Effects of ferric derisomaltose on postoperative anaemia in adult spinal deformity surgery: a study protocol for a randomised controlled trial

STRENGTHS AND LIMITATIONS OF THIS STUDY

  • Randomised controlled trial designed to maximise the strength of the study power.

  • The primary outcome is an objective indicator.

  • Multiple other indicators are used to evaluate the efficacy of ferric derisomaltose, including laboratory parameters and quality-of-life assessment.

  • The study is limited by the single-centre design with relatively small sample size.

Introduction

Postoperative anaemia is common among patients receiving major surgery, often attributed to preoperative anaemia, perioperative blood loss (surgical bleeding, coagulopathy and phlebotomies) and postoperative blunted erythropoiesis.1 Spinal deformity surgery is a complex and invasive procedure that may result in significant blood loss. For patients undergoing elective orthopaedic surgery, postoperative anaemia occurred with an estimated incidence ranging from 51% to 87%,2 while spinal surgery patients had a particularly high incidence of anaemia, often up to 80%.3 4 Anaemia can be associated with several negative consequences including impaired wound healing, increased risk of infection, decreased physical function and quality of life, and even increased mortality.4 5 Therefore, optimising treatment for postoperative anaemia is critical for patients receiving spinal deformity surgery.

Various strategies for the treatment of postoperative anaemia have been proposed, including blood transfusions, erythropoietin-stimulating agents and iron supplementation.1 Oral iron supplements were traditionally recommended to treat postoperative iron-deficiency anaemia, but their efficacy is limited by poor absorption, gastrointestinal side effects and the need for long-term treatment.6 7 Also, for surgical patients with perioperative anaemia, more than half showed evidence of absolute iron deficiency, and 10%–15% could be functional iron deficiency, which is an iron sequestration status characterised by insufficient mobilisation of iron stores due to increased demands. For example, inflammation, which is common among postoperative patients, can disturb the utilisation of ferritin essential for erythropoiesis.8 In this case, intravenous iron has the advantage over oral iron in overcoming this barrier and thereby achieve effective erythropoiesis. Previous studies have shown promising results for the use of intravenous iron therapy in patients after spinal deformity surgery but still lacking standard practice.9

Ferric derisomaltose is a third-generation intravenous iron supplement that has been demonstrated to be effective and safe in treating iron-deficiency anaemia in patients with chronic kidney disease, heart failure, and receiving bariatric surgery and total knee arthroplasty.10–13 Compared with traditional iron supplements, the third-generation iron supplement allows for higher doses of iron administration (up to 1000 mg or even more) over a shorter period of time (15–60 min), which greatly improves patient compliance and reduces medical interventions while increasing haemoglobin (Hb) levels rapidly.14–16 However, the use of ferric derisomaltose in adult patients receiving spinal deformity surgery has not been examined so far.

This study aims to investigate the efficacy and safety of intravenous administration of ferric derisomaltose compared with oral iron supplementation in anaemic patients after spinal deformity surgery. Correction of Hb levels, response in reticulocyte parameters, iron stores, postoperative complications, length of hospital stay, functional recovery and quality of life will be evaluated. The results of this study will provide more clinical evidence to establish a targeted and effective perioperative iron supplementation protocol.

Materials and analysis

Study setting

This is a single-centre, phase 4, randomised controlled trial with two parallel groups, aiming to investigate the effectiveness and safety of ferric derisomaltose compared with oral ferrous succinate in patients with postoperative anaemia after adult spinal deformity surgery. The study will be conducted at Peking Union Medical College Hospital, Beijing, China. The study was initiated in August 2023 after ethical approval and trial registration. We expect to recruit all patients and complete major trial steps by the summer of 2025.

Selection of subjects

Patients over 18 years of age who are admitted for evaluation for spinal deformity surgery will be screened for participation. Baseline information will be collected after informed consent. Hb will be assessed at postoperative day (POD) 1, and patients will be included if Hb at POD1 showed a decrease of ≥20 g/L compared with baseline, or if 70 g/L≤Hb≤110 g/L was found at POD1. The full inclusion and exclusion criteria are listed in table 1.

Table 1

Inclusion and exclusion criteria

Study randomisation and withdrawal

Eligible patients will be recruited on POD1 and randomised in a 1:1 ratio to receive either intravenous iron therapy or oral iron therapy. Block randomisation with random sizes from 4 to 8 was used. Allocation concealment was achieved by using sealed envelopes opened before enrolment. Participants are free to decline participation and can withdraw at any time during the study.

Interventional methods

Recruited participants will receive intervention on POD1 after randomisation. This trial has two intervention groups. The intervention for the treatment group was an intravenous administration of ferric derisomaltose, whose dosage was calculated based on body weight and Hb profile described in table 2 (the maximal dose should not exceed 20 mg/kg body weight, rounded off to the nearest 100 mg). Ferric derisomaltose will be administered in 250 mL of 0.9% m/V sodium chloride solution over 15–30 min as a single dose. Patients in the control group will be given oral ferrous succinate (100 mg three times a day) for 4 weeks.

Table 2

Simplified table of ferric derisomaltose demand

Study procedures

The schedule of interventions and data collection is meticulously outlined in table 3. The study process is thoroughly illustrated in figure 1. During the preoperative screening phase, after informed consent, demographic data, medical history and preoperative laboratory test results will be collected 1–3 days before surgery. At POD1, eligible participants will be enrolled and randomly assigned to receive ferric derisomaltose infusion or oral ferrous succinate. Perioperative transfusion algorithm will be followed by the suggestion from Chinese Society of Anesthesiology: red blood cells (RBC) would be transfused at a threshold of Hb concentration <70 g/L, apheresis platelets would be administered when platelet count <50×109/L and fresh frozen plasma would be transfused when the results of prothrombin time (PT)/ activated partial thromboplastin time (aPTT) are more than 1.5 times prolonged. In the presence of massive bleeding and haemodynamic instability, empirical transfusion therapy was allowed without the results of laboratory tests. Vital signs, laboratory results including complete blood count, reticulocyte count and reticulocyte Hb content, coagulation, and iron-deficiency anaemia indicators (serum iron, serum ferritin, transferrin saturation (TSAT), serum transferrin receptor (sTFR)), EQ-5D questionnaire (European Quality of Life-5 Dimensions), FACIT-fatigue questionnaire, and Barthel Index questionnaire, will be examined at all visits.17–19 Adverse events and concomitant treatment will be recorded at all visits. The study drugs will be retrieved, and compliance will also be assessed and documented at the final visit.

Figure 1
Figure 1

Flow chart of overall study design. POD, postoperative day.

Table 3

Study flow charts of study procedures

Outcome measures

The study outcomes are listed in table 4. The primary outcome of this study is the change in Hb concentrations from POD1 to POD14. Secondary outcomes include reticulocyte parameters, iron-deficiency anaemia indicators, Hb changes from POD1 to other visits, allogeneic RBC infusion rates, quality-of-life assessment and prognostic outcomes.

Table 4

Study outcomes

Assessment of study endpoints

Laboratory data

Complete blood count, reticulocyte count and reticulocyte Hb content, and iron-deficiency anaemia indicators (serum iron, serum ferritin, TSAT, sTFR) will be measured on all postoperative visits and compared.

Quality of life

Quality of life will be assessed by the EQ-5D-3L, FACIT-fatigue and Barthel Index questionnaire at POD5, at POD14, at POD35, respectively. EQ-5D-3L questionnaire is an instrument to evaluate individuals’ quality of life, using five dimensions including mobility, self-care, usual activities, pain/discomfort and anxiety/depression for assessment. A single composite index will be generated by combining the levels of the five dimensions. FACIT-fatigue questionnaire is a tool to evaluate individuals’ quality of life that consists of 13 modules regarding fatigue, physical function, emotional status and satisfaction with life assessment. Barthel Index questionnaire is an instrument to assess the degree of dependence in various areas of daily living to assist rehabilitation.

Other prognostic outcomes

Length of hospital stay: The number of hospitalised days is an important indicator for evaluating the effectiveness of treatment plans and the efficiency of hospital management.

Incidence of adverse events: an important indicator for evaluating the safety and efficacy of ferric derisomaltose and ferrous succinate.

Incidence of postoperative infection: a critical indicator for perioperative quality assurance.

Safety considerations

Any adverse event during the period from enrolment to the end of the study will be monitored and recorded at each visit. The record includes the terminology of adverse events, the start and end dates, the time of reporting, the severity grading, whether it caused the participant’s withdrawal from the study and the outcomes. Serious adverse events refer to any harmful medical event that meets one or more of the following conditions: (1) cause death, (2) life-threatening, (3) require or prolong in-patient hospitalisation and (4) cause persistent or significant disability/incapacity.

Sample size consideration

The main objective of this study is to conduct a clinical trial on the superior efficacy of ferric derisomaltose over oral ferrous succinate in the treatment of postoperative anaemia in patients receiving spinal deformity surgery. The sample size was calculated based on a two-sided significance test and the preliminary results from the literature review and pilot studies.20 The SD of the Hb on POD1 is 8.7 g/L. On account of superiority trial design, we consider 5 g/L higher in the increase of Hb from POD1 to POD14 between the treatment group and the control group to represent a clinically significant improvement. With a power of 80%, a two-sided type I error of 0.05 and a drop-out rate of 20%, a total of 120 patients are aimed to be enrolled.

Data analysis

Statistical analysis will be conducted using the R software (V.4.0.1, http://cran.r-project.org) for Windows (IBM) by the Translational Medicine Research Center of Peking Union Medical College Hospital. All hypothesis tests will be performed at a two-sided 5% significance level. Descriptive statistics will be used to summarise continuous variables, quantitative variables will be reported as the mean±SD (SD) when variables follow a normal distribution or median (25th–75th IQR) when variables fit the skewed distribution. Two-sample mean comparisons will be performed using t-tests, and two-sample composition comparisons will be performed using χ2 tests. Non-parametric tests, such as rank-sum tests, will be used for metric data that do not follow a normal distribution. Differences with p<0.05 are considered statistically significant. Categorical variables will be compared using χ2 or Fisher’s exact test. The means of two samplers were compared using Student’s t-test or the non-parametric Mann-Whitney U test. Differences with p<0.05 are considered statistically significant.

Ethics and dissemination

This study has been approved by the Research Ethics Committee of Peking Union Medical College Hospital (reference number: I-22PJ696, approved on 9 November 2022) and has been registered in ClinicalTrials.gov (registration number: NCT05714007), strictly following the Standard Protocol Items: Recommendations for Interventional Trials statement.21 This study will be performed according to the guidelines of the Declaration of Helsinki. This protocol will be strictly followed, and any modifications will be made in writing and submitted to the ethics committee for approval. Participants will be given detailed written and verbal instructions regarding the purpose of the study by trained study providers prior to the start of the screening. All the participants will provide their written informed consent to participate in this study.

Results of this study are to be published and disseminated in peer-reviewed journals and are planned to be presented at conferences in China and internationally, strictly following the Consolidated Standards of Reporting Trials guidelines.22 23

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Data statement

All data in this study will be maintained in the Department of Orthopedics of Peking Union Medical College Hospital to ensure privacy. Only medically qualified investigators will involve in the original clinical assessment/safety data. Data verification, participants list, summary tables and statistical analyses will be performed by statistical analysts. Data from the study will be regularly updated on the Clinical Trial Registry website (NCT05714007 (https://clinicaltrials.gov/)). Detailed study results can be obtained by reading subsequent publications or by contacting the corresponding author.

Discussion

Adult spinal deformities are a range of heterogeneous abnormalities including scoliosis, kyphosis, lordosis and spondylolisthesis, all of which can lead to imbalances in the structural support of the spine.24 25 Despite significant advances in surgical techniques and equipment, spinal deformity surgery is still one of the most invasive surgical procedures that may cause significant blood loss and postoperative anaemia,26–28 which brings the requirement for blood transfusions and the increase the associated risks including infections, thromboembolic events, extended hospital stay and may even affect prognosis.29–31 However, currently, there is no standard perioperative treatment for postoperative anaemia in this group of patients.

Iron supplementation has been widely used in the management of perioperative anaemia. According to PREPARE study, a significant proportion of patients received elective orthopaedic surgeries with normal preoperative Hb levels became anaemic postoperatively. However, they were rarely evaluated for iron status, and iron therapy was believed to be underused, indicating the importance of iron supplement.3 In addition, though there has been accumulating evidence showing the limitations of oral iron therapy that may neither be adequate nor be effective compared with intravenous iron, oral iron supplementation is still currently the first-line treatment for iron-deficiency patients.32 The underuse of intravenous iron in clinical practice could possibly be explained that traditional intravenous iron cannot be applied in high doses in a single infusion due to the instability of its chemical structure and stressful damage to organs, thus repeated administration is often required, making it inconvenient for clinical use.

Ferric derisomaltose has higher stability in structure and more favourable features as a newer intravenous iron preparation, which has demonstrated its effectiveness in treating anaemia of different aetiologies, including iron-deficiency anaemia, chronic kidney disease, chronic heart failure, etc. In surgical settings, it has been reported that in patients undergoing hip or knee arthroplasty, administration of ferric derisomaltose significantly reduced postoperative anaemia rates, along with improved Hb concentration, serum iron concentration and TSAT compared with the placebo13 33 However, it still lacks evidence evaluating the role of intravenous ferric derisomaltose in patients undergoing spinal deformity surgery.

To our knowledge, this will be the first randomised controlled trial investigating the potential benefit of ferric derisomaltose on the early improvement of postoperative anaemia and iron status, as well as the quality of life in patients undergoing spinal deformity surgeries. Based on the facts that perioperative anaemia could be associated with a number of unfavourable outcomes including prolonged hospitalisation, increased postoperative delirium and other morbidities,34 35 among which some complications are unique for spine surgery, especially in the prone position, for example, postoperative visual loss,36 it is worth studying whether patients receiving spinal deformity surgery may benefit from intravenous ferric derisomaltose treatment. For the potential risks of ferric derisomaltose, according to previous studies, parenteral iron administration is generally safe with very low risk of serious adverse events reported.37 Minor infusion reactions including nausea, mild hypotension and myalgia are expected and will be treated appropriately once occur.

There are some limitations to this investigation. First, anaemia threshold is subject to discrepancies that exist between the male and female populations.38 We will incorporate gender-matching analysis to mitigate any inherent gender biases that may exist. Second, considering the currently low transfusion rate at our institution and the relatively small sample size in this study, postoperative allogeneic blood transfusion rates, an important clinical indicator for perioperative blood management may be difficult to obtain with differential results and needs to be considered for outcome assessment in future larger trials.39 Finally, it is worth mentioning that this study does not include the treatment in case of preoperative anaemia, which may potentially cause a slight degree of bias. Relevant subgroup analysis of the baseline will be conducted in forthcoming investigations. Also, future studies should investigate the optimal dose and duration of ferric derisomaltose, as well as its long-term effects on prognosis.

In conclusion, despite the limitations, this study is expected to provide high-quality clinical evidence for the effectiveness of postoperative adequate intravenous ferric derisomaltose and the development of a simple and targeted postoperative iron supplementation programme to accelerate postoperative recovery of patients undergoing adult deformity surgery.

Ethics statements

Patient consent for publication

Acknowledgments

We express our genuine appreciation to all the participants and the surgeons, anaesthesiologists and nurses who played a vital role in the study’s implementation, as well as Pharmacosmos who provides the study medication, and has provided a grant for conducting the study. Furthermore, we extend our sincere appreciation to Dr Zhang Yuelun for his participation in randomisation for this study.

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