Total hip arthroplasty (THA) is an effective treatment which provides pain relief and function restoration to patients suffering from end-stage hip disease. Over 500,000 THAs are performed each year in the UK and USA [1]. Approximately 400,000 primary THAs were performed in China in 2015, a number that has been increasing by 25%-30% per year [2]. However, most patients undergoing THA are elderly and combined with a high prevalence (24%) of preoperative anemia, which is widely accepted as a predictive factor of postoperative allogeneic transfusion. Moreover, the procedure is also associated with substantial blood loss leading to a high prevalence (51%) of postoperative anemia which may therefore cause the relatively high rate (45%) of postoperative allogeneic blood transfusion [3]. Allogeneic transfusion carries a substantial risk of transfusion-associated complications requiring additional treatment and increased length of stay [4]. Many blood-saving strategies have been reported, of which recombinant human erythropoietin (rhEPO) has demonstrated effectiveness in reducing hemoglobin (Hb) level drop and blood transfusion requirements according to numerous randomized controlled trials [5, 6, 7, 8, 9].
For now, there exists two main protocols of the perioperative use of rhEPO in patients who are scheduled for total joint arthroplasty (TJA). One is weekly application of large-dose rhEPO for 2–4 weeks before surgery, which is called the long-term regimen [9]. The other one is daily application of small-dose rhEPO from 0–5 days preoperatively to a few days (less than a week) postoperatively, which is called the short-term regimen [5, 6, 7, 8]. However, the weekly protocol has some obvious drawbacks: The long-term of treatment requested the patients to come back to hospital weekly for injections, which would therefore cause inconvenience to the patients and it would also increase the preoperative waiting interval. When encountering patients with poor compliance, it would be even more difficult to implement the treatment. Besides, initial high peak levels from high once weekly doses may be wasted, as erythropoietin receptors on progenitor cells in bone marrow may become saturated; when these receptors are again free for binding, the level of serum erythropoietin will fall [10]. Compared with the weekly protocol, the short-term daily protocol with small amounts of rhEPO could maintain a more constant low but more effective level of serum erythropoietin without causing inconvenience to the patient [10]. Besides, previous studies also reported that repeated administration of rhEPO is more effective in stimulating the reticulocyte response than the weekly large-dose of the same total amount of rhEPO [11].
Cao et al. [6] advocated that a daily dose (150 IU/kg) of rhEPO started from 3 days before arthroplasty is more effective than being applied from the day of surgery in increasing Hb level, reducing blood loss without additional complications, they also concluded that the application of rhEPO since the day of surgery cannot significantly reduce the blood loss or increase the Hb level after arthroplasty compared with no application of rhEPO. On the contrary, Na et al. [8] applied 3000 IU of rhEPO subcutaneously during the operation and the postoperative period, they found that compared with the control (placebo) group, application of rhEPO since the day of surgery could effectively attenuated anemia and decreased transfusion requirements in patients undergoing arthroplasty, which was coincident with the conclusion of Bernabeu-Wittel et al. [5] with the similar rhEPO regimen. Furthermore, Kourtzis et al. [7] advocated the rhEPO regimen that each patient undergoing arthroplasty received 10,000 IU (150 IU/kg) of rhEPO daily subcutaneously for 5 days preoperatively and 3 days postoperatively which is also the current protocol implemented in our center, they found a markedly reduction of 94% in the utilization of allogeneic blood in patients received the rhEPO protocol than the control (placebo) group. Although there exist various regimens, the optimal regimen of short-term daily administration of rhEPO for THA patients are yet to be established.
In this study, a prospective double-blinded randomized placebo-controlled trial comparing three different short-term daily rhEPO-based treatment protocols for blood-saving purpose in THA was conducted. We hypothesized that the daily small-dose of rhEPO started from 5 days before THA which is the current protocol in our center is more effective in blood-saving than starting rhEPO treatment from 3 days preoperatively and the protocol of applying rhEPO from the day of surgery.
Patients and methods
This double-blinded randomized placebo-controlled trial was registered in the Chinese Clinical Trial Registry (20/09/2019) and the registration number is ChiCTR1900026064. Approval was obtained from the Clinical Trials and Biomedical Ethics Committee of West China Hospital. The study was conducted at the Department of Joint Surgery of West China Hospital, Sichuan University, in accordance with the CONSORT (Consolidated Standards of Reporting Trials) Statement. Written informed consent was obtained from all participants prior to surgery.
Patients
We recruited consecutive adult patients (18 to 85 years of age) from September 2019 to May 2020 who were scheduled for primary unilateral THA. Exclusion criteria included a diagnosis other than osteoarthritis or osteonecrosis of the femoral head, a known allergy to rhEPO or ferralia, an Hb level more than 130 g/L or less than 90 g/L, use of spinal anesthesia, a history of a hematopoietic or hemorrhagic disorder, a history of deep venous thrombosis (DVT) or pulmonary embolism (PE), an ongoing anticoagulant treatment with anticoagulant therapy (warfarin or heparin) within 1 week prior to surgery, an ongoing treatment with ferralia and/or rhEPO within 3 months before admission, preoperative hepatic or renal dysfunction and serious cardiac and/or cerebrovascular comorbidities, and refusal of participation.
Interventions and surgical procedures
The patients were randomized to 1 of 3 interventions: Patients in group A received 10,000 IU (150 IU/kg) of subcutaneous rhEPO (1 ml) daily from 5 days preoperatively to 3 days postoperatively (9 doses in total); Patients in group B received 1 ml of subcutaneous normal saline daily from 5 days preoperatively to 3 days preoperatively and then 10,000 IU (150 IU/kg) of subcutaneous rhEPO daily until 3 days postoperatively (6 doses in total). Patients in group C received 1 ml of subcutaneous normal saline daily from 5 days preoperatively to one day preoperatively and then 10,000 IU (150 IU/kg) of subcutaneous rhEPO daily from the day of surgery to 3 days postoperatively (4 doses in total). If the Hb level was over 150 g/L, rhEPO was not administered. All patients received a 100 mg (dissolved into 100 ml of normal saline) dose of intravenous ferric carboxymaltose, which has been widely accepted as an effective partner with rhEPO for the blood-saving purpose in patients undergoing arthroplasty [8]. The placebo (normal saline) has the same appearance (colorless and clear liquid) as rhEPO.
All the THAs were performed by the same surgical team (One main surgeon and three assistants) using a posterolateral approach and a single brand of cementless acetabular and femoral components (DePuy Synthes) under general anesthesia. No autologous blood transfusion or postoperative drain were used(12).
Thromboembolism prophylaxis and transfusion protocol
All the patients received thromboembolic prophylaxis according to a standardized protocol at our institution, which is a combination of physical prophylaxis and chemoprophylaxis [12]. The patients received physical prophylaxis by means of an intermittent inflatable pump system on the day after surgery. As for the chemoprophylaxis, a half-dose (2000 IU in 0.2 mL) of low-molecular-weight heparin was given to patients subcutaneously 6 h postoperatively and a full dose (4000 IU in 0.4 mL) was repeated at 24-h intervals subsequently until discharge. After discharge, all patients routinely received 10 mg rivaroxaban for 10 days. During hospitalization, the patients were examined daily for any clinical symptoms of DVT. Ultrasound examinations were also performed routinely at preoperatively, discharge, and the 2-week follow-up. A chest contrast-enhanced spiral computed tomography was performed immediately for any clinical signs of PE [12].
A standardized blood-transfusion protocol of the National Ministry of Health was followed for all patients: Blood transfusion was indicated for any patients with a Hb level of < 70 g/L, or a Hb level between 70 and 100 g/L but with symptomatic anemia (severe mental status changes, palpitations, and/or pallor) [12].
Outcome measurements
The primary outcomes included the Hb levels of the three groups at different time points, the rate and amount of allogeneic transfusion, and intraoperative and total blood loss. Secondary outcomes included the reticulocyte count, complications and patient satisfaction level. All the blood samples were obtained before each injection of rhEPO at 7 time points (on the preoperative day 5, 3, and 1, and on the postoperative day 1, 3, 14, and 21), except the operation day, on which blood samples were obtained both at one hour preoperatively and immediately after surgery. Blood loss was calculated from the change in hematocrit using the formula of Nadler et al. and Gross plus the volume transfused [13, 14]. Besides, all the complications, including DVT, PE and other adverse effects related to rhEPO (nausea, fever, headache, myalgia, etc.) were also assessed during the first 3 weeks postoperatively. Moreover, patient satisfaction level was evaluated with a simple satisfaction questionnaire at the time of discharge (We used the table of satisfaction with 6 options: Extremely satisfied, very satisfied, Somewhat satisfied, Neither satisfied nor dissatisfied, Somewhat dissatisfied and Very dissatisfied) [15].
Randomization and blinding
A random allocation sequence was computer-generated and concealed in consecutively numbered, opaque, sealed envelopes by a research statistician not involved in the data analysis. One of 2 experienced surgeons enrolled the patients, and the other one recorded basic detail. The envelope was opened after the enrollment of patients, and the study medication and placebo were prepared by a dedicated nurse not involved with patient care or outcome measurement. Patients, surgeons, anesthesiologists, care providers, and data collectors were all blinded to the allocation sequence.
Statistical analysis and sample size
The sample size was determined in relation to the difference in the postoperative decrease in Hb level among the 3 study groups using G*Power Version 3.1.7 (Franz Faul; UniKiel, Germany) software. On the basis of our preliminary data of 60 patients who underwent unilateral primary total hip arthroplasty and were assessed for the same measure, the mean decrease in Hb level (and standard deviation) was 41.5 ± 6.39 g/dL. A reduction of 10% (4 g/dL) in the decrease in Hb level in the experimental group (daily dose of 10,000 IU from 5 days preoperatively to 3 days postoperatively) compared with the control group (placebo only) was recorded as a clinically meaningful difference. On the basis of this information, 60 patients were required in each arm, with an alpha of 5%, power of 85%, and an anticipated 20% dropout rate.
Distributions of demographic data, baseline data, surgical characteristics, and primary and secondary outcomes were assessed using measures of central tendency (mean, standard deviation) for quantitative variables and with percentages for qualitative variables. Continuous variables were compared using one-way analysis of variance. When significant differences were detected, the 3 experimental groups were compared with each other using the Tukey's post hoc honest significant difference test. Categorical variables were compared using the chi-squared or Fisher's exact tests. All data analyses were performed using SPSS for Windows, Version 19.0 (SPSS Inc, Chicago, IL). Significance was set at P < 0.05.
