|Year : 2016 | Volume
| Issue : 1 | Page : 1-7
Clinical efficacy of tranexamic acid administration via different routes during total hip arthroplasty: study protocol for a prospective randomized controlled trial
Kai-di Zhou, Hong-yi Wang, Yu-fei Yan, Wei-xiang Hong, Jian-min Feng
Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai Institute of Traumatology and Orthopedics, Shanghai, China
|Date of Web Publication||16-Mar-2016|
Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai Institute of Traumatology and Orthopedics, Shanghai
Source of Support: None, Conflict of Interest: None
Background: Intravenous injection or topical application of tranexamic acid during total hip arthroplasty has been shown to effectively reduce blood loss. There is no consensus on differences in clinical efficacy and safety between these two administration methods. To determine the optimal clinical efficacy of tranexamic acid during hip replacement, we will compare differences between these two administration methods during total hip arthroplasty.
Methods/Design: The study protocol is a prospective, paired (1:1:1), double-blind, randomized controlled clinical trial. A total of 174 patients who will receive hip replacement at Ruijin Hospital, Shanghai Jiao Tong University, China will be randomly divided into three groups, with 58 patients per group. Before the end of surgery, in the placebo group, 60 mL of physiological saline will be used to soak the articular cavity for at least 3 minutes and then be sucked away; in the topical tranexamic acid group, 60 mL of physiological saline containing 3 g tranexamic acid will be used and then sucked away; in the intravenous tranexamic acid group, 100 mL of physiological saline containing 10 mg/kg tranexamic acid will be intravenously administered 15 minutes before surgery and then again 3 hours later. The primary outcome is total blood loss on postoperative day 3, which is calculated using Nadler's and Gross's formula. Secondary outcomes include blood transfusion rates, drainage output within 2 days postoperation, amount of human serum albumin used during hospitalization, postoperative blood coagulation indices, and incidences of deep venous thrombosis and other thromboembolic events during postoperative day 1-week 6.
Discussion: This protocol is powered to provide reference information for the rational use of tranexamic acid by comparing clinical efficacy of the drug between intravenous and topical administration routes.
Trial registration: ClinicalTrials.gov identifier: NCT02312440; registered on 28 November 2014.
Ethical approval: This study protocol was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University, China (permission No. (2014)-47-2) and will be performed in accordance with the Declaration of Helsinki.
Keywords: clinical trial; tranexamic acid; articular cavity; intravenous injection; total hip arthroplasty; deep venous thrombosis; human serum albumin; safety; randomized controlled clinical trial
|How to cite this article:|
Zhou Kd, Wang Hy, Yan Yf, Hong Wx, Feng Jm. Clinical efficacy of tranexamic acid administration via different routes during total hip arthroplasty: study protocol for a prospective randomized controlled trial. Clin Trials Orthop Disord 2016;1:1-7
|How to cite this URL:|
Zhou Kd, Wang Hy, Yan Yf, Hong Wx, Feng Jm. Clinical efficacy of tranexamic acid administration via different routes during total hip arthroplasty: study protocol for a prospective randomized controlled trial. Clin Trials Orthop Disord [serial online] 2016 [cited 2019 Aug 19];1:1-7. Available from: http://www.clinicalto.com/text.asp?2016/1/1/1/178819
| Introduction|| |
Total hip arthroplasty is a main surgical method to treat hip-joint diseases. In addition to the complications of femoral head replacement, other complications include postoperative anemia, acetabular prosthesis loosening and dislocation, and local response after wearing of the ultra-high-molecular-weight polyethylene surface in the loading area. We have systematically studied the complications of total hip arthroplasty and the imaging methods used for their diagnosis [Table 1] (He et al., 2008; Zhang et al., 2014; Jiang et al., 2015a, b) and strengthening perioperative management is very important for increasing the clinical efficacy of total hip arthroplasty.
|Table 1: Complications and their diagnosis of total hip arthroplasty included in our previous studies|
Click here to view
Intraoperative blood loss and postoperative anemia are very common symptoms and also key management aspects in the perioperative period of total hip arthroplasty (Sprigg et al., 2014; Gregersen et al., 2015; Sizer et al., 2015; Wong et al., 2015). Approximately one third of patients undergoing total hip arthroplasty need allogeneic blood transfusion. However, allogeneic blood transfusion is used with caution because of possible disease propagation, immunosuppression and transfusion reaction (Spahn, 2010). Therefore, there is a need to develop a new method to replace or reduce blood loss in the perioperative period of total hip arthroplasty.
Tranexamic acid is mainly used to treat hemorrhage caused by acute or chronic, local or systematic hyperfibrinolysis (Röggla and Jilma, 2014; Aguilera et al., 2015). It is often used to treat surgical hemostasis and its overdose can lead to thrombosis, hemorrhage, whole-body spasm and kidney disease (Banerjee et al., 2013; Sprigg et al., 2014; Ker et al., 2015). A meta analysis has shown that intravenous tranexamic acid can greatly reduce blood loss without concerns of deep venous thrombosis and pulmonary thrombosis (Wei and Liu, 2015). There is no consensus for its precise clinical efficacy and safety issues.
To acquire the optimal administration route and clinical efficacy of tranexamic acid during total hip arthroplasty and to develop a safer and more effective hemostasis protocol, we designed a study protocol for prospective, paired (1:1:1), double-blind, randomized controlled clinical trials that compares the hemostatic effects and safety of tranexamic acid between intravenous and topical administration routes. This protocol will provide evidence for the rational use of tranexamic acid in the peri-operative period of total hip arthroplasty.
| Methods/Design|| |
A prospective, paired (1:1:1), double-blind, randomized, controlled clinical trial.
This protocol was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University, China (permission No. (2014)-47-2).
Sixty patients who will be scheduled to undergo total hip arthroplasty for the first time in the Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University, China will be included in this study. Written informed consent should be obtained prior to involvement in the clinical trial. The patients involved in this study protocol should meet the following criteria.
- Primary unilateral total hip replacement patients, including those with hip joint pain but who have no improvement after over 6 months of conservative treatment with non-steroid anti-inflammatory drugs, those with X-ray diagnosed coxarthrosis or arthritis and those who cannot work, sleep or be active because of hip joint pain
- Age > 18 years
- Either sex
- With informed consent signed by the patient himself/herself or their relative, and approval by the medical ethics committee
- Refusal to provide informed consent
- Hypersensitive response to tranexamic acid
- Lying in bed for 3 weeks or more prior to surgery
- Use of anticoagulant drug within 1 week prior to surgery
- Coagulation disorders: preoperative blood platelet count < 150 × 109/L, international normalized ratio > 1.4, prolonged activated partial thromboplastin time, prothrombin time, and thrombin time (> 1.4 fold relative to normal)
- Breast feeding
- Severe ischemic heart disease (cardiac function grade III and IV); sleep apnea syndrome; renal dysfunction; retinopathy (dyschromatopsia)
- Hip joint infection, severe leg and foot vascular pathology or neuropathy or severe restrictive neurological function disorder that influences hip function
- A history of thromboembolism, including deep venous thrombosis, pulmonary thrombosis, myocardial infarction and cerebral infarction
- Participating or previously participated in another clinical trial in the past year
- The need to undergo total hip arthroplasty again
- Unable to cooperate with physician for various reasons
- Failure of total hip arthroplasty
- Those who have poor compliance or cannot accomplish the clinical trial or those who the researchers consider cannot enter the clinical trial
- On request of the patients
- Presence of severe adverse reactions
- Participants who researchers consider cannot continue with the clinical trial
Randomization and interventions
The entire process of the double-blind clinical trial will be arranged and controlled by the designers, Jian-min Feng and Kai-di Zhou.
One day prior to surgery, all patients will be randomly divided into groups using computer generated random numbers and the same researcher will inform the patients via mobile phone according to group management.
The pharmacists who will not participate in the clinical trial will prepare the drug according to advice for each patient. Physiological saline or tranexamic acid will be prepared by assistant nurses and then injected into the articular cavity by surgical physicians. Tranexamic acid will be intravenously administered by the anesthetists who will not participate in the clinical trial. All patients included in the treatment and evaluation, physicians and nurses will be temporarily designated to each group and all of them will not know the group management. All nursing personnel and data analyzers will be randomly assigned.
The researcher who will evaluate whether patients will be scheduled to undergo total hip arthroplasty and will be included in this clinical trial on the second day and the names of the patients who have signed informed consent will be given to another researcher. A total of 174 patients will be randomly and evenly divided into three groups using a 1:1:1 paired method. Before the end of surgery, in the placebo group, 60 mL of physiological saline will be used to soak the articular cavity for at least 3 minutes and then be sucked away; in the topical tranexamic acid group, 60 mL of physiological saline containing 3 g tranexamic acid will be applied and then sucked away; in the intravenous tranexamic acid group, 100 mL of physiological saline containing 10 mg/kg tranexamic acid will be intravenously administered 15 minutes before surgery and then again 3 hours later.
Four surgeons will be responsible for hip operations using an anterolateral approach. All patients will undergo acute hypervolemic hemodilution and controlled hypotension during anesthesia. All patients will orally take 10 mg rivaroxaban tablets for anticoagulation for 15 days post-surgery. After surgery, cephalosporin will be used to prevent infection and clindamycin will be used when patients are allergic to cephalosporin.
All patients will inform the researchers about their discomforts, who will be responsible for safety reports, and the last follow up will be at postoperative week 6.
An overview of the time frame of the study is shown in [Figure 1].
Total blood loss, which can be calculated according to the erythrocrit change at postoperative day 3 compared to prior to surgery (Nadler et al., 1962; Gross, 1983)
- Postoperative blood transfusion indication: hemoglobin level < 80 g/L or < 100 g/L with anemic symptom complications
- Drainage output: Recorded by a nurse at approximately 36 hours post-operation
- Amount of human serum albumin used during hospitalization
- Blood coagulation: including activated partial thromboplastin time, thrombin time, prothrombin time, international normalized ratio, fibrinogen, fibrin degradation product, and serum level of dimer. The inhibitory effect of tranexamic acid on hyperfibrinolysis can be determined according to these blood coagulation indice The timing of trial outcome evaluation is shown in [Table 2].
Data collection and management
The required trial information will be transcribed from medical records by two researchers, once per month. The transcribed trial data will be dated and uploaded to the designated computer for later use. A data table will be created by the researcher responsible for group assignment. When all participants have been followed up, the two tables will be rechecked and a password will be designated by the primary researchers, drug registration applicant, statistician and the researcher who devised the group assignment method. The database containing the two tables will not be changed and will be saved for later referral. Group assignment will be accessible for the first time. The placebo, intravenous tranexamic acid, and topical tranexamic acid groups will be replaced with groups A, B and C. The database will be statistically analyzed by the statistician and group assignment will be accessible for the second time.
Sample size calculation
Sample size will be calculated using PASS 14.0 software. Based on the outcomes from Gomez-Barrena et al. (2014), it is hypothesized that topical tranexamic acid has non-inferiority compared to intravenous administration. If β ≤ 0.1, power = 90%, significance level α = 0.025 (one-sided), then sample size n = 51 per group can meet the clinical efficacy of non-inferiority. It is estimated that 20% of the sample size will be lost, and an approximate sample size n = 60 per group will be needed, and a sample size n = 58 per group will be used.
SAS 8.0 software (SAS, Cary, NC, USA) will be used for data analysis. The normally distributed measurement data will be expressed as the mean with standard deviation and minima and maxima. The non-normally distributed measurement data will be expressed as q1, median and q3. The numerical data will be expressed as the constituent ratio. Fisher's test will be used to compare numerical data between groups. When homogeneity of variance occurs, the normally distributed numerical data will be tested using one-way analysis of variance; when heterogeneity of variance occurs, the normally distributed numerical data will be tested using Tamhanes T2 test. The non-normally distributed numerical data (q1, median and q3) will be tested using the Kruskal-Wallis rank sum test.
The normally distributed measurement data (drainage output, total blood loss, amount of human serum albumin used, and blood coagulation indices) will be tested using one-way analysis of variance and Bonferroni correction.
The chi-square test will be used to test the differences in safety indices and blood transfusion rate between groups, with a significance level α = 0.05 (two-sided).
Trial quality assurance and control
The Ethics Committee of Ruijin Hospital of China will be designated to temporarily evaluate the trial safety and to ensure the integrity and validity of recorded data. All adverse events should be recorded and severe adverse events should be reported within the designated time and recorded. The trial will be terminated if the risk of thromboembolic events increases in patients after the use of tranexamic acid.
| Discussion|| |
In this randomized controlled trial protocol, the primary outcome, the erythrocrit, is an internationally accepted standard used to determine total blood loss during total hip arthroplasty (Nadler et al., 1962; Gross, 1983). In addition, the amount of blood transfused and the incidence of thromboembolic events will be recorded and blood transfusion-related indices, such as fibrinogen, will be analyzed to monitor the incidence of disseminated intravascular coagulation. This trial protocol is designed to analyze the hematostatic effects of topical and intravenous tranexamic acid including possible adverse events with the purpose of determining an effective administration method of tranexamic acid to reduce the blood loss in the perioperative period of total hip arthroplasty. 
Participant recruitment at time of submission.
Conflicts of interest
JMF and KDZ designed this trial protocol, collected data, wrote the paper, and approved the final version of this paper. HYW, YFY and WXH also participated in trial design and conduction. All authors approved the final version of this paper.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reivewed by international expert reviewers.
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[Table 1], [Table 2]