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Tranexamic acid in Patients with hip fracture surgery: A systematic review and meta-analysis of efficacy and safety
⁎Corresponding author: Shin-Da Lee. shinda@mail.cmu.edu.tw
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Meta-analysis assesses the safety and efficacy of Tranexamic Acid (TXA) in patients with hip fracture surgery compared to placebo.
On September 28, 2023, qualified RCT studies, including randomized control trials and cohort study, of intravenous Tranexamic Acid (TXA) in patients undergoing hip fracture surgery was searched. Review Manager was used for the meta-analysis.
The TXA group had significantly lower intraoperative total blood loss and overall blood loss across eighteen investigations. The blood transfusion rate in the TXA group was lower than that in placebo group. TXA maintained higher hemoglobin levels on the postoperative first and third day. TXA did not raise any possible complication or problems such as deep vein thrombosis, pulmonary embolism, and mortality.
The TXA treatment in patients undergoing hip fracture surgery reduced intraoperative blood loss, overall blood loss, transfusion rate, and length of hospital stay effectively and appeared to be safe to use without significant complication or problems.
Abstract
Highlights
•Analysis of 18 trials demonstrates TXA's effectiveness in hip fracture surgery, significantly reducing intraoperative blood loss and transfusion risk, while improving postoperative hemoglobin levels with no significant thrombotic risks.
Keywords
Tranexamic acid (TXA)
Hip fracture surgery
Blood loss
Meta-analysis
1 Introduction
According to reports, by 2050, it's anticipated that 6.3 million hip fractures will occur. With a reported frequency of 10 % in males and 20 % in women.1,2 Hip fractures remain a serious public health issue as long as life expectancy rises everywhere. In addition to frequently causing impairments, these injuries have an estimated 20 % death rate among people over 65 in the first year following surgical discharge in more severe instances.3 Surgical intervention within 24 h is the mainstay of care for hip fractures; early intervention has been shown to improve outcomes and lower mortality and perioperative complications.4
Inadequate hemostatic control is one possible consequence of the surgical surgery of hip fractures. One often-used pharmacological medication to reduce blood loss during surgical procedures is tranexamic acid (TXA). A lysine derivative inhibits lysine's binding sites on plasminogen and reversibly binds to it, which stops formed clots from degrading and works as an anti-fibrinolytic.5 Regarding clinical efficacy, TXA is an affordable medication that can be applied topically or intravenously.6 Regarding TXA, time is crucial since it should be done by the peak fibrinolysis rate, which is thought to happen approximately 6 h after surgery and lasts up to 18 h.7 Perioperative TXA usage can effectively suppress plasmin activation and minimize blood loss by counteracting fibrinolysis during this peak phase. TXA has effectively reduced blood loss following various orthopedic procedures, such as acetabular and pelvic fractures,8,9 humeral fractures,10 and knee arthroplasty.11,12
The hemoglobin levels may decrease slowly after hip replacement surgery, based on previous specific meta-analyses examining the safety of tranexamic acid (TXA).,13 a lower incidence of allogeneic transfusions,14 and reduced overall blood loss during surgery..14,15 According to Myers study,16 there is a possibility that TXA may cause post-traumatic venous thromboembolism in association with aberrant coagulation. Still, meta-analyses have not discovered any elevated risk of thromboembolic events between tranexamic acid intervention and placebo groups for hip arthroplasties, which aligns with results from randomized clinical trials.17–19
New evidence-based research has been incorporated into the meta-analysis to assess the literature systematically. Tranexamic acid in patients with hip fracture surgery is evaluated according to evidence-based guidelines. This meta-analysis, which focuses on patients having these hip operations, aims to help medical professionals develop a more sophisticated grasp of the prudent application of tranexamic acid as a preventative approach to lessen blood loss and avoid complications following surgery. A thorough review of various prospective studies and randomized clinical trials (RCTs) is part of this study, which helps to create a set of solid recommendations that apply to clinical practice.
2 Methods
2.1 Registrant number
Under the registration number CRD42023451132, currently available is a review from PROSPERO.
2.2 Information sources and methods of searching
Our observations confirmed that the PRISMA standards were followed.20 From the date of creation until October 25, 2023, a thorough search across several databases was carried out. PubMed, additional unindexed citations, and continuous daily research, utilizing Ovid Embase, Ovid's Cochrane Database for Systematic Reviews, Before Print, Ovid MEDLINE (R), Epub, Ovid Embase, and Scopus for data retrieval, were among the databases that were included in this list, with suggestions from the principal investigator of the study, a seasoned librarian created and implemented the search strategy. To locate studies on tranexamic acid usage for hip fractures, a controlled vocabulary search was conducted, augmented with keywords. Supplementary Item 1 contains the actual approach and lists all search terms utilized and their combinations (Fig. 1).
2.3 Qualification standards and evaluation of quality
Studies that meet the following requirements should be included:(1)RCTs that use prospective cohort studies or randomized controlled trials.(2)Involves adult patients aged 18 and up undergoing hip surgery and comparing intravenous tranexamic acid to a placebo for the treatment of hip fractures.(3)the study's primary goal is to evaluate the overall blood loss(4)secondary outcomes include assessing transfusion rates(5)studies published from 2018 onwards were considered.
Excluded from the study were reports, case series, conference papers, and non-English articles. The two authors separately evaluated each trial's quality using the Cochrane Handbook's “risk of bias” table..20
2.4 Statistical methods
We used the inverse variance approach to assess our data's combined means and proportions; for continuous and dichotomous data, we used the Mantel-Haenszel method. This method assigns weights based on the variance of each study. Through a two-arm analysis assessing studies reporting the outcomes of both treatments, to directly compare these two methods, a thorough examination was conducted. The Q statistic and I2 were used to evaluate the heterogeneity in effect size estimates amongst studies. I2 values between 0 and 25 % indicate negligible statistical heterogeneity, while values above 25 % suggest increasing heterogeneity, 26 and 50 % indicate mild heterogeneity, and 51 and 100 % show extreme heterogeneity.20 The random effects model is employed when I2 is greater than 50 %. At the same time, the fixed effects model is utilized when I2 is less than 50 %.20
When not specifically stated, the mean and standard deviation (SD) of the Handbook of Cochrane Reviews for Systematic Interventions20 formulas were applied to convert the median to the mean. A careful digitizing procedure is used when the mean and standard deviation (SD) are only shown graphically. WebPlotDigitizer version 4.4 was used to extract data from graphical charts.
(https://automeris.io/WebPlotDigitizer/).
Review Manager software version 5.4 will be used for the ensuing data processing. The standards for compliance with this analytical technique were established by the Cochrane Collaboration in Copenhagen, Denmark, in 2020.
3 Results
3.1 Patient characteristics and study selection
A preliminary review of electronic databases revealed 438 studies. After removing duplicates, articles underwent screening based on inclusion and exclusion criteria. 54 papers in all were evaluated, and each one's complete text was carefully examined for eligibility. In the end, 63.4 % of the 2350 studies that matched the qualifying criteria were female, and 14 were included in the meta-analysis. 3 non-randomized prospective cohort studies and 11 randomized clinical trials made up a total of 14 studies. The research that was included was released in 2017 and 2022. Of the total number of patients, 1178 were given a placebo and 1172 were given TXA. Table 1 gives a thorough overview of the characteristics of the listed studies. At the time of the operation, the patient's ages ranged from 65.7 to 84.3 years.
| Study | Publication Year | Study Type | Total Participants (C/TXA) | Gender (M/F) | Control Mean Age (years) | TXA Mean Age (years) | TXA Dose | Placebo Used |
| Lei et al. | 2017 | RCT | 77 (40/37) | 12/65 | 79.20 ± 6.50 | 77.80 ± 9.80 | 1 g in 200 mL | Saline (200 mL) |
| Watts et al. | 2017 | RCT | 138 (69/69) | 43/95 | 82.20 ± 10.00 | 81.00 ± 10.00 | 15 mg/kg at incision & closure, 2 doses (10 min) | Saline (100 mL) |
| Schiavone et al. | 2018 | RCT | 90 (43/47) | 27/63 | 84.30 ± 8.30 | 84.30 ± 8.30 | 15 mg/kg at time of surgical incision | Saline (15 mg/kg) |
| Tian et al. | 2018 | RCT | 100 (50/50) | 33/67 | 79.30 ± 6.60 | 77.74 ± 6.50 | 10 mg/kg 10 min | NR |
| Zhi-Chao et al. | 2018 | Prospective Cohort | 108 (52/56) | 41/55 | 72.33 ± 7.03 | 72.13 ± 6.88 | 1 g in 250 mL of physiological saline preoperatively | Normal (250 mL) |
| Chen et al. | 2019 | RCT | 176 (88/88) | 76/100 | 77.40 ± 6.80 | 76.80 ± 7.00 | 15 mg/kg in 100 mL saline, 15 min, 2 doses 3 h apart | Saline (100 mL) |
| Luo et al. | 2019 | RCT | 90 (46/44) | 43/47 | 76.10 ± 9.30 | 75.10 ± 8.00 | 15 mg/kg 15 min before & 3 h after surgery | Saline (100 mL) |
| Zhou et al. | 2019 | RCT | 100 (50/50) | 37/63 | 77.80 ± 6.40 | 75.10 ± 8.27 | 1 g in 100 mL, 15 min before surgery | NR |
| Ahmed et al. | 2020 | RCT | 120 (60/60) | 59/61 | 65.87 ± 8.60 | 65.60 ± 8.17 | 15 mg/kg preoperative | Saline (same dose) |
| Hao et al. | 2020 | RCT | 65 (32/33) | 20/45 | 72.25 ± 7.65 | 75.15 ± 9.36 | 1 g 30 min before operation | Physiological saline |
| Qingyan et al. | 2020 | RCT | 30 (15/15) | 15/15 | 73.10 ± 5.25 | 71.20 ± 6.00 | 1 g before the operation | Saline (100 mL) |
| Qiu et al. | 2020 | Prospective Cohort | 80 (40/40) | 43/37 | 66.90 ± 5.80 | 68.20 ± 7.30 | 15 mg/kg 20 min before surgery | Saline (15 mg/kg) |
| Zhang et al. | 2020 | RCT | 122 (61/61) | 62/60 | 76.10 ± 16.60 | 79.10 ± 11.90 | 1 g in 100 mL saline, 10 min before & 3 h after surgery | Saline (100 mL) |
| Zhaopeng et al. | 2020 | Prospective Cohort | 60 (30/30) | 24/36 | 82.57 ± 7.87 | 79.70 ± 7.40 | 0.5 g within 30 min before incision | 100 mL 5 % glucose solution |
| AlSumadi et al. | 2021 | Prospective Cohort | 613 (306/307) | 171/441 | 82.00 ± 8.80 | 82.00 ± 8.50 | 1 g on induction of surgery | NR |
| Huang et al. | 2021 | RCT | 156 (78/78) | 83/73 | 76.90 ± 5.40 | 77.70 ± 5.60 | 20 mg/kg 30 min before surgery | NR |
| Narkbunnam et al. | 2021 | RCT | 60 (30/30) | 16/44 | 73.10 ± 5.25 | 78.80 ± 6.50 | 750 mg (250 mg/5 mL) | Normal saline (20 mL) |
| Nikolaou et al. | 2021 | RCT | 165 (88/77) | 41/124 | 83.40 ± 12.00 | 82.90 ± 8.80 | 15 mg/kg in 100 mL saline, 5 min before surgery | Saline (100 mL) |
| Image 1 | ||||||||
3.2 Features of the research incorporated into the analysis
A total of 18 eligible studies, encompassing 2350 participants who received either a placebo or tranexamic acid (TXA), were included in this comprehensive analysis. Among these participants, females accounted for 60.70 %, while in the TXA group, the percentage was 62.03 %. With a 95 % confidence interval of −0.02 to 0.56 and an I2 of 0 %, The TXA group and the placebo group had BMI values of 23.51 kg/m2 and 23.25 kg/m2, respectively, suggesting no discernible difference between the two groups.
Preoperative comorbidities reported in the placebo group included 123 cases of hypertension, 71 cases of diabetes, 84 cases of cardiac disease, and 22 cases of pulmonary disease. Twenty cases of pulmonary disease, 84 cases of cardiac disease, 79 cases of diabetes, and 123 cases of hypertension were found in the TXA group.
Intertrochanteric fractures were the most common hip fractures, with 1179 cases (598 in the TXA group and 581 in the placebo group). There were 262 cases of trochanteric fractures, with 88 in the TXA group and 134 in the placebo group. For operative time, the TXA group had an average of 79.99 ± 30.96 min, and the placebo group had 80.30 ± 32.07 min, with no significant difference (MD = −0.87 min, 95 % CI −2.06 to 0.32, I2 = 0 %). Table 1 shows that 7 studies used a 1-g dose, while others used 10–20 mg/kg, and the placebo group mostly received saline.
3.3 Total blood loss with TXA
Sixteen studies, encompassing a total of 2182 patients, systematically reported the overall blood loss following the completion of hip fracture surgery. Within this cohort, 1095 patients underwent Tranexamic Acid (TXA) treatment, while 1087 patients were administered a placebo (refer to Fig. 2). In the subsequent analysis, using a random-effects model, we took heterogeneity into account. When comparing the TXA group's mean total blood loss (618.91 mL) with that of the placebo group (807.30 mL), a significant reduction was observed. The TXA and placebo groups had a mean difference of 196.91 mL, with an I2 value of 92 % and a 95 % confidence interval spanning from −247.59 to −146.23.
3.4 Risk of bias
The quality assessment of the included studies was presented in Fig. 7. The quality assessment for the selected prospective studies and randomized clinical trials was rated as high. Patients serve as representatives of the overall experience of the investigators, and the confirmation of exposure and outcomes is quite comprehensive. The duration of the follow-up was also adequate.
3.5 Clinical and general study enrolled characteristics
In 18 eligible studies, 2350 patients were treated with tranexamic acid (TXA) or a placebo. There were 60.70 % and 62.03 % female participants in the TXA and placebo groups, respectively. The TXA group's BMI was 23.51 kg/m2, while the placebo group's was 23.25 kg/m2. The two groups' body mass index (BMI) values did not differ statistically significantly (MD = 0.27 kg/m2 (95 % CI -0.02, 0.56), I2 = 0 %). Preoperative comorbidities were 84 cases of heart disease, 22 cases of lung disease, 71 cases of diabetes, and 123 cases of hypertension in the placebo group. Twenty cases of pulmonary disease, 84 cases of cardiac disease, 79 cases of diabetes, and 123 cases of hypertension were found in the TXA group.
The study included hip fractures categorized as intertrochanteric fractures (1179 cases), femoral neck fractures (262 cases), and trochanteric fractures (176 cases). Among these, the TXA group and placebo group included 581 and 598 intertrochanteric fracture cases, 128 and 134 femoral neck fracture cases, and 88 trochanteric fracture cases, respectively. Analysis of operative time showed an average of 79.99 ± 30.96 min for the TXA group and 80.30 ± 32.07 min for the placebo group (MD = −0.87 min, 95 % CI −2.06 to 0.32, I2 = 0 %). Some studies did not report dosage details, with the placebo group often receiving saline.
3.6 Blood lost with TXA
Comprehensive data on the total blood loss after hip fracture procedures were supplied by 2182 participants in sixteen trials. Among them, 1095 patients underwent tranexamic acid (TXA) treatment, while 1087 patients received a placebo (Fig. 2A). Heterogeneity was taken into consideration using a random-effects model. The TXA group dropped 618.91 mL, while the placebo group lost 807.30 mL. A noteworthy observation was the substantial reduction in blood loss observed between the TXA and placebo groups: 196.91 mL (95 % CI −247.59, −146.23, I2 = 92 %), suggesting a preference for the TXA group.
3.7 Intraoperative hemorrhage
Eight hundred and two individuals reported intraoperative blood loss in nine trials. Of them, 401 underwent TXA treatment, while an additional 401 received a placebo (Fig. 2B). Heterogeneity was taken into consideration using a random-effects model. Reveals that the TXA group encountered an average blood loss of 103.60 mL, whereas the placebo group documented a total blood loss of 136.09 mL. As per the random-effects model, The TXA group experienced a less significant decrease in intraoperative blood loss than the other group, which was found to be −26.86 mL (95 % CI <unk>36.96, <unk>16.78, I2 = 62 %).
3.8 Obscure blood loss
Out of the 994 participants in the pertinent studies, 498 received TXA, and 496 were administered a placebo (refer to Fig. 2C). The heterogeneity led to the application of a random-effects model. The analysis using a random-effects model revealed that the placebo group reported a total concealed blood loss of 619.48 mL, while the TXA group demonstrated a mean of 438.86 mL (Table 1). While contrasting the TXA group with the placebo group, the results showed a lower concealed blood loss; the difference was −183.44 mL (95 % CI −233.58, −133.31, I2 = 90 %).
3.9 Blood Transfusion Rate with TXA
Seventeen studies with 2230 patients reported blood transfusion rates. Of them, 1112 underwent TXA treatment, while 1118 got a placebo (Fig. 3). When the fixed-effects model was applied, no discernible heterogeneity was detected. Contrasted with the placebo group, where 456 out of 1118 patients (40.79 %) underwent a blood transfusion, With 232 out of 1112 patients (20.86 %) receiving blood transfusions, the TXA group showed a decreased blood transfusion rate (OR: 0.35,95 % CI: 0.28, 0.42, I2 = 0 %).
3.10 Stay of Hospitalization with TXA
Eight studies involving 765 participants reported hospital stay duration. TXA was given to 380 patients, and 385 received a placebo. The TXA group had shorter stays of hospital (mean 11.19 days) than the placebo group (mean difference = −1.46 days, 95 % CI −1.58 to −1.33, I2 = 44 %). (Fig. 4A).
3.11 Hb levels following surgery (Days 1 and 3) with TXA
Ten studies involving 1582 participants reported postoperative hemoglobin (Hb) levels on day 1, with 794 in the TXA group and 788 in the placebo group. The TXA group had a higher mean Hb level (104.42 g/L vs. 95.55 g/L), with significant improvement (MD = 6.77 g/L, 95 % CI 4.30 to 9.24, I2 = 83 %) using a random-effects model. On day 3, seven trials (829 participants: 414 TXA, 415 placebo) showed TXA maintained higher Hb levels (91.46 g/L vs. 84.30 g/L), again demonstrating significant benefit (MD = 7.02 g/L, 95 % CI 3.30 to 10.74, I2 = 82 %). (Table 1) (Fig. 5).
3.12 Complication or Problems Following Surgery with TXA
Deep vein thrombosis (DVT) rates were reported from twelve studies with 1661 individuals. TXA was administered to 831 patients, while a placebo was administered to 830 patients (Fig. 6A). 34 out of the 831 patients in the TXA group had DVT, compared to the placebo group's 171 patients, 28 out of 830 patients had DVT. A fixed-effect model was utilized.
3.13 Pulmonary embolism
The rates of pulmonary embolism (PE) were reported from seven investigations with 1391 patients. Sixty-nine patients received TXA treatment, while 702 individuals received a placebo (Fig. 6B). PE was reported to have occurred in seven of the 689 individuals in the TXA group and nine of the 702 participants in the placebo group. An inflexible model was utilized. Between the TXA and placebo groups, no variation was observed in the incidence of pulmonary embolism (PE), resulting in an odds ratio of 0.82 (95 % CI 0.33, 2.05, I2 = 0 %).
3.14 Deaths
On the occurrence of postoperative deaths, eight investigations with 1494 patients were published. Patients received TXA treatment for 743 and placebo treatment for 751 (Fig. 6C). There was a set model used. Comparing the TXA group to the control, there were 55 recorded deaths as opposed to 44 deaths. Mortality did not differ between TXA and placebo (OR 1.27, 95 % CI 0.84, 1.91; I2 = 0 %.).
4 Discussion
This systematic review and meta-analysis, which included 18 trials with a total of 2,350 participants, thoroughly investigated the impact of tranexamic acid (TXA) on hip fracture surgeries. The TXA treatment in patients undergoing hip fracture surgery decreases intraoperative blood loss, overall blood loss, transfusion, and Length of Hospital Stay. Based on 498 patients undergoing hip fracture surgery, the TXA treatment decreases both intraoperative and overall blood loss. These findings are consistent with earlier studies, reinforcing TXA's effectiveness in reducing bleeding by stabilizing fibrin clots Due to less blood loss, the use of TXA notably reduces the transfusion rate in patients undergoing hip fracture surgery. This finding is clinically important, as fewer transfusions lower the risks of transfusion reactions and infections, as well as decrease overall hospitalization expenses. Patients with hip fracture surgery who received TXA experienced shorter hospital stays than those received placebo.This can be linked to enhanced recovery during the perioperative period and fewer complications, such as decreased transfusion rates. A shorter hospital stay aids in patient recovery and improves the efficiency of the healthcare system, particularly for older patients. Postoperative hemoglobin levels on the first and third postoperative days were maintained notably higher in the TXA group compared to the placebo group, implying that TXA effectively minimizes operative blood loss and maintain higher oxgen supply in blood. Maintaining elevated Hb levels after surgery is especially important for elderly patients with limited physiological reserves, as it supports their functional recovery. This finding suggested that TXA can be safely integrated into perioperative care without raising safety concerns. The occurrence of deep vein thrombosis and pulmonary embolism (PE) was not significantly different between the TXA and placebo groups. These findings is consistent with increasing evidence that TXA has a safe profile regarding thromboembolic events. Mortality rates showed no significant difference between the TXA and placebo groups, suggesting that the use of TXA in hip fracture surgeries does not elevate the risk of death. Concerning the impact of TXA on postoperative complications, the analysis revealed that the use of TXA did not raise the risk of common postoperative complications, such as deep vein thrombosis, pulmonary embolism, infections, delayed wound healing and mortality. While this meta-analysis offers strong evidence regarding the efficacy and safety of TXA, certain limitations should be noted such as aging, neurological, or cardiovascular patients undergoing hip surgeries. Aging patients undergoing hip surgery are more vulnerable to more complications. Future studies should focus on stratified analyses to ensure that the TXA are applicable to the high-risk group such as aging, neurological, or cardiovascular patients undergoing hip surgeries. In summary, TXA significantly decreased blood loss and blood transfusion rate during hip fracture surgeries, leading to shorter hospital stays as well as did not raise the likelihood of serious complications or death. These findingss endorse TXA as a safe and effective option for managing bleeding in patients undergoing hip fracture surgery.
5 Conclusion
TXA treatment in patients undergoing hip fracture surgery reduced intraoperative blood loss, overall blood loss, transfusion rate, and length of hospital stay effectively and appeared to be safe to use without significant complication or problems such as thromboembolic risk or death.
CRediT authorship contribution statement
Hsuan-Wei Liu: Writing – original draft, Writing – review & editing. Shin-Da Lee: Supervision, Validation, Visualization, Roles.
Consent to participate
No patient-identifiable data was collected in this study. Only anonymous data was collected. Prior permission was obtained from the Deputy Data Protection Officer before collecting anonymous data. This study was considered a low-risk retrospective chart review by the Research Ethics Committee of China Medical University Hospital, and therefore explicit consent from the participants in the study was not required.
Consent for publication
Not applicable’ for that section.
Data availability
The datasets generated for this study are available upon request to the authors.
Ethics approval
The present review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023451132.
Data collection and sources
•Data used comes from legal and publicly available repositories.•Data usage complies with respective terms.•Best practices in data collection were followed, with proper acknowledgment of data sources.
Funding
Not applicable’ for that section.
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