinical concerns, transfusions place considerable strain on blood-supply systems and healthcare resources, particularly during periods of limited stock availability. For example, the National Health Service Blood and Transplant issued warnings in late 2022 regarding critically low blood reserves [5, 7]. Taken together, these observations have prompted widespread implementation of Patient Blood Management strategies aimed at minimizing unnecessary transfusion wherever possible [5, 7].

Postoperative anemia remains extremely common after cardiac surgery, affecting up to 94% of patients [8]. Even among individuals entering surgery with a normal hemoglobin level, perioperative factors, including hemodilution, operative blood loss, coagulopathy, inflammation, and suppressed erythropoiesis, often contribute to a sharp decline in Hb and, consequently, a significant likelihood of transfusion [1, 9]. Preoperative anemia is recognized as a well-established, modifiable risk factor for transfusion and adverse outcomes [1]. However, less attention has been paid to patients who are technically non-anaemic but may have limited iron reserves or functional iron deficiency that only becomes clinically evident in the perioperative period [9, 10]. This distinction is important because normal Hb alone does not necessarily guarantee adequate iron availability to support postoperative erythropoiesis.

Intravenous iron has emerged as a fast and efficient strategy to replenish iron stores, particularly when the time before surgery is short. Compared to oral iron, IV formulations offer superior bioavailability, faster hematologic response, and greater tolerability, which makes them attractive in preoperative settings [2, 11]. Randomized trials and meta-analyses have shown that preoperative IV iron reduces transfusion requirements in anaemic or iron-deficient patients undergoing cardiac surgery [9], and more recently, a meta-analysis of non-anaemic patients undergoing major surgery, including cardiac procedures, suggested a similar reduction in transfusion risk with IV iron supplementation [12]. Despite these promising signals, the evidence base remains sparse for non-anaemic adults undergoing cardiac surgery, and published trials have yielded mixed findings, making it difficult to draw firm conclusions [2, 10, 13]. Given this uncertainty, further clarity is needed. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials evaluating preoperative IV iron specifically in non-anaemic adults undergoing cardiac surgery. By focusing exclusively on this population, we aimed to determine whether IV iron lowers perioperative RBC transfusion exposure and improves hematologic and clinical outcomes, even when baseline hemoglobin is normal. Ultimately, these results may help refine Patient Blood Management (PBM) protocols and inform future guideline recommendations.

Methods

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement [14]. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251161421) before starting the review.

Search strategy and data sources

A comprehensive literature search was developed in consultation with PRISMA guidance to identify randomized controlled trials evaluating preoperative intravenous iron in non-anaemic adults undergoing cardiac surgery. We searched five electronic databases, PubMed, Embase, Scopus, Web of Science, and the Cochrane Library, from inception through October 2025, restricted to English-language studies. The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to IV iron, cardiac surgery, anemia, and transfusion. Full search strings for each database are provided in the additional file.

To ensure completeness, we also manually screened reference lists of eligible trials and recent reviews. Search results were imported into Rayyan software for automated duplicate removal and blinded screening [15].

Evaluation of eligible studies

Two reviewers independently screened titles and abstracts according to predefined inclusion and exclusion criteria. We included studies that met the following eligibility criteria : (1) Study Design: Randomized controlled trials (RCTs) only (2) Population: Adult patients (≥ 18 years) undergoing cardiac surgery (CABG, valve surgery, or combined procedures) who are non-anaemic at baseline (normal hemoglobin according to WHO definitions: Hb ≥ 13 g/dL for men, ≥ 12 g/dL for women), (3) Intervention: Preoperative intravenous (IV) iron administration (any formulation, any dose and any timing prior to surgery), (4) Comparator: Placebo, saline, or standard care/no IV iron, (5) Outcomes: our primary outcome of interest was the need for Postoperative red blood cell transfusion: (The incidence of red blood cell transfusion, The number of units transfused ), the secondary outcomes were (Postoperative hemoglobin level, Postoperative iron indices, length of ICU stay, length of hospital stay(LOS), Overall postoperative infection, All-cause mortality, Adverse events possibly related to IV iron (hypersensitivity, anaphylaxis).

We excluded studies if they: (1) Studies including patients with preoperative anemia or iron deficiency only (2) Observational studies, case reports, case series, non-randomized trials, conference abstracts without full data, (3) Studies on non-cardiac surgery populations, (4) Studies that administered only oral iron (no intravenous iron arm), (5) Studies not reporting transfusion outcomes or insufficient data for extraction, (6) Studies administering IV iron both pre- and postoperatively, (7) Studies combining IV and oral iron therapy in the intervention group, (8) studies that were not published in English.

After title and abstract screening, we retrieved the full texts of potentially eligible studies and assessed them for final inclusion. When disagreements arose, we resolved them through discussion, and if necessary, a third reviewer provided a final decision. We documented the study selection process according to PRISMA guidelines.

Data extraction

We designed a standardized Excel form to extract relevant data from each included study. Two reviewers independently collected information on study characteristics (first author, publication year, number of centers), patient demographics (sample size, age, sex, comorbidities, BMI, and preoperative hemoglobin level), follow-up duration, type of surgery, type of control, intervention details such as the type of intravenous iron formulation, dose, administration timing, and treatment duration. We also extracted the postoperative clinical outcomes data, including the incidence of red blood cell transfusion, the number of units transfused, the postoperative hemoglobin level, postoperative Iron indices (e.g. serum iron, Ferritin levels and transferrin saturation), length of ICU stay, LOS, Overall postoperative infection, All-cause mortality, Adverse events possibly related to IV iron (hypersensitivity, anaphylaxis). We also recorded the primary outcome and the definition of “non-anaemic ” used by each trial.

Outcome and definition

The primary outcome was the need for red blood cell transfusion after cardiac surgery (The incidence of red blood cell transfusion, The number of units transfused ), the secondary outcomes included Postoperative hemoglobin level, Postoperative iron indices (e.g. serum iron, Ferritin levels and transferrin saturation), length of ICU stay, LOS, Overall postoperative infection, All-cause mortality, Adverse events possibly related to IV iron (hypersensitivity, Anaphylaxis). The postoperative hemoglobin level was compared between the IV Iron group and the control group at three times: the first 48 h postoperatively, the first postoperative week, and 4–6 weeks postoperatively.

Risk of bias and certainty of evidence

Risk of bias was assessed independently by two reviewers using the Cochrane Risk-of-Bias tool for randomized trials (ROB 2) [16]. Each study was evaluated across five domains (randomization, deviations from intended interventions, missing data, outcome measurement, and selective reporting), and graded as low risk, some concerns, or high risk. The GRADE framework was used to assess the certainty of evidence for each outcome, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias [17]. Evidence was rated as high, moderate, low, or very low.

Statistical analysis

We performed meta-analyses to pool risk ratios (RR) or odds ratios (ORs) for dichotomous outcomes, mean difference (MD), and standardized mean difference (SMD) for continuous outcomes, all with 95% confidence intervals (CIs).

We evaluated statistical heterogeneity using the I² statistic and Cochran’s Q test, with higher I² values indicating greater heterogeneity. We used a random-effects model as a primary model for analyses, except where the heterogeneity is absent or low (I² < 10%), we used the fixed-effects model. Furthermore, we conducted a sensitivity analysis for all outcomes to evaluate the robustness of our findings by sequentially excluding each study one at a time [18]. When necessary, we estimated the means and standard deviations using the Wan et al. method [19].

In trials reporting only baseline and endpoint values, mean change scores were calculated as the difference between baseline and final measurements, and standard deviations of these changes were imputed using recommended Cochrane methods [21].

We conducted all statistical analyses using Review Manager (RevMan) version 5.3. A p-value of 0.05 was used as a threshold for statistical significance across all analyses [20].

Results

Study screening and selection

The study selection process is summarized in the PRISMA flow diagram (Fig. 1). A total of 529 records were identified from PubMed (n = 114), Embase (n = 59), Scopus (n = 102), Web of Science (n = 163), and the Cochrane Library (n = 91). After removing 204 duplicates using the Rayyan software, 325 titles and abstracts were screened. Of these, 313 records were excluded, most commonly for being non-randomized or involving anaemic populations. Twelve full-text articles were assessed in detail, and nine were excluded for reasons such as wrong intervention (n = 3), study protocol without results (n = 4), or insufficient data (n = 1). Ultimately, three randomized controlled trials published between 2015 and 2024 met the inclusion criteria and were included in both qualitative and quantitative synthesis (n = 338 participants).

Fig. 1.

PRISMA flowchart for the database searching and screening process

Table 1 summarizes the key characteristics of the included studies comparing the RBC transfusion incidence or hemoglobin levels between non-anaemic patients receiving preoperative intravenous iron (IV Iron group) and those receiving controls (control group) after cardiac surgery. Three randomized controlled trials met the inclusion criteria, enrolling a total of 338 patients who underwent cardiac surgery (Johansson 2015, Kiviniemi 2024, and Friedman 2023) [2, 10, 13]. All studies were single-center RCTs evaluating the effect of preoperative intravenous (IV) iron therapy compared with placebo or standard care. The type of surgery varied slightly across trials: Johansson [13] included patients undergoing coronary artery bypass grafting (CABG), valve replacement, or a combination, Kiviniemi [10] enrolled those undergoing coronary, aortic, or mitral valve or ascending aortic surgery, and Friedman [2] included patients undergoing elective or urgent single cardiac surgery.

Table 1.

Characteristics of included studies

N⁰, number; NoA, non-anemic; NA, not available; Hb, hemoglobin; CABG, coronary artery bypass graft; IV, intravenous

The IV iron formulations and dosing regimens differed among studies. Johansson [13], administered iron isomaltoside 1000 mg as a single preoperative dose; Kiviniemi [10], used ferric carboxymaltose 1000 mg given 2 to 21 days before surgery; and Friedman [2], used IV ferric carboxymaltose 1000 mg administered 24–72 h before surgery. All comparators received a placebo (saline) without IV iron supplementation. Hemoglobin thresholds for inclusion were similar, typically requiring patients to be non-anaemic, with baseline mean hemoglobin ranging from 14.0 to 14.65 g/dL. The primary outcomes varied across studies but generally included perioperative red blood cell transfusion requirements, change in hemoglobin concentration, and postoperative outcomes such as infection rate. The follow-up duration ranged from 4 weeks to 12 months.

Overall, the included studies demonstrated methodological consistency in design and patient population, but heterogeneity was observed in iron formulations, timing of administration, and primary outcome definitions.

Table 2 summarizes the baseline characteristics of patients from the three RCTs (IV iron vs. control). The mean age of patients ranged from 62 to 67 years, with no significant intergroup differences. Male sex predominated, comprising 84% to nearly 90% of study participants. The prevalence of current smoking ranged from 0% to 27%, and diabetes mellitus was reported in 23% to 47% of participants, with comparable proportions between the IV iron and control arms. Mean body mass index (BMI) was consistent across studies, ranging from 28.0 to 29.7 kg/m². Baseline hemoglobin concentrations were similar between groups, averaging 14.0 to 14.65 g/dL, indicating that most participants were non-anaemic at enrollment. A previous history of stroke was infrequently reported, observed in approximately 5% of patients in one study [10].

Table 2.

Patient baseline characteristics

Overall, demographic and clinical variables at baseline were well balanced between treatment and control groups across the included trials, suggesting comparable study populations before intervention.

Outcomes

Primary outcomes

Incidence of red blood cell transfusion

Across randomized controlled trials enrolling non-anaemic adults undergoing cardiac surgery, preoperative intravenous (IV) iron significantly reduced the incidence of perioperative red blood cell (RBC) transfusion compared with placebo or standard care (RR = 0.62; 95% CI 0.43–0.88; p = 0.008; I² = 0%). This corresponds to an approximate 38% relative reduction in transfusion risk, with no evidence of heterogeneity among studies.

Number of transfused units

When transfusion requirements were analyzed as a continuous outcome, IV iron recipients required, on average, one fewer unit of RBCs than controls (MD = − 1.08 units; 95% CI − 1.61 to − 0.54; I² = 0%), indicating a consistent reduction in transfusion burden. Inclusion of a third study with imputed data produced virtually identical results (MD = − 1.09 units; 95% CI − 1.56 to − 0.62; I² = 0%), confirming that the imputed estimate did not materially alter the overall effect.

Secondary outcomes

Postoperative hemoglobin trends

Early postoperative hemoglobin levels (within 48 h) did not differ significantly between IV iron and placebo (MD = − 0.15 g/dL; 95% CI − 0.51 to 0.21; p = 0.42; I² = 0%), suggesting comparable early postoperative profiles. Similarly, hemoglobin measured during the first postoperative week showed no significant difference (MD = 0.13 g/dL; 95% CI − 0.33 to 0.60; p = 0.58; I² = 36%; τ² = 0.06).

At 4–6 weeks postoperatively, however, IV iron was associated with a significant increase in hemoglobin compared with placebo (MD = 0.84 g/dL; 95% CI 0.41–1.26; p = 0.0001; I² = 6%), indicating a sustained hematologic benefit during recovery.

Iron indices

Preoperative IV iron markedly increased serum ferritin compared with placebo (SMD = 1.51; 95% CI 0.85–2.17; p < 0.00001), although heterogeneity was substantial (I² = 82%). Exclusion of Friedman 2023 strengthened the pooled effect (SMD = 1.82; 95% CI 1.17–2.47) and reduced heterogeneity (I² = 56%), suggesting that this study was the main contributor to between-study variability.

Serum iron did not significantly differ between groups (MD = 10.06 µmol/L; 95% CI − 9.06 to 29.19; I² = 88%; τ² = 242.43). After excluding Johansson 2015, heterogeneity was resolved (I² = 0%), and the result remained nonsignificant, confirming that variability was driven by this trial.

Transferrin saturation was significantly higher with IV iron (MD = 7.25; 95% CI 0.54–13.95; p = 0.03), though heterogeneity was high. Excluding Johansson 2015 maintained statistical significance (MD = 4.39; 95% CI 0.61–8.17; I² = 0%), reinforcing a robust improvement in iron utilization indices.

Clinical outcomes

Postoperative infection rates were comparable between groups (11.9% [20/168] with IV iron vs. 10.4% [17/164] with placebo), with no significant difference on pooled analysis, suggesting no increased infection risk attributable to IV iron.

All-cause mortality was rare and identical between groups (RD = − 0.00; 95% CI − 0.03 to 0.03; p = 1.00; I² = 19%), based on 2 versus 1 death across included trials. Adverse events potentially related to IV iron were infrequently reported, and none of the included studies documented serious hypersensitivity or anaphylactic reactions.

Certainty of evidence (GRADE)

Using the GRADE framework, the overall certainty of evidence for the primary outcome “reduction in perioperative red-blood-cell transfusion” was rated as moderate, limited mainly by small sample sizes and some study-level bias. Certainty for secondary outcomes ranged from low to moderate, primarily downgraded for imprecision and heterogeneity across studies. These findings indicate moderate confidence that preoperative IV iron reduces transfusion requirements in non-anaemic cardiac surgery patients, though further adequately powered RCTs are warranted to confirm the magnitude of benefit (Figs. 2, 3, 4 and 5). (see Additional file)

Fig. 2.

Forest plot comparing IV iron and control for primary outcome. A Forest plot for incidence of red blood Transfusion; B Forest plot for number of units transfused

Fig. 3.

Forest plot comparing IV iron and control for postoperative hemoglobin level. A Forest plot for hemoglobin change on the first 48 h postoperatively; B Forest plot for hemoglobin change on the first postoperative week; C Forest plot for hemoglobin change on 4-6 Weeks postoperatively

Fig. 4.

Forest plot comparing IV iron and control for postoperative Iron indices. A Forest plot for serum ferritin level change; B Forest plot for serum iron change; C Forest plot for transferrin saturation (%) change

Fig. 5.

Forest plot comparing IV iron and control for postoperative Clinical outcomes. A Forest plot for overall postoperative infection; B Forest plot for All-cause of mortality

Risk of bias assessment

Overall risk of bias was judged low to moderate. One trial demonstrated low risk across all RoB 2 domains [13], while the remaining two studies [2, 10] raised some concerns. In Friedman et al. [2], concerns arose from limited detail regarding the randomization process and selective reporting of secondary outcomes. Additionally, two trials [2, 10] did not report transfusion thresholds, introducing some concerns regarding the measurement of outcomes, as transfusion practices may vary across settings despite the use of objective endpoints. All trials employed double-blind allocation. Because only three trials were included, formal assessment of publication bias was not performed, consistent with Cochrane guidance [21] (Fig. 6).

Fig. 6.

Risk of bias assessment of included randomized controlled trials using the RoB 2 tool

Discussion

In this systematic review and meta-analysis of randomized controlled trials enrolling exclusively non-anaemic adults undergoing cardiac surgery, preoperative IV iron was associated with a reduction in perioperative RBC transfusion, although this finding should be interpreted cautiously given the limited number of included trials and overall sample size. Across three double-blind trials, IV iron reduced the relative risk of receiving at least one perioperative RBC transfusion by around 38% (RR 0.62; 95% CI 0.43–0.88) and lowered transfusion burden by approximately one unit per patient (MD − 1.08 units). Early postoperative hemoglobin (Hb) values were similar between groups, but IV iron recipients had higher Hb concentrations 4–6 weeks after surgery, indicating improved hematologic recovery during the convalescent phase. IV iron also increased ferritin and transferrin saturation without increasing postoperative infection or mortality. As IV iron administration has side effects, all included studies in this review excluded patients who had known hypersensitivity or allergic reactions to iron medications. Whereas other unwanted side effects like nausea, vomiting, headache, dizziness, and faintness may happen, which usually don’t need medical attention as they may go away with time [23]. However, the included studies did not provide information on the incidence of these minor side effects. Friedman et al. mentioned that they used an adverse events questionnaire, including questions regarding dizziness, headache, and transient ischemic attack symptoms, and reported no differences in these side effects between the ferric carboxymaltose and placebo groups. Whereas Johansson et al. mentioned that the safety profile of iron administration in their trial is very favorable, reporting that no adverse effects were observed in the iron isomaltoside group. Kiviniemi et al. also reported that IV iron administration in their study was generally safe with no serious adverse events.

Certainty in the transfusion outcomes was rated as moderate using GRADE. Given that only three randomized controlled trials were included, these findings should be considered exploratory and hypothesis-generating rather than definitive.

These findings may have potential clinical relevance within contemporary patient blood-management (PBM) pathways; however, they should be interpreted in the context of the limited available evidence. Even with normal baseline Hb, cardiac surgery patients are prone to postoperative anemia due to hemodilution, cardiopulmonary bypass-related hemolysis, and blood loss, and a substantial proportion still receive allogeneic transfusion exposures linked to infection, organ dysfunction, prolonged hospitalization, and mortality. The observed transfusion-sparing effect is biologically plausible. At least one included trial reported baseline transferrin saturation around 20%, consistent with limited iron reserves in some non-anaemic patients, suggesting the presence of functional iron deficiency despite normal baseline hemoglobin levels; PBM guidance considers transferrin saturation < 20% (especially with low ferritin in inflammatory states) compatible with iron deficiency and supports IV iron when time is short or oral iron is unsuitable [11]. IV iron rapidly replenishes iron stores and improves iron availability, facilitating more efficient erythropoiesis during convalescence. Accordingly, groups had similar early Hb nadirs, but IV-iron recipients showed higher Hb at follow-up, a pattern consistent with attenuation of postoperative iron-restricted anemia and a reduced need for subsequent transfusions.

Importantly, the classification of patients as non-anaemic does not necessarily indicate normal iron status. A proportion of patients with normal baseline hemoglobin may have underlying functional iron deficiency, characterized by insufficient iron availability to support erythropoiesis despite apparently normal hemoglobin levels. This distinction is particularly relevant in the perioperative setting, where inflammation and surgical stress may further impair iron utilization.

Therefore, the observed benefit of preoperative intravenous iron in this analysis may, at least in part, reflect correction of unrecognized or functional iron deficiency rather than a direct effect in truly iron-replete individuals. This consideration should be taken into account when interpreting the findings.

Our results refine a heterogeneous literature on perioperative IV iron. Prior cardiac-surgery reviews, often dominated by anaemic or mixed populations, generally suggested reductions in transfusion and improved Hb but were constrained by clinical heterogeneity [22]. An updated cardiac-focused meta-analysis likewise reports reduced transfusion risk and improved postoperative Hb and iron indices with IV iron, supporting its integration within PBM [1]. By restricting randomized trials in non-anaemic cardiac patients, our analysis isolates the incremental value of IV iron where benefit has been uncertain and demonstrates a consistent effect despite differences in formulation and timing. Among the included trials, context-dependent patterns emerged: Johansson et al. (iron isomaltoside 1000, 1000 mg perioperatively; n = 60) showed IV iron significantly improved 4-week Hb and increased the proportion of non-anaemic patients at 4 weeks without excess adverse events, though transfusion numbers did not differ significantly [13]. Similarly, Friedman et al. (ferric carboxymaltose, 1000 mg 24–72 h pre-op; n = 200) demonstrated a remarkable reduction in transfusion incidence and units transfused [2]. In contrast, Kiviniemi et al. (ferric carboxymaltose, single 1000 mg dose 2–21 days pre-op; n = 78) found no difference in their composite primary endpoint or transfusion rates during index admission (≈ 15–18%), though post-hoc analysis showed fewer readmissions by 3 months and higher iron stores at 3 months in the IV-iron arm [10]. Similarly, in anaemic cohorts under restrictive thresholds, IV iron often raises ferritin without lowering transfusion requirements [1].

Taken together, these data suggest that the magnitude of benefit in non-anaemic patients is greatest where baseline transfusion risk remains appreciable, and the functional iron deficiency is common. IV iron should therefore be viewed as one component of a multimodal PBM strategy, not a stand-alone intervention expected to yield uniform effects across centers; this positioning aligns with international PBM/anemia consensus guidance [11].

This review has notable strengths. The clinical question, population, and outcomes were prespecified in a PROSPERO-registered protocol, reducing analytic flexibility. We included only double-blind randomized trials in adult non-anaemic cardiac surgery patients, yielding a relatively homogeneous and high-quality evidence base. Objective transfusion endpoints were consistently reported, and statistical heterogeneity for the primary outcomes was negligible (I² = 0%); however, this should be interpreted with caution, as important clinical heterogeneity existed across the included studies, and we applied a structured risk-of-bias assessment and the GRADE framework.

However, study limitations must be acknowledged. The evidence base consists of only three single-center randomized controlled trials with relatively modest sample sizes, and one trial was stopped early for futility. The limited number of included studies and small cumulative sample size reduce the precision of the pooled estimates and limit the generalizability of the findings. As a result, this meta-analysis is underpowered to detect differences in rare but clinically important outcomes, such as mortality, major cardiovascular events, or severe hypersensitivity reactions.

In addition, important clinical and methodological heterogeneity exists across the included trials, including differences in intravenous iron formulation, dosing, timing of administration (ranging from the day of surgery to several weeks preoperatively), transfusion thresholds, concomitant patient blood management strategies, and definitions of “non-anaemic ” status. Although statistical heterogeneity for the primary outcomes was low, this should be interpreted cautiously, as these clinical differences may still influence the magnitude and generalizability of the observed effects.

Furthermore, classification of patients as non-anaemic does not necessarily reflect normal iron status. Baseline iron indices were not consistently reported across studies, limiting the ability to distinguish between truly iron-replete individuals and those with functional iron deficiency, which may have contributed to the observed treatment effect.

A key limitation of this analysis is that red blood cell transfusion, as the primary outcome, is not a fully objective endpoint and is influenced by institutional protocols and clinician judgment. Transfusion decisions may vary based on local practices, perioperative management strategies, and individual clinician thresholds. Moreover, transfusion thresholds were inconsistently reported across studies, with some trials not clearly defining hemoglobin triggers for transfusion. This variability may introduce bias, limit comparability across studies, and potentially influence the observed magnitude of reduction in transfusion rates.

Finally, safety data remain limited, and the small number of included trials precluded a reliable assessment of publication bias. Subgroup effects, including the role of underlying iron deficiency, differences between procedure types, and optimal timing of intravenous iron administration, also remain uncertain.

Overall, this review suggests that in non-anaemic adults undergoing cardiac surgery, preoperative IV iron reduces perioperative RBC transfusion exposure and enhances medium-term hematologic recovery, without evidence of increased postoperative infection or mortality and with no reported serious hypersensitivity or anaphylaxis. These data support the selective incorporation of IV iron into comprehensive PBM programs, particularly in centers where expected transfusion risk remains substantial and where iron deficiency or low iron stores are prevalent, even in the absence of anemia. At the same time, the current evidence is not sufficient to recommend universal prophylactic IV iron for all non-anaemic cardiac surgery candidates. Large, pragmatic, multicenter RCTs restricted to non-anaemic patients, using standardized iron and transfusion protocols, careful characterization of baseline iron status, and robust clinical and economic endpoints, are now warranted to confirm these findings and to define optimal timing, dosing, and patient selection [2, 9, 11, 13].

Conclusions

Preoperative intravenous iron may reduce the incidence of red blood cell transfusion and the number of units transfused in non-anaemic adults undergoing cardiac surgery. However, given that the current evidence is based on a small number of single-center randomized trials with moderate certainty, these findings should be interpreted with caution.

At present, the results should be considered hypothesis-generating, and large, well-designed multicenter randomized trials are needed to confirm these observations and define the clinical role of preoperative IV iron in this population.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

IV

Intravenous

RBC

Red blood cells

PBM

Patient Blood Management

Hb

Hemoglobin

MD

Mean difference

ORs

Odds ratios

RR

Risk ratio

CI

Confidence interval

ICU

Intensive care unit

LOS

Length of hospital stay

RCTs

Randomized controlled trials

SMD

Standardized mean difference

BMI

Body mass index

MI

Myocardial infarction

Author contributions

ZAM: Led the study conception and design, coordinated protocol development, supervised the overall project and Conducted statistical analyses; AAL, drafted the search strategy, managed the search updates, Conducted statistical analyses, Performed risk-of-bias assessments using the Cochrane ROB 2 tool and contributed to the GRADE certainty evaluations. MA and MYE, independently Performed title/abstract screening, full-text review, contributed to eligibility adjudication and revised the manuscript critically for methodology and interpretation. MOA and AE; Extracted data using the standardized form, verified extracted variables for accuracy and Drafted the main manuscript; LA AA and HA; assisted with data visualization, writing-original draft; YA; Performed risk-of-bias assessments using the Cochrane ROB 2 tool and contributed to the GRADE certainty evaluations.All authors contributed to the interpretation of findings, participated in manuscript revisions, and approved the final submitted version.

Funding

No external funding and the authors conducted this study without financial support from commercial, public, or not-for-profit agencies.

Data availability

We included all data generated or analyzed during this study in this published article and the extracted data with analytic code are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.