Patients and methods: This retrospective study analyzed patients who underwent cardiovascular surgery between February 2021 and January 2024. Patients with preoperative anemia treated with intravenous iron replacement were compared with nonanemic patients. Data on demographics, preoperative conditions, surgical details, and postoperative outcomes were analyzed.

Results: Of the 193 patients (142 males, 51 females; mean age: 62±10 years; range, 27 to 82 years) analyzed, 173 survived, and 20 did not. Surviving patients were younger and had a lower body mass index. Comorbidities such as congestive heart failure and a history of cerebrovascular events were associated with mortality. Laboratory results showed significant differences in hemoglobin levels and iron binding capacity between survivors and nonsurvivors. The study found no significant differences in surgical procedures or reoperation rates between the groups. However, nonsurvivors had more postoperative complications. Multivariate analysis identified cardiopulmonary bypass time and new-onset acute renal failure as independent risk factors for 30-day mortality. Anemic patients treated with intravenous iron replacement had comparable perioperative outcomes to nonanemic patients, including similar lengths of intensive care unit and hospital stays and mortality rates.

Conclusion: Treatment of preoperative anemia with intravenous iron replacement in patients undergoing cardiovascular surgery resulted in outcomes comparable to those of nonanemic patients. This suggests that short-term intravenous iron replacement may be an effective strategy to improve surgical readiness and outcomes in anemic patients.

In the preoperative period, patients who received IV iron replacement (IVIR) have shown positive effects on important perioperative outcomes of open heart surgery, according to some publications.[7,8] Most studies use other treatments along with IVIR, and they typically focus on outcomes related to the amount of red blood cell (RBC) transfusions during the perioperative period. However, there are few studies that have compared the data of anemic patients receiving IVIR with nonanemic patients, particularly with respect to key surgical outcomes, and that have been conducted in a single center with patients undergoing standard surgical procedures. Hence, this study aimed to compare surgical outcomes between patients scheduled for cardiovascular surgery diagnosed with anemia according to World Health Organization (WHO) criteria who received IVIR and those who were not anemic.

The study collected data from the patient records in the hospital information system. The data on the patients' demographic characteristics, treatment history, preoperative data, surgical procedure details, postoperative complications, length of hospital stay, and several factors related to mortality were collected. The severity of heart disease was assessed using the New York Heart Association (NYHA) functional class and Canadian Cardiovascular Society angina grade. EuroSCORE II was calculated for the prediction of the risk of mortality. We excluded patients with incomplete data, those who had not received IVIR despite being anemic, and those who received RBC suspension prior to surgery (Figure 1).

Figure 1. Flowchart on the selection of the patients.
RBC: Red blood cell; IVIR: Intravenous iron replacement.

The primary endpoint was 30-day mortality between the anemic and nonanemic groups. Secondary endpoints were the duration of cardiopulmonary bypass (CPB) and aortic cross-clamp, ICU length of stay, hospital length of stay, and in-hospital mortality. Additionally, several features including demographic characteristics, pre-operative measures, surgical procedure, post-operative complications, and survival measures were analyzed between survivors and nonsurvivors.

Statistical analysis
The data collected were analyzed using IBM SPSS version 20.0 software (IBM Corp., Armonk, NY, USA). Categorical variables were presented as frequencies and proportions, while continuous variables were expressed as mean ± standard deviation (SD) (min-max) and medians (interquartile range), depending on the distribution of the data. Comparisons for continuous data were made using the independent samples t-test or the Mann-Whitney U test, depending on whether the data were parametric. The chi-square test was used to compare categorical variables. Variables that were found to be significant in the univariate analysis underwent multivariate analysis using logistic regression. A p-value <0.05 was considered statistically significant.

Table 1 Characteristics of the patients

Table 1 Continued

Table 1 Continued

Table 1 Continued

Nonsurvivors had lower hemoglobin levels, and there was a significant difference in iron binding capacity between the two groups. The presence of WHO-defined anemia was not different between survivors and nonsurvivors, which may be related to sex-related cut-offs. Nonsurvivors had lower alanine aminotransferase levels and reduced glomerular filtration rates.

Periprocedural data
Although specific cardiovascular risk scores, such as EuroSCORE (European System for Cardiac Operative Risk Evaluation) II, showed a significant divergence indicating a higher predicted risk in nonsurvivors, other clinical and procedural history factors, such as a history of balloon angioplasty or coronary stents, did not show a statistical difference in distribution between survivors and nonsurvivors. When considering bleeding and thrombotic risks, a significantly higher proportion of nonsurvivors were classified into higher bleeding risk categories.

No significant differences were found in the types of surgery performed or in the rates of reoperation between survivors and nonsurvivors when analyzing surgical procedures. However, the timing of surgery emerged as a significant factor. Emergent and early surgery had a higher percentage of nonsurvivors compared to elective surgery. In terms of the technical aspects of surgery, nonsurvivors had a significantly longer CPB time. However, there were no significant differences between the groups in terms of the duration of aortic cross-clamping or the use of off-pump or minimally invasive extracorporeal circulation.

When analyzing postoperative complications, it was found that nonsurvivors experienced significantly more arrhythmias, including atrial fibrillation, ventricular fibrillation, ventricular tachycardia, and atrioventricular block. Nonsurvivors also had higher rates of low cardiac output, requiring intra-aortic balloon pump support. Nonsurvivors had significantly higher rates of myocardial infarction and reexploration for bleeding or tamponade. The difference in RBC transfusion between survivors and nonsurvivors highlights the impact of anemia and the need for blood transfusions on mortality. The median RBC transfusion in the survivors and nonsurvivors groups was 2 and 7 units, respectively (p<0.001). Additionally, nonsurvivors experienced significantly more acute renal failure and respiratory complications, such as pneumonia, pulmonary edema, and adult respiratory distress syndrome.

b>Survival analysis
The survival analysis showed no significant difference in the median length of stay in the intensive care unit (ICU) between survivors and nonsurvivors. However, the duration of mechanical ventilation was significantly longer in nonsurvivors. It is worth noting that the median length of hospital stay did not differ significantly between the survivors and nonsurvivors groups. The rates of in-hospital and 30-day mortality provide a direct measure of short-term outcomes after cardiovascular surgery, with rates of 9.3% and 10.4%, respectively. The multivariate analysis revealed that CPB time (hazard ratio=1.019, 95% confidence interval [CI]: 1.006-1.033, p=0.004) and the development of newly onset acute renal failure (hazard ratio=36.8, 95% CI: 4.7-284.9, p=0.001) were two independent risk factors for 30-day mortality.

Main endpoints
When comparing anemic patients who received IVIR to those without anemia, significant differences were observed in the NYHA functional class (p=0.001) and the prevalence of congestive heart failure. Anemic patients had higher NYHA classes and a higher prevalence of congestive heart failure (37.3% in anemic patients vs. 15.9% in nonanemic patients, p=0.001). Furthermore, it was discovered that anemic patients have a higher preoperative bleeding risk score (p=0.001). The difference in EuroSCORE II scores between anemic and nonanemic patients (median score: 1.79 vs. 1.15; p=0.003) emphasizes the higher risk profile of anemic patients. It is worth noting that there was a slightly higher incidence of emergent cases in nonanemic patients (%7.1 vs. %3.0 p=0.040). There were no significant differences in the duration of CPB and aortic cross-clamp, ICU length of stay, hospital length of stay, in-hospital mortality, and 30-day mortality between the anemic and nonanemic groups.

Given the significant role of anemia as a factor, the importance of its correction and management prior to surgery has often been studied. Several publications discuss managing anemic patients before surgery, particularly with regard to IVIR therapy. Cladellas et al.[7] conducted a study to assess the effects of treating anemia with recombinant human erythropoietin and iron prior to cardiac surgery on postoperative outcomes and RBC transfusion needs. The study compared a group of 75 patients who received recombinant human erythropoietin at a dose of 500 IU/kg/day for four weeks and a fifth dose 48 h prior to surgery, along with IV iron sucrose supplementation, with an observation group of 59 untreated patients. After adjusting for confounding variables, the study found that the combined therapy was independently associated with reduced postoperative morbidity and in-hospital mortality. Specifically, the intervention reduced postoperative renal failure, decreased the rate of RBC transfusion from 93% in the observation cohort to 67%, and shortened hospital stays.

In their study, Spahn et al.[8] investigated the impact of immediate preoperative combination treatment on reducing perioperative RBC transfusions and improving outcomes in patients with anemia or isolated iron deficiency who were scheduled for elective cardiac surgery. The study involved 505 patients who were randomly assigned to receive either a placebo or a combination treatment comprising IV ferric carboxymaltose, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid on the day before surgery. The primary outcome was the number of RBC transfusions during the first seven days after surgery. The combination treatment led to a significant reduction in the median number of RBC transfusions required during the first seven days. Similar reductions were observed on the postoperative Day 90. Additionally, patients in the treatment group exhibited higher hemoglobin concentrations, reticulocyte counts, and reticulocyte hemoglobin content during the first seven days.

Another study by Evans et al.[19] aimed to evaluate the effectiveness of preoperative IV iron administration in anemic patients undergoing cardiac surgery. Out of the 447 patients analyzed, 75 (17%) were anemic and received IV iron treatment, while 72 (16%) were anemic but did not receive any treatment. The aim of the treatment was to achieve a hemoglobin level of ≥130 g/L on the day of surgery. The anemic patients who were successfully treated showed a mean increase in hemoglobin of 17 g/L and received significantly fewer blood transfusions than the untreated anemic patients. The study concluded that anemic patients who were successfully treated required less blood perioperatively. More than half of these patients did not require any transfusion at all.

Klein et al.[20] conducted a prospective multicenter study to investigate the feasibility and effectiveness of introducing a preoperative IV iron service as a national initiative in cardiac surgery. The primary feasibility outcome was to determine if the clinics could be established, while the primary effectiveness outcome was the change in hemoglobin concentration between intervention and surgery. The study found that out of 11 hospitals, seven successfully established iron clinics and recruited 228 patients. Patients with anemia who received IV iron showed a significant increase in hemoglobin concentration from baseline to preoperative, with a mean increase of 8.4 g/L (p<0.001). However, despite the increase in hemoglobin, the study was unable to demonstrate an effect on transfusion rates or patient outcomes, possibly due to the small sample size.

Another study by Kong et al.[21] aimed to determine an effective treatment for preoperative anemia associated with iron deficiency in elective cardiac surgery patients. The study was a singlecenter, open-label, randomized trial involving 156 participants. It compared the effectiveness of IV ferric derisomaltose and subcutaneous darbepoetin (intervention group) to oral ferrous sulfate (control group) in patients with low preoperative hemoglobin levels and iron deficiency. The study's main results indicate that the intervention group had significantly lower odds of requiring RBC transfusion compared to the control group. Additionally, there was a significant increase in hemoglobin levels from randomization to surgery in the intervention group.

Shokri and Ali[22] assessed the impact of preoperative IV iron infusion on hemoglobin levels, blood transfusion needs, and the occurrence of postoperative adverse events in patients undergoing coronary artery bypass grafting. The randomized study enrolled 80 patients aged 52 to 67 years who were assigned to receive either IV ferric carboxymaltose (iron group) or saline (placebo group) seven days before surgery. The study revealed that iron therapy was linked to a lower incidence of anemia four weeks after discharge, significantly higher Hb levels preoperatively, postoperatively, and four weeks after discharge, and shorter hospital and ICU stays. Additionally, iron therapy led to a decreased requirement for packed RBCs after the operation. The study concluded that the treatment is associated with higher postoperative hemoglobin levels, shorter hospital and ICU stays, and reduced perioperative RBC transfusion requirements.

Jafari et al.[23] conducted a study to assess the effectiveness of IV iron sucrose and erythropoietin in reducing transfusion requirements for patients with preoperative iron deficiency anemia undergoing on-pump coronary artery bypass grafting surgery. The study was an open-label, randomized clinical trial that enrolled 114 patients who were divided into two groups: intervention (iron plus erythropoietin) and control. The intervention group received a 200 mg IV dose of iron sucrose and a 100 IU/kg bolus of erythropoietin one to two days prior to surgery. The results showed a significant reduction in the number of RBC units transfused per patient in the intervention group compared to the control group. Additionally, the intervention group exhibited a noteworthy rise in ferritin levels on the seventh postoperative day and experienced shorter stays in both the ICU and hospital. No adverse events were reported in either group.

After evaluating all presented studies, it is observed that administering IVIR to anemic patients before cardiovascular surgery results in positive outcomes for the examined endpoints. However, some publications report contrary results. A recent metaanalysis on the impact of anemia on outcomes after cardiac surgery also conducted a secondary analysis of seven studies involving 1,012 patients and found that short-term preoperative treatments for anemia did not significantly reduce mortality.[18] Similarly, Quarterman et al.[24] presented a retrospective observational review from January 2017 to December 2019. The study evaluated the effectiveness of preoperative IV iron in treating patients with iron deficiency anemia scheduled for elective cardiac surgery. Among the 190 patients who received IV iron, there was a median increase in hemoglobin of 8.0 g/L. However, patients who received IV iron had a significantly higher incidence of transfusion (60%) compared to the nonanemic cohort (22%). Additionally, the treated group had significantly higher rates of new need for renal replacement therapy and stroke, but there was no significant difference in in-hospital mortality.

The present study indicates that patients with anemia who received IVIR prior to cardiovascular surgery had perioperative outcomes comparable to those of nonanemic patients. This includes similar lengths of ICU and hospital stays, as well as in-hospital and 30-day mortality rates. This is consistent with most published literature. These findings suggest that IVIR is a viable strategy to improve the surgical readiness of anemic patients and to bring their outcomes in line with those of their nonanemic counterparts. However, the precise mechanisms by which IV iron influences surgical outcomes, particularly through potential effects on cellular functions, remain to be fully understood.

It is important to note that this study has several limitations. These limitations include its retrospective and observational nature, patient selection based on specific criteria, lack of comparative data with nonsupplemented anemic patients, and exclusion of nonanemic patients who were indicated for iron supplementation. Due to its observational nature, this study cannot establish a cause-and-effect relationship regarding the mechanism of action of iron supplementation.

In conclusion, perioperative outcomes for anemic patients who received IVIR did not differ from patients without anemia. Nonetheless, nonsurvivors had lower preoperative hemoglobin levels, suggesting that more severe anemia may be associated with poorer outcomes. The findings suggest that short-term IVIR may positively impact immediate surgical outcomes, although it is important to consider that many factors influence the complex process of cardiovascular surgery. In addition to correcting hemoglobin levels, further investigation is needed to determine the potential impact of IVIR on cellular function and overall patient recovery and outcomes.

Ethics Committee Approval: The study protocol was approved by the Izmir Bakırçay University Ethics Committee (date: 21.02.2024, no: 210224/1467). The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Concept, design, analysis, literature review, writing the article: F.D.K., A.D.; Control, supervision: Ş.B.; Data collection: F.D.K., A.D., Ö.F.R., D.C., E.O.M.; Materials: F.D.K., A.D., Ö.F.R., D.C., E.O.M.; Critical review: Ş.B.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

1) Elmahrouk A, Ewila H, Eltigani A, Kindawi A, Abdelaziz A, Badr A. Preoperative hemoglobin concentration as an independent predictor for outcome after coronary artery bypass grafting. JESCTS 2016;24:265-9. doi: 10.1016/j. jescts.2016.11.004.

2) Jabagi H, Boodhwani M, Tran DT, Sun L, Wells G, Rubens FD. The effect of preoperative anemia on patients undergoing cardiac surgery: A propensity-matched analysis. Semin Thorac Cardiovasc Surg 2019;31:157-63. doi: 10.1053/j. semtcvs.2018.09.015.

3) Kulier A, Levin J, Moser R, Rumpold-Seitlinger G, Tudor IC, Snyder-Ramos SA, et al. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. Circulation 2007;116:471-9. doi: 10.1161/ CIRCULATIONAHA.106.653501.

4) Özhan A, Akgül E, Parlar Aİ, Çekirdekçi A. The association of blood transfusion and acute kidney injury in diabetic coronary artery bypass grafting patients. Cardiovasc Surg Int 2021;8:13-9. doi: 10.5606/e-cvsi.2021.1065.

5) Özkan S, Kaplan M, Tarçın Ö, Erer HB, Balcı AY, Yekeler İ. Preoperative anemia in cardiovascular surgery patients. Turk Gogus Kalp Dama 2011;19:110-5.

6) Ferraris VA, Hochstetler M, Martin JT, Mahan A, Saha SP. Blood transfusion and adverse surgical outcomes: The good and the bad. Surgery 2015;158:608-17. doi: 10.1016/j. surg.2015.02.027.

7) Cladellas M, Farré N, Comín-Colet J, Gómez M, Meroño O, Bosch MA, et al. Effects of preoperative intravenous erythropoietin plus iron on outcome in anemic patients after cardiac valve replacement. Am J Cardiol 2012;110:1021-6. doi: 10.1016/j.amjcard.2012.05.036.

8) Spahn DR, Schoenrath F, Spahn GH, Seifert B, Stein P, Theusinger OM, et al. Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: A prospective randomised trial. Lancet 2019;393:2201-12. doi: 10.1016/S0140-6736(18)32555-8.

9) Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405. doi: 10.1182/blood- 2016-03-643544.

10) Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating morphologic, clinical, and genomic data. Blood 2022;140:1200-28. doi: 10.1182/blood.2022015850.

11) Shirzad M, Karimi A, Dowlatshahi S, Ahmadi SH, Davoodi S, Marzban M, et al. Preoperative anemia associated in-hospital mortality and morbidity in isolated coronary artery bypass graft surgery. Cent Eur J Med 2010;5:308-14. doi: 10.2478/s11536-009-0094-6.

12) Spadaccio C, Nenna A, Candura D, Rose D, Moscarelli M, Al-Attar N, et al. Total arterial coronary artery bypass grafting in patients with preoperative anemia. J Card Surg 2022;37:1528-36. doi: 10.1111/jocs.16425.

13) Ranucci M, Pavesi M, Pistuddi V, Baryshnikova E. Preoperative anemia correction in cardiac surgery: A propensity-matched study. J Cardiothorac Vasc Anesth 2021;35:874-81. doi: 10.1053/j.jvca.2020.07.015.

14) Miceli A, Romeo F, Glauber M, de Siena PM, Caputo M, Angelini GD. Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery. J Cardiothorac Surg 2014;9:137. doi: 10.1186/1749-8090-9-137.

15) Kumar S, Khurana NK, Awan I, Memon S, Memon MK, Sohail H, et al. The effect of preoperative hematocrit levels on early outcomes after coronary artery bypass graft. Cureus 2021;13:e12733. doi: 10.7759/cureus.12733.

16) van Straten AH, Hamad MA, van Zundert AJ, Martens EJ, Schönberger JP, de Wolf AM. Preoperative hemoglobin level as a predictor of survival after coronary artery bypass grafting: A comparison with the matched general population. Circulation 2009;120:118-25. doi: 10.1161/ CIRCULATIONAHA.109.854216.

17) Kulier A. Anemia and morbidity and mortality in coronary bypass surgery. Curr Opin Anaesthesiol 2007;20:57-64. doi:10.1097/ACO.0b013e328013da20.

18) Lau MPXL, Low CJW, Ling RR, Liu NSH, Tan CS, Ti LK, et al. Preoperative anemia and anemia treatment in cardiac surgery: A systematic review and meta-analysis. Can J Anaesth 2024;71:127-42. doi: 10.1007/s12630-023- 02620-1.

19) Evans CR, Jones R, Phillips G, Greene G, Phillips M, Morris-Clarke R. Observational study of pre-operative intravenous iron given to anaemic patients before elective cardiac surgery. Anaesthesia 2021;76:639-46. doi: 10.1111/ anae.15396.

20) Klein AA, Chau M, Yeates JA, Collier T, Evans C, Agarwal S, et al. Preoperative intravenous iron before cardiac surgery: A prospective multicentre feasibility study. Br J Anaesth 2020;124:243-50. doi: 10.1016/j.bja.2019.11.023.

21) Kong R, Hutchinson N, Hill A, Ingoldby F, Skipper N, Jones C, et al. Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial). Br J Anaesth 2022;128:796-805. doi: 10.1016/j.bja.2022.01.034.

22) Shokri H, Ali I. Intravenous iron supplementation treats anemia and reduces blood transfusion requirements in patients undergoing coronary artery bypass grafting-A prospective randomized trial. Ann Card Anaesth 2022;25:141-7. doi: 10.4103/aca.aca_209_20.

23) Jafari S, Talasaz AH, Salehiomran A, Ariannejad H, Jalali A. Effects of iron sucrose and erythropoietin on transfusion requirements in patients with preoperative iron deficiency anemia undergoing on-pump coronary artery bypass graft. J Tehran Heart Cent 2022;17:7-14. doi: 10.18502/jthc. v17i1.9319.

24) Quarterman C, Shaw M, Hughes S, Wallace V, Agarwal S. Anaemia in cardiac surgery - a retrospective review of a centre's experience with a pre-operative intravenous iron clinic. Anaesthesia 2021;76:629-38. doi: 10.1111/ anae.15271.