Association between Intravenous Iron Therapy and Short-term Mortality Risk in Older Patients Undergoing Hip Fracture Surgery: An Observational Study

doi:10.21203/rs.3.rs-320715/v1

Download PDF

Research Article

Association between Intravenous Iron Therapy and Short-term Mortality Risk in Older Patients Undergoing Hip Fracture Surgery: An Observational Study

https://doi.org/10.21203/rs.3.rs-320715/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background: Anemia is common among ortho-geriatric hip fracture patients and is associated with prolonged recovery and increased postoperative mortality rate. Intravenous iron seems to increase hemoglobin recovery and reduce the mortality rate in patients undergoing orthopedic surgeries. This study investigated the association between short-term mortality risk and intravenous iron therapy in older patients undergoing hip fracture surgery.

Methods: This observational study included 210 patients undergoing hip fracture surgery from July 2018 to Maj 2020. These 210 patients were alive and had a hemoglobin ≤ 6.5mmol/L on the 3^rd postoperative day. In May 2019 a local intravenous iron therapy protocol was implemented and recommended intravenous iron (Monofer ©) if hemoglobin on the 3^rd postoperative day was ≤ 6.5 mmol/L. According to treatment of postoperative anemia between 1^st and 3^rd day post-surgery, the patients were divided into four groups: No treatment (n=52), blood transfusion (n=38), IV Monofer (n=80) and blood transfusion & IV Monofer (n=40). Primary outcome was 30-day mortality post-surgery. The secondary outcome was the impact on hemoglobin level 14-30 days postoperatively. Multivariable Cox regression was used to estimate the 30-day mortality standardized for covariates.

Results: Of 210 patients, 17 (8.1%) died within 30-days after surgery. There was a significantly lower mortality among the patients who received IV Monofer compared to those who received no treatment (HR: 0.17, 95% CI: [0.03-0.93], P = 0.041). Among the 86 patients with available hemoglobin measurements within 14 to 30 days post-surgery, there was no significant difference in hemoglobin level between the various treatment groups (mean 6.6 mmol/L, P = 0.1165).

Conclusion: IV Monofer on the 3^rd postoperative day in older hip fracture patients seemed to reduce 30-day mortality compared with no treatment. No significant differences in hemoglobin levels between 14-30 days post-surgery across treatment groups were found, although this was assessed in a subset of patients with available hemoglobin levels warranting further study.

Trial registration: NA

Orthopedic Surgery

hip fractures

older people

mortality

anemia

iron

Anemia is a severe complication among older people undergoing hip fracture surgery. Evidence suggests that anemia is associated with prolonged recovery, decreased mobility and increased postoperative mortality rate (1–6). Development of anemia is multifactorial: blood lost at the fracture site and during surgery, iatrogenic hemodilution, the presence of chronic diseases and inhibition of erythropoiesis and functional iron deficiency due to trauma- and surgery induced inflammation (7–9). In the postoperative period guidelines recommend treatment of severe anemia with allogenous blood transfusion (ABT). Besides heavy expense, ABT causes a higher risk of postoperative bacterial infections because of a immunological suppression, thus extending the hospitalization (10–12). The alternative to ABT is stimulation of erythropoiesis with erythropoietin (EPO) and iron which seems to be associated with improved patient outcomes, reduced blood product utilization, reduced mortality and product-related cost savings (13–22).

Several studies investigated the efficacy of intravenous (IV) iron administration perioperatively in patients undergoing major surgeries. On one hand, studies suggested that IV iron preoperatively is associated with reduced ABT rate, fewer nosocomial infections, decreased mortality, higher postoperative hemoglobin-concentration and shorter hospitalization (12, 17, 19–21, 23–26). On the other hand, a recent review concluded that the evidence for administration of IV iron preoperatively is deficient (27). As for postoperative IV iron administration the results are also contradictory. Kim et al. investigated the implementation of a strict transfusion protocol and postoperative IV iron among patients undergoing orthopedic hip surgery. They found that postoperative IV iron was related to a significant lower number of transfused blood units pr. patient and higher hemoglobin-concentration six weeks postoperatively (28). Contrarily, Moppett et al. have found no benefit of three daily doses of IV iron on the hemoglobin recovery seven day postoperatively among older patients undergoing hip fracture surgery (29, 30).

As such, the evidence for administration of IV iron among older patients undergoing major orthopedic surgeries is scarce and conflicting. Therefore, in older patients undergoing hip fracture surgery, we wanted to investigate the impact of postoperative IV iron therapy on 30-day mortality and hemoglobin level 14–30 days postoperatively.

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.

Study population

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.

Study interventions

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.

Data collection

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).

Statistical analysis

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.

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)

Patients

In total 400 patients were recruited in the two study periods. After excluding patients not fulfilling the inclusion criteria, a total of 210 patients with hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day were included. We identified 52 patients with no treatment, 38 receiving ABT, 80 receiving IV Monofer and 40 receiving IV Monofer & ABT.

Characteristics

The characteristics of the study population reported are presented in Table 1. The population consisted of 107 (51%) females and 103 (49%) males and the average age was 83.5 (± 8.7) years. There was no significant difference among the treatment groups regarding gender, age, BMI, CCI, admission source and length of stay. However, patients in ABT and in IV Monofer & ABT group had significantly more polypharmacy than patients in the other treatment groups. Furthermore, the patients receiving no treatment had significantly lower perioperative blood loss (185.7 ± 108.9mL), fewer extracapsular fractures (44.2%) and fewer fixations with intramedullary nails (55.2%) than the other patients. Additionally, there was a significant difference in hemoglobin preoperatively and postoperatively among the treatment groups. The highest preoperative hemoglobin is 7.9 (± 0.7) mmol/L in the IV Monofer group and the lowest is 6.8 (± 1) mmol/L in the IV Monofer & ABT group. The boxplot in Fig. 2 shows the distribution of the hemoglobin postoperative day three by the three possible treatment groups plus no treatment. Finally, a notable result was the significant change in choice of treatment in the two study periods, p < 0.0001. In study period 2, N = 103, 101 patients (98%) received IV Monofer, 34 patients (33%) received ABT and only 1 (1%) received no treatment. Contrarily, in study period 1, N = 107, 19 patients (17.8%) received IV Monofer, 42 patients (39.3%) received ABT and 51 patients (47.6%) received no treatment.

Table 1

Demographics among patients with hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day
	No treatment (n = 52)	ABT (n = 38)	IV Monofer (n = 80)	IV Monofer & ABT (n = 40)	Total (n = 210)	p-value
Gender
Female	28 (53.8)	20 (52.6)	41 (51.2)	18 (45.0)	107 (51.0)
Male	24 (46.2)	18 (47.4)	39 (48.8)	22 (55.0)	103 (49.0)	0.853
Age	82.6 (9.1)	83.2 (7.1)	83.6 (8.9)	84.7 (9.2)	83.5 (8.7)	0.709
BMI (kg/m²)	24.1 (4.2)	24 (5.1)	24.2 (3.9)	23.2 (3.8)	23.9 (4.2)	0.655
Charlson Comorbidity Index	1.9 (2)	2.7 (2.1)	1.9 (2.2)	2.1 (1.7)	2.1 (2.1)	0.219
Polypharmacy (≥ 5 medications)	34 (65.4)	33 (86.8)	55 (68.8)	34 (85.0)	156 (74.3)	0.023*
Admission source
Home-independent	38 (73.1)	27 (71.1)	55 (68.8)	29 (72.5)	149 (71.0)
Nursing home	14 (26.9)	11 (28.9)	25 (31.2)	11 (27.5)	61 (29.0)	0.951
Study period
1)	51 (98.1)	37 (97.4)	12 (15.0)	7 (17.5)	107 (51.0)
2)	1 (1.9)	1 (2.6)	68 (85.0)	33 (82.5)	103 (49.0)	< 0.001*
Fracture
Intracapsular	29 (55.8)	14 (36.8)	31 (38.8)	13 (32.5)	87 (41.4)
Extracapsular	23 (44.2)	24 (63.2)	49 (61.2)	27 (67.5)	123 (58.6)	0.098
Operation
Arthroplasty	19 (36.5)	16 (42.1)	23 (28.8)	7 (17.5)	65 (31.0)
Intramedullary nails	19 (36.5)	21 (55.3)	48 (60.0)	30 (75.0)	118 (56.2)
AO screws	2 (3.8)	0 (0.0)	3 (3.8)	1 (2.5)	6 (2.9)
Dynamic hip screws	7 (13.5)	1 (2.6)	4 (5.0)	1 (2.5)	13 (6.2)
other	5 (9.6)	0 (0.0)	2 (2.5)	1 (2.5)	8 (3.8)	0.014*
Time to theatre (days)	0.6 (0.5)	0.8 (0.8)	0.8 (0.5)	0.7 (0.6)	0.7 (0.6)	0.425
Preoperative Hgb (mmol/L)	7.7 (0.8)	7.4 (1)	7.9 (0.7)	6.8 (1)	7.5 (0.9)	< 0.001*
Missing	9	5	19	10	43
Perioperative blood loss (mL)	185.7 (108.9)	387.1 (414.1)	205.1 (159.9)	254.7 (196.1)	246.8 (241.1)	0.001*
Missing	17	7	21	8	53
Hgb postoperative day 1 (mmol/L)	6.3 (0.6)	5.4 (0.8)	6.1 (0.6)	5.1 (0.6)	5.8 (0.8)	< 0.001*
Missing	2	0	0	0	2
Hgb postoperative day 3 (mmol/L)	5.8 (0.5)	5.4 (0.7)	5.6 (0.5)	5.2 (0.7)	5.6 (0.6)	< 0.001*
Hgb postoperative between day 14–30 (mmol/L)	6.3 (0.7)	6.4 (0.5)	6.8 (0.6)	6.6 (0.8)	6.6 (0.7)	0.116
Missing because deceased	5	4	2	4	15
Missing because no hgb control	28	21	48	12	109
Length of stay (days)	6.5 (3.9)	7.1 (4)	5.9 (2.1)	6.9 (2.6)	6.5 (3.1)	0.177
Discharged to
Home-independent	18 (34.6)	14 (36.8)	37 (46.2)	14 (35.0)	83 (39.5)
Nursing home	34 (65.4)	20 (52.6)	43 (53.8)	24 (60.0)	121 (57.6)
Dead in hospital	0 (0.0)	4 (10.5)	0 (0.0)	2 (5.0)	6 (2.9)	0.023*
Readmission/transmission to ICU^$
Readmitted	13 (25.0)	5 (13.2)	14 (17.5)	10 (25.0)	42 (20.0)
Transmitted to ICU^$	0 (0.0)	0 (0.0)	1 (1.2)	1 (2.5)	2 (1.0)	0.558
30-day mortality postoperative	5 (9.6)	4 (10.5)	3 (3.8)	5 (12.5)	17 (8.1)	0.316
Data are presented as mean ± SD (age, BMI, Charlson Comorbidity Index, perioperative blood loss, time to theatre, hemoglobin levels, length of stay) or number of patients and percentage (all others). ^$Intensive Care unit.
The Table 1 should appear after the section “Characteristics”

Mortality within 30 days after surgery

In the population of 210 patients with hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day 17 died during 30-day follow up (8.1%). When stratified after treatment of postoperative anemia the mortality was 9.6 (no treatment), 10.5 (ABT), 3.8 (IV Monofer), and 12.5% (IV Monofer & ABT), respectively. The survival curves are illustrated in Fig. 3. The results of the average treatment effect analysis and multivariable Cox regression model of the 210 patients stratified by treatment of postoperative anemia are shown in Table 2. The lowest mortality was observed in the IV Monofer treatment group (HR: 0.41, 95% CI: [0.089–1.887], P = 0.254). The average treatment effect analysis shows that the lowest standardized absolute mortality risk was observed in the two groups that received IV Monofer. Thus, the average risk in IV Monofer and IV Monofer & ABT group was 2.31 and 9.5%, respectively. Additionally, the highest average mortality risk was observed in the no treatment and ABT group, with 18.49% and 17.77%, respectively. Hence, the IV Monofer group had an average mortality risk 16.31% lower than the no treatment group and 15.46% lower than the ABT group.

Table 2
ATE analysis			Multivariable Cox Regression model
	Average risk	CI (95%)	Hazard ratio	CI (95%)	p-value
No treatment	0.184	[0.07–0.29]	1	Reference
ABT	0.178	[0.06–0.30]	1.00	[0.245–4.087]	0.998
IV Monofer	0.023	[0.00–0.05]	0.41	[0.089–1.887]	0.254
IV Monofer & ABT	0.095	[0.03–0.16]	1.60	[0.399–6.434]	0.505
Estimation of the average treatment effect and multivariable Cox regression model among the patients with hgb postoperative day three ≤ 6.5 mmol/L stratified by treatment of postoperative anemia (30-day follow-up) n = 210. The multivariable analysis is adjusted for age, gender, CCI, polypharmacy, admission source and infection in hospital.

The results of the average treatment effect analysis and multivariable Cox regression when comparing the no treatment group with IV Monofer group and the ABT group with the IV Monofer & ABT group, respectively, are presented in Table 3 and Table 4. Administration of IV Monofer was associated with significantly decreased mortality risk compared to no treatment (HR: 0.17, 95% CI: [0.03–0.93], P = 0.041). However, the combination of IV Monofer & ABT showed a trend towards increased mortality compared to ABT alone (HR: 1.34, 95% CI: [0.269–6.653], P = 0.7215).

Table 3
ATE analysis			Multivariable Cox Regression model
	Average risk	CI (95%)	Hazard ratio	CI (95%)	p-value
No treatment	0.196	[0.027–0.364]	1	Reference
IV Monofer	0.024	[0.000–0.051]	0.17	[0.03–0.93]	0.041*
Estimation of the average treatment effect and multivariable Cox regression model among patients with hgb postoperative day three ≤ 6.5mmol/L stratified by no treatment and IV Monofer (30-day follow-up) n = 132. The multivariable analysis is standardized for covariates

Table 4
ATE analysis			Multivariable Cox regression model
	Average risk	CI (95%)	Hazard ratio	CI (95%)	p-value
ABT	0.220	[0.039–0.400]	1	Reference
IV Monofer & ABT	0.072	[0.009–0.135]	1.34	[0.269–6.653]	0.7215
Estimation of the average treatment effect and multivariable Cox regression model among patients with hgb postoperative day three ≤ 6.5mmol/L stratified by ABT and IV Monofer & ABT (30-day follow-up) n = 78. The multivariable analysis is standardized for covariates.

Hemoglobin levels 14–30 days after surgery

When assessing the average hemoglobin postoperatively between day 14 and 30 a total of 124 (59%) patients was missing a hemoglobin level. Of the 124 patients missing hemoglobin level between 14 to 30 days after surgery, 15 (12%) were missing because they died before a new hemoglobin level was measured. The characteristics of these patients are reported in Additional file 1 Table 1. Furthermore, 109 (88%) patients had missing hemoglobin because it was not controlled at a general practitioner or at the Geriatric outpatient clinic. Therefore, of the 210 patients only 41% of them had their hemoglobin level controlled. Nevertheless, the patients treated with IV Monofer had the highest hemoglobin levels 14–30 days after surgery (6.8 ± 0.6 mmol/L) and the patients without treatment had the lowest (6.3 ± 0.7 mmol/L). Yet, no significant result between the four treatments group were found.

This study analyzed the impact of a new IV iron therapy protocol among older patients with hip fracture and postoperative anemia according to 30-day mortality and hemoglobin levels 14–30 days postoperatively. The major finding was that the patients with hemoglobin ≤ 6.5 mmol/L on the 3rd postoperative day who only received IV Monofer had a significantly decreased risk of 30-day mortality compared to the patients with no treatment. The patients in the IV Monofer and the no treatment group had no significant difference in their comorbidity and pre- or postoperative hemoglobin level that could explain the decreased short-term mortality in the IV Monofer group. A plausible reason to the decreased short-term mortality is that 98.1% of the patients in the no treatment group was hospitalized in study period 1 before the implementation of the IV iron therapy protocol. Consequently, the patients with postoperative anemia in study period 1 without indication of ABT was not treated with IV Monofer. Therefore, our data suggested that the patients with hemoglobin below 6.5 mmol/L but above transfusion limit might benefit from IV Monofer.

In general, few studies have reported the postoperative mortality after perioperative IV or oral iron therapy among patients undergoing major orthopedic surgical procedures (20, 23, 28, 29, 40–43). A retrospective analysis of 2547 patients after orthopedic surgery reported a mortality of 4.8% in 1000 patients receiving either iron sucrose (Venofer) or iron sucrose + recombinant human EPO perioperatively, against 9.4% in the control population of 361 patients (23). Likewise, Cuenca J. et al. found that iron sucrose preoperatively in elderly patient undergoing displaced subcapital hip fracture repair (n = 20) compared to a control group (n = 57) had a lower 30-day mortality rate (0 vs. 19.3%) (20). However, as stated in the systematic review by Smith et al. the evidence for preoperative IV iron therapy in improving clinical outcomes in patients undergoing major orthopedic surgery is little. Nevertheless, our findings concur with these previous studies regarding significant reduction in postoperative mortality although our IV iron therapy was in the postoperative phase.

Furthermore, we reported the average correction of the postoperative anemia. The increase in postoperative hemoglobin after the treatment with either ABT and/or IV Monofer was based on the first measured hemoglobin level within 14–30 days postoperatively. In summary, we found no significant difference in hemoglobin between the various treatment options. However, we acknowledge that the missing data on the patients’ hemoglobin level between 14 to 30 days postoperatively was affecting the results. Thus, the patients who had hemoglobin measured between 14 to 30 days after surgery are probably not representative of the exact hemoglobin in this postoperative period of all the patients in our study. Nevertheless, when comparing our results with other studies we acknowledge that the results on whether perioperative IV iron significantly recovers the hgb postoperatively are conflicting (24, 28, 29, 42–45). Johansson et al. explored whether Monofer results in a better regeneration of hemoglobin-concentration and prevented anemia compared to placebo in preoperative non-anemic patients undergoing cardiac surgery. They showed that a single, perioperative 1000-mg dose of Monofer significantly increased the hemoglobin-concentration (mean 1.18 mmol/L) and prevented anemia four weeks after surgery (24). Contrary, the study by Moppett et al. among older people with hip fracture showed that three doses of 200mg Venofer on three separate days had no remarkable effect on final hemoglobin-concentration on the 7th day postoperatively (29). Additionally, we acknowledge that the hemoglobin recovery especially depends on when the hemoglobin is measured postoperatively as studies have shown that IV Monofer requires several weeks before the physiological effect on the hemoglobin level is measurable (24, 44). Nevertheless, no such systematic long-term follow-up on the hemoglobin was part of the present IV iron therapy protocol in our study. Therefore, further prospective, and randomized controlled trials examining efficacy of postoperative IV Monofer therapy regarding hemoglobin recovery among older hip fracture patients are required.

Strength and limitations

A strength of the study is the availability of information and the registration of clinical variables from the patients’ medical records and the national Shared Medication Record. Furthermore, the study shows that the implementation of the IV iron therapy protocol in the clinical setting caused a change in choice of treatment since a large percentage of the patients in study period 2 received IV Monofer. However, our study had several limitations. The observational nature of the study implies only associations therefore no causal relations can be concluded. First, the risk of confounding is related to the nature of the study. Therefore, in the survival analysis we applied standardization to ensure that the study population had similar age, gender, comorbidity, polypharmacy, admission source and hospital infection status to evaluate the impact of IV Monofer on outcomes. Second, we acknowledge that the size of the study population affected the statistical power. Third, 59% of the patients did not have available hemoglobin measurements after discharge from hospital as patients were not systematically followed up with blood tests at their general practitioner or at the geriatrician ambulatory. Therefore, the patients who had hemoglobin measured in the 14-30-day span after surgery are likely not representative of the true hemoglobin distribution of all patients, if all patients had a hemoglobin measured in this period. In other words, the hemoglobin measured was driven by a clinical contact and thus, conclusions regarding the efficacy of Monofer in increasing the hemoglobin level postoperatively cannot adequately be made from our data.

In conclusion, the patients with hemoglobin ≤ 6.5 mmol/L on the 3^rd postoperative day who only received IV Monofer had a significantly decreased risk of 30-day mortality compared to the patients with no treatment. Furthermore, no significant differences in hemoglobin levels between 14-30 days post-surgery across treatment groups were found, although this was assessed in a subset of patients with available hemoglobin levels.

IV: Intravenous; EPO: Erythropoietin; ABT: Allogenous blood transfusion; CCI: Charlson Comorbidity Index; BMI: Body-Mass-Index; ICU: Intensive Care unit; ICD: International Classification of disease; NPU: Nomenclature for Properties and Units; ATE: Average Treatment Effect Analysis

Ethics approval and consent to participate

This is a quality development project where the systematic use of IV iron was implemented in the surgical ward, and therefore, the regional ethical committee of Northern Denmark waived the need for approval. The study was registered within the Danish Data Protection Authority (reference number 2008-58-0028)

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

There is no funding for this article.

Authors' contributions

SZC: collected and analyzed data and wrote the manuscript. MLK.: assisted collecting and analyzing data and revised the manuscript. KHK: assisted analyzing data and revised the manuscript. JR: assisted analyzing the data. MMM, LTH, CC and DM participated in the conception and design of the study and the protocol. All authors read and approved the final manuscript.

Acknowledgements

The authors would like to thank all the participating patients and health care professionals at the Department of Orthopedic Surgery, Aalborg University Hospital, Hjørring, Denmark and the Department of Geriatric Medicine, North Denmark Regional Hospital, Hjørring, Denmark.

Foss NB, Kristensen MT, Kehlet H. Anaemia impedes functional mobility after hip fracture surgery. Age Ageing. 2008;37(2):173–8.
Gruson KI, Aharonoff GB, Egol KA, Zuckerman JD, Koval KJ. The relationship between admission hemoglobin level and outcome after hip fracture. J Orthop Trauma. 2002;16(1):39–44.
Halm EA, Wang JJ, Boockvar K, Penrod J, Silberzweig SB, Magaziner J, et al. The effect of perioperative anemia on clinical and functional outcomes in patients with hip fracture. J Orthop Trauma. 2004;18(6):369–74.
Vochteloo AJH, Borger Van Der Burg BL, Mertens BJA, Niggebrugge AHP, De Vries MR, Tuinebreijer WE, et al. Outcome in hip fracture patients related to anemia at admission and allogeneic blood transfusion: An analysis of 1262 surgically treated patients. BMC Musculoskelet Disord [Internet]. 2011;12(1):262. Available from: http://www.biomedcentral.com/1471-2474/12/262
Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: An independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res. 2002;102(2):237–44.
Wu WC, Schifftner TL, Henderson WG, Eaton CB, Poses RM, Uttley G, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. J Am Med Assoc. 2007;297(22):2481–8.
Van Iperen CE, Kraaijenhagen RJ, Biesma DH, Beguin Y, Marx JJM, Van De Wiel A. Iron metabolism and erythropoiesis after surgery. Br J Surg. 1998;85(1):41–5.
Muñoz M, Romero A, Morales M, Campos A, García-Erce JA, Ramírez G. Iron metabolism, inflammation and anemia in critically ill patients. A cross-sectional study. Nutr Hosp. 2005;20(2):115–20.
Van De Wiel A. Anemia in critically ill patients. Eur J Intern Med. 2004;15(8):481–6.
Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneicblood transfusion increases the risk of postoperative bacterial infection: A meta-analysis. J Trauma. 2003;52(5):908–14.
Shokoohi A, Stanworth S, Mistry D, Lamb S, Staves J, Murphy MF. The risks of red cell transfusion for hip fracture surgery in the elderly. Vox Sang. 2012;103(3):223–30.
Cuenca J, García-Erce JA, Martínez F, Pérez-Serrano L, Herrera A, Muñoz M. Perioperative intravenous iron, with or without erythropoietin, plus restrictive transfusion protocol reduce the need for allogeneic blood after knee replacement surgery. Transfusion. 2006;46(7):1112–9.
National Blood Authority Australia. Three Pillars of Patient Blood Management [Internet]. Commonwealth of Australia. 2012. p. 1. Available from: https://www.blood.gov.au/system/files/documents/pbm-3-pillars.pdf
Leahy MF, Hofmann A, Towler S, Trentino KM, Burrows SA, Swain SG, et al. Improved outcomes and reduced costs associated with a health-system–wide patient blood management program: a retrospective observational study in four major adult tertiary-care hospitals. Transfusion. 2017;57(6):1347–58.
Meybohm P, Herrmann E, Steinbicker AU, Wittmann M, Gruenewald M, Fischer D, et al. Patient Blood Management is Associated with a Substantial Reduction of Red Blood Cell Utilization and Safe for Patient’s Outcome: A Prospective, Multicenter Cohort Study with a Noninferiority Design. Ann Surg. 2016;264(2):203–11.
Muñoz M, Acheson AG, Bisbe E, Butcher A, Gómez-Ramírez S, Khalafallah AA, et al. An international consensus statement on the management of postoperative anaemia after major surgical procedures. Anaesthesia. 2018;73(11):1418–31.
Rineau E, Chaudet A, Chassier C, Bizot P, Lasocki S. Implementing a blood management protocol during the entire perioperative period allows a reduction in transfusion rate in major orthopedic surgery: A before-after study. Transfusion. 2016;56(3):673–81.
Holt JB, Miller BJ, Callaghan JJ, Clark CR, Willenborg MD, Noiseux NO. Minimizing Blood Transfusion in Total Hip and Knee Arthroplasty Through a Multimodal Approach. J Arthroplasty [Internet]. 2016;31(2):378–82. Available from: http://dx.doi.org/10.1016/j.arth.2015.08.025
Yoon BH, Lee BS, Won H, Kim HK, Lee YK, Koo KH. Preoperative iron supplementation and restrictive transfusion strategy in hip fracture surgery. CiOS Clin Orthop Surg. 2019;11(3):265–9.
Cuenca J, García-Erce JA, Martínez AA, Solano VM, Molina J, Muñoz M. Role of parenteral iron in the management of anaemia in the elderly patient undergoing displaced subcapital hip fracture repair: Preliminary data. Arch Orthop Trauma Surg. 2005;125(5):342–7.
García-Erce JA, Cuenca J, Muñoz M, Izuel M, Martínez AA, Herrera A, et al. Perioperative stimulation of erythropoiesis with intravenous iron and erythropoietin reduces transfusion requirements in patients with hip fracture. A prospective observational study. Vol. 88, Vox Sanguinis. 2005. p. 235–43.
Frew N, Alexander D, Hood J, Acornley A. Impact of a blood management protocol on transfusion rates and outcomes following total hip and knee arthroplasty. Ann R Coll Surg Engl. 2016;98(6):380–6.
Muñoz M, Gõmez-Ramírez S, Cuenca J, García-Erce JA, Iglesias-Aparicio D, Haman-Alcober S, et al. Very-short-term perioperative intravenous iron administration and postoperative outcome in major orthopedic surgery: A pooled analysis of observational data from 2547 patients. Transfusion. 2014;54(2):289–99.
Johansson PI, Rasmussen AS, Thomsen LL. Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: A randomized double-blind placebo-. Vox Sang. 2015;109(3):257–66.
Muñoz M, Naveira E, Seara J, Cordero J. Effects of postoperative intravenous iron on transfusion requirements after lower limb arthroplasty. Br J Anaesth. 2012;108(3):532–4.
Pujol-Nicolas A, Morrison R, Casson C, Khan S, Marriott A, Tiplady C, et al. Preoperative screening and intervention for mild anemia with low iron stores in elective hip and knee arthroplasty. Transfusion. 2017;57(12):3049–57.
Smith A, Moon T, Pak T, Park B, Urman RD. Preoperative Anemia Treatment With Intravenous Iron in Patients Undergoing Major Orthopedic Surgery: A Systematic Review. Geriatr Orthop Surg Rehabil. 2020;11:215145932093509.
Kim SK, Seo WY, Kim HJ, Yoo JJ. Postoperative intravenous ferric carboxymaltose reduces transfusion amounts after orthopedic hip surgery. CiOS Clin Orthop Surg. 2018;10(1):20–5.
Moppett IK, Rowlands M, Mannings AM, Marufu TC, Sahota O, Yeung J. The effect of intravenous iron on erythropoiesis in older people with hip fracture. Age Ageing. 2019;48(5):751–5.
Rowlands M, Forward DP, Sahota O, Moppett IK. The effect of intravenous iron on postoperative transfusion requirements in hip fracture patients: Study protocol for a randomized controlled trial. Trials [Internet]. 2013;14(1):1. Available from: Trials
Mynster T, Krøijer R. Klinisk Retningslinje │Kraeft DCCG [Internet]. [cited 2020 Aug 24]. Available from: www.dmcg.dk/kliniske-retningslinjer
Pollock RF, Muduma G. Intravenous iron treatments for iron deficiency anemia in inflammatory bowel disease: a budget impact analysis of iron isomaltoside 1000 (Monofer) in the UK. Expert Opin Drug Deliv [Internet]. 2017;14(12):1439–46. Available from: https://doi.org/10.1080/17425247.2017.1393412
Mørch MM, Hansen LT. Monofer, intravenøs behandling af jernmangel - Ældremedicinsk afsnit 205B og Ortopædkirurgisk afsnit 109 [Internet]. [cited 2021 Mar 4]. Available from: https://pri.rn.dk/Sider/30366.aspx
Pharmacosmos. Monofer 100mg/ml solution for injection/infusion - Summary of Product Characteristics (SmPC) - (emc) [Internet]. [cited 2021 Mar 4]. Available from: https://www.medicines.org.uk/emc/medicine/23669
Bæch J. Blodtransfusion, gældende for Region Nordjylland [Internet]. [cited 2021 Mar 4]. Available from: https://pri.rn.dk/Sider/6658.aspx
Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 2017 Oct;17(1):230.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83.
Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994 Nov;47(11):1245–51.
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2018.
Serrano-Trenas JA, Ugalde PF, Cabello LM, Chofles LC, Lázaro PS, Benítez PC. Role of perioperative intravenous iron therapy in elderly hip fracture patients: A single-center randomized controlled trial. Transfusion. 2011;51(1):97–104.
Parker MJ. Iron supplementation for anemia after hip fracture surgery: A randomized trial of 300 patients. J Bone Jt Surg - Ser A. 2010;92(2):265–9.
Heschl M, Gombotz H, Haslinger-Eisterer B, Hofmann A, Böhler N, Meier J. The efficacy of pre-operative preparation with intravenous iron and/or erythropoietin in anaemic patients undergoing orthopaedic surgery. Eur J Anaesthesiol. 2018;35(4):289–97.
Bernabeu-Wittel M, Romero M, Ollero-Baturone M, Aparicio R, Murcia-Zaragoza J, Rincón-Gómez M, et al. Ferric carboxymaltose with or without erythropoietin in anemic patients with hip fracture: a randomized clinical trial. Transfusion. 2016;56(9):2199–211.
Derman R, Roman E, Modiano MR, Achebe MM, Thomsen LL, Auerbach M. A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia. Am J Hematol. 2017;92(3):286–91.
Loupec T, Thuile C, Pencole M, Maissiat G, Dangelser G, Capdevila X, et al. for Major Orthopedic Surgery. 2018;(October):710–20.

AddiotionalFile1.docx
Additional file 1 (wordfile.docx). Table 1 Demographics of patients who died before hemoglobin level between day 14 to 30 was measured.

Download PDF

Review #1 received at journal
28 Mar, 2021
Editorial decision: Minor revision
28 Mar, 2021
Reviewer #2 agreed at journal
15 Mar, 2021
Reviewers invited by journal
15 Mar, 2021
Reviews received at journal
15 Mar, 2021
Reviewer #1 agreed at journal
15 Mar, 2021
First submitted to journal
11 Mar, 2021
Editor assigned by journal
10 Mar, 2021
Submission checks completed at journal
10 Mar, 2021
Editor invited by journal
10 Mar, 2021

You are reading this latest preprint version

Association between Intravenous Iron Therapy and Short-term Mortality Risk in Older Patients Undergoing Hip Fracture Surgery: An Observational Study

Status:

Version 1

Abstract

Figures

Background

Methods

Study design and setting

Outcome and follow-up

Study population

Study interventions

Data collection

Comorbidities and concomitant medication

Statistical analysis

Results

Patients

Characteristics

Mortality within 30 days after surgery

Hemoglobin levels 14–30 days after surgery

Discussion

Strength and limitations

Conclusion

Abbreviations

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors' contributions

Acknowledgements

References

Supplementary Files

Status:

Version 1