Study design and setting
This observational, single-center study of IV iron therapy included older patients admitted with an acute hip fracture at the Department of Orthopedic Surgery, Aalborg University Hospital, Hjørring, Denmark. In May 2019, a new local IV iron therapy protocol was implemented at the department and recommends IV iron isomaltoside 1000 (Monofer®) after surgery for hip fracture on 3rd postoperative day if hemoglobin ≤ 6.5 mmol/L (≤ 10.4 g/dL) day three postoperatively. Therefore, the study investigates the time before (from July 2018 to May 2019) and after (August 2019 to May 2020) the implementation of the protocol.
Outcome and follow-up
The primary outcome of the study is to analyze the 30-day mortality after surgery. The secondary outcome is to evaluate the efficacy of IV Monofer on the hemoglobin within 14 to 30 days postoperatively, although no systematic long-term follow-up on the hemoglobin was part of the IV iron therapy protocol.
Patients admitted with an acute hip fracture at the Department of Orthopedic Surgery, Aalborg University Hospital, Hjørring, Denmark from July 2018 to May 2019 (study period 1) and from August 2019 to May 2020 (study period 2) were included. Thus, the study period 1 was before the implementation of the iron treatment protocol and IV iron was therefore administered non-systematically. In study period 2, IV iron was administered systematically to all patients with a hemoglobin ≤ 6.5 mmol/L on 3rd postoperative day. This eligibility criteria of the iron therapy protocol is based on the evidence from major colorectal surgeries among patients diagnosed with colorectal cancer (31, 32). Therefore, all patients with a hemoglobin > 6.5 mmol/L on the 3rd postoperative day were excluded. Furthermore, the patients who died in hospital before day three and the patients who were discharged immediately after surgery were excluded. Finally, the patients who fulfilled the eligibility criteria to IV iron but did not receive it because of patient denial, missing cooperation, or transfer to another hospital before day three was excluded.
An international consensus states postoperative anemia as hemoglobin < 6.83 mmol/L (< 11.0 g/dL) (16). In this study, a hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day was defined as eligible according to the iron therapy protocol (33). However, due to the non-systematic administration of IV iron in study period 1, IV iron was in this first period only prescribed to some patients after medical assessment by a geriatrician. Furthermore, if the postoperative anemia was severe, the treatment was initiated the 1st day after the surgery. After the implementation of the iron therapy protocol, IV iron was administered systematically. The patients with a hgb ≤ 6,5 mmol/L on the 3rd postoperative day were administered IV iron. The patients received a single dose of IV iron isomaltoside 1000 (Monofer®, Pharmacosmos) 20 mg/kg diluted in 100mL isotone saline solution with an infusion time of 30 minutes while they were observed for adverse reactions (33, 34). The indications for ABT followed the current local guidelines (35). Therefore, the patients with a hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day were divided according to which treatment of postoperative anemia they received between day one and day three postoperatively. Accordingly, whether they received no treatment, IV iron, ABT or both IV iron & ABT, see Fig. 1.
The data collection was performed in two steps and was obtained from the patients’ medical records retrospectively. Information was obtained on hospital admission date, hospital discharge date, number of readmissions, type of hip fracture, body-mass-index (BMI), 30-days mortality postoperatively, hgb at day one preoperatively, at day one and day three and between day 14 and 30 postoperatively, number of ABT, administration of IV Monofer and concomitant comorbidities. The type of hip fracture was coded according to the World Health Organization International Classification of disease (ICD) and the type of orthopedic procedure were classified according to Nomenclature for Properties and Units (NPU-codes). Secondly, we registered whether the patients were admitted from and discharged to home or nursing home and if they were readmitted to hospital. Finally, we registered, date of surgery, reoperation during hospitalization, when IV Monofer, ABT and antibiotics were administered, type of anesthesia and operation and perioperative blood loss.
Comorbidities and concomitant medication
At hospitalization we identified confounding factors such as comorbidities and concomitant medication. We consulted the national Shared Medication Record for information about the patients’ medication at submission time. Furthermore, we identified the occurrence of polypharmacy. Polypharmacy was defined as five or more medications according to a systematic review which found this to be the most commonly reported definition of polypharmacy (36).
Clinically relevant comorbidities were obtained from the patients’ medical records and classified according to the Charlson’s Comorbidity index (CCI) and includes: previous myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, connective tissue disease, peptic ulcer disease, mild to severe liver disease, diabetes mellitus with or without complications, hemiplegia, moderate to severe chronic kidney disease, localized or metastatic solid tumor, leukemia, lymphoma and AIDS (37, 38).
Categorical variables were presented as counts and percentages, and continuous variables as median and 25th and 75th percentiles. The x2 test was used to evaluate differences for categorical variables, and the Kruskal-Wallis test to evaluate differences for non-normally distributed continuous variables. Kaplan–Meier cumulative mortality curves were plotted for the four treatments of postoperative anemia to illustrate the crude 30-day mortality incidence.
Using multivariable Cox regression and average treatment effect analysis (ATE), we reported the 30-day absolute and relative mortality risk standardized for the age, sex, medication, and comorbidity distribution of all patients eligible for analysis.
A two-sided p-value was considered statistically significant below 0.05. All data management and analyses were performed using and R, version 3.5.0.(39)