This was a single-center, single-blind, randomized controlled trial. The study was conducted at the Department of Orthopedics in Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine and registered in the Chinese Clinical Trial Registry (ChiCTR1900025013). The study was approved by the institutional review board (Ethics Committee of Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine). All experimental procedures were conducted according to the Standards of Reporting Trials (CONSORT) recommendations for randomized controlled trials, and all participants provided written informed consent prior to enrolment.
Sample size calculation
The sample size was calculated based on the amount of hidden blood loss (HBL) during TXA therapy. The overall standard deviation was σ = 250, and the allowed error estimate was δ = 200. These values were estimated using the statistical formula
Predicting an estimated dropout rate of 10%, 104 subjects would be required to yield a statistical power of 90% with a significance level of 0.05.
From September 2019 to May 2020, we consecutively screened patients aged 50–75 years old who underwent primary unilateral TKA for RA. Doppler ultrasound examination without deep vein thrombosis (DVT). The exclusion criteria included a diagnosis of other types of arthritis than RA, renal dysfunction, or severe cardiovascular or cerebrovascular diseases, and patients with prolonged use of oral anticoagulant drugs. The elimination criteria included acquired color vision disorder, active intravascular coagulation patients, and a history of seizures.
Randomization and drug administration
All eligible patients were randomized into two groups using computer-generated randomization by a statistician who was not involved in the trial. The group data were saved by the statistician. Allocation was concealed in consecutively numbered, sealed, opaque envelopes. IV-TXA (1 g) was administered 10 min prior to skin incision by an anesthesiologist, and articular-injection TXA (1.5 g) was administered via articular injection by a surgeon after cavity suture during the surgery. The patients were allocated into two groups: group A, one dose of IV-TXA (1 g) at postoperatively 3 h; group B, three doses of IV-TXA (1 g) at postoperatively 3, 6, and 12 h. The doses were administration by a nurse after surgery. The surgeon, anesthesiologist, and statistician were blinded to the trial. Only the nurses knew of the patients’ enrolment.
Perioperative anti-rheumatic treatment
Methotrexate and hydroxychloroquine were to be used during the perioperative period. Leflunomide was to discontinued at 1 week before surgery. The use of other disease-modifying anti-rheumatic drugs was to be discontinued at 2 days before surgery and restarted at 1–2 days after gastrointestinal function recovery. The use of newer biologic agents, such as tumor necrosis factor alpha, was to be discontinued at four to five half-lives before surgery and restarted after wound healing and infection elimination[22,23].
Surgical procedure and postoperative management
For perioperative prophylaxis, cefazolin sodium antibiotics were administered at 30 min before surgery, and 24–48 h after surgery. General anesthesia was administered an anesthetist. Blood pressure was controlled to within 80–100 mmHg / 60–70 mmHg throughout the procedure. Tourniquet was inflated to 100 mmHg above the systolic pressure before incision and deflated after incision closure. The surgery was performed by a single surgeon using the same technique. All patients received a surgeon-selected, cemented, posterior-stabilized prosthetic design with patellar resurfacing. Drains and blood salvage after surgery were not performed for these patients. Postoperatively, the elastic bandage was compressed, and operated limb was bandaged for 24 h. The patients were discharged on the post-operative day (POD) 14 when they met discharge criteria, which included independent mobility and no wound leakage, swelling, and pain, or infection, independent mobility.
During hospitalization, all patients received physical prophylaxis and chemoprophylaxis for venous thromboembolism. The patients were asked to performed equal-length contractions of the femoral quadriceps, and ankle pump movements, lower-extremity strength training, and motion exercises on the day after surgery. At 6 h after surgery, perioperative oral rivaroxaban (10 mg, once a day for 14 days) was prescribed to prevent thrombosis. Blood transfusions was given to patients with postoperative Hb level of less than 70 g/L or any organ dysfunction related to anemia regardless of Hb level.
Perioperative hematocrit (Hct) and Hb levels, coagulation index, and renal function were measured preoperatively, and on POD 1, 3, 7, and 14.
The Nadler formula was used to estimate patient blood volume (PBV), and the Gross formula was used to calculate blood loss based on PBV and Hct drop.
Intraoperative blood loss (IBL) was estimated based on the amount of liquid in the negative pressure drainage bottle + the amount of liquid in the gauze – the amount of saline. A piece of gauze was soaked in approximately 20 mL of the liquid.
PBV = K1 × height3 (m3) + K2 × weight (kg) + K3. For males: K1 = 0.3669, K2 = 0.03219, K3 = 0.6041. For females: K1 = 0.3561, K2 = 0.03308, K3 = 0.1833. Total red blood cell loss (TBL) = PBV × (Hctpre – Hctpost)/ Hctave, where Hctpre = initial pre-operative Hct level, Hctpost = lowest Hct postoperative, Hctave = average of Hctpre and Hctpost. HBL is defined as TBL minus IBL plus transfusion. Thus, HBL = TBL – IBL + transfusion.
Patients were monitored for adverse events (DVT, PE, wound complications, infection, acute renal failure). Transfusion rate and adverse events were assessed postoperatively during inpatient hospital stay.
Analyses were performed using SPSS Version 25.0 (IBM Corp., Armonk, New York). Data of continuous variables were evaluated for normal distribution using the Shapiro-Wilk test, and presented as means ± standard deviations (SDs). Differences between groups were compared using two independent sample t-tests. Pearson’s chi-square test was used to analyze categorical variables. A P -value of less than 0.05 indicated statistical significance.