Perioperative Administration of Tranexamic Acid and Low Molecular Weight Heparin for Enhanced Blood Management in Intertrochanteric Fractures: A Randomized Controlled Study

Introduction

With the rapid aging of the population in China, the incidence of hip fractures is gradually increasing, imposing a significant healthcare burden [1–3]. It is projected that the number of hip fracture cases in China will rise from 700 000 in 2013 to 4.5 million by 2050, representing a 6-fold increase [4]. In particular, hip fractures among the elderly predominantly manifest as femoral neck fractures and intertrochanteric fractures (IF), with the latter accounting for 40–60% of all cases [4]. IF commonly occurs in the elderly due to osteoporosis, involves the area between the greater and lesser trochanter of the proximal femur, and varies from stable to unstable based on structural integrity [5]. Diagnosis is primarily through radiographs, with treatment often involving surgical options like intramedullary nailing or sliding hip screws, depending on the fracture’s stability [5]. For elderly patients with IF, surgical intervention is recommended to alleviate pain and ensure early mobilization [4]. Timely surgery can significantly reduce the risk of complications associated with conservative therapy, such as decubitus ulcers, hypostatic pneumonia, infections, and DVT [6]. Currently, an increasing number of surgeons favor the use of intramedullary nailing (IMN) devices for stabilizing unstable IF [7]. Multidisciplinary rapid recovery management programs have been successfully implemented in various clinical sciences, with a primary focus on rapid surgical fixation and perioperative blood management (PBM) [8]. Timely surgeries allow early fracture stabilization, thus enhancing nursing maneuverability and quality and accelerating functional recovery while minimizing secondary injuries [9]. Surgery for intertrochanteric fractures, while critical for patient recovery, carries inherent risks such as DVT and hemorrhage [10]. Current management guidelines emphasize the importance of early detection and the implementation of prophylactic measures against DVT, along with meticulous surgical techniques to minimize bleeding [11]. PBM protocols are integral to optimizing patient outcomes and mitigating these complications, ensuring a balance between anticoagulation therapy and maintaining hemostasis.

Tranexamic acid (TXA) and low molecular weight heparin (LMWH) play pivotal roles in the perioperative management of patients undergoing surgery, particularly in orthopedic procedures such as those for intertrochanteric fractures. The postoperative administration of TXA, a antifibrinolytic drug, is utilized to reduce surgical bleeding by inhibiting the breakdown of fibrin clots, thereby decreasing the need for blood transfusions and improving surgical field visibility [12]. TXA has demonstrated a significant reduction in blood loss, with an excellent safety profile, rendering it an indispensable medication for PBM in hip surgery [13,14]. However, consensus has yet to be reached regarding the optimal timing and dosage of perioperative TXA [15,16]. LMWH is a key prophylactic agent against venous thromboembolism (VTE), including DVT. It works by enhancing the activity of antithrombin III, thus inhibiting thrombin formation and factor Xa, crucial steps in the coagulation cascade [17]. LMWH is widely acknowledged to significantly reduce the occurrence of DVT following hip fracture procedures, and it is generally recommended for use within 24 h postoperatively [18,19]. A study performed by Zhou et al included 100 IF patients and aimed to investigate the effectiveness and safety of TXA in reducing bleeding and the need for transfusion, indicating that TXA significantly reduced total, intraoperative, and hidden blood loss compared to the control group, without increasing the rate of complications [10]. In addition, a systematic review and meta-analysis by Jiang et al investigated the efficacy and safety of TXA in IF patients treated with intramedullary fixation. The study included 9 randomized controlled trials with 972 patients, indicating that TXA significantly reduced total blood loss, intraoperative blood loss, hidden blood loss, and transfusion rate compared to the control group [20].

To attain the most suitable postoperative anticoagulation state, while simultaneously maintaining a low thrombosis rate and maximizing the anticoagulation effect, hemoglobin levels, and minimizing postoperative bleeding, we propose a novel postoperative blood management regimen: 4 doses of intravenous TXA (administered 30 min preoperatively and at 3, 6, and 9 h postoperatively), in combination with LMWH (administered 12 h postoperatively). Therefore, this prospective study from a single center aimed to compare the perioperative control of blood loss in 79 patients undergoing IMN surgery for IF using 3 regimens of combined different doses of TXA and LMWH.

Material and Methods

ETHICS STATEMENT:

This double-blinded randomized comparative study received approval from the ethics committee of Suzhou Yongding Hospital (201911) and was conducted in accordance with the principles of the Helsinki Declaration governing human research ethics. Written informed consent, including surgical methods and details of possible regimens and the possible complications during hospitalization, was obtained from all patients prior to their surgical procedure.

STUDY DESIGN:

This study focused on patients who underwent IMN for IF from January 2020 to July 2023. All Patients were strictly enrolled followed the inclusion and exclusion criteria. The inclusion criteria were: (1) Diagnosis of IF according to the AO classification, confirmed by X-ray or CT imaging; (2) Deemed suitable for the IMN procedure for IF by clinical assessment; and (3) Injury duration ≤48 h. The exclusion criteria were: (1) Allergic to TXA or LMWH; (2) Creatinine clearance <30 ml/min; (3) Active malignancies; (4) High risk of deep vein thrombosis (eg, cardiovascular event within the past year, congenital thrombophilia, previous history of DVT); (5) Long-term use of anticoagulants; (6) IF occurring >48 h ago; (7) Active bleeding.

We randomly allocated 79 patients into 3 study groups using computer-generated numbers: the control group (32 patients), the 1-dose TXA (Haixin Medicine Industry, Jiangxi, China) group (25 patients), and the 4-dose TXA group (22 patients). All groups were administered LMWH (Aspen, Guangzhou, China) 12 h postoperatively.

Upon admission, all patients were immediately prepared for surgery to initiate surgical treatment within 24 h of admission. Blood tests were conducted upon admission and on postoperative days 1, 3, and 7. The control group did not receive perioperative TXA but did undergo LMWH treatment (Nadroparin calcium injection, 38 IU/kg) 12 h postoperatively. The 1-dose TXA group received a preoperative intravenous infusion of 1.0 g TXA (tranexamic acid injection, 5 ml: 0.5 g) 30 mins before surgery, with no subsequent doses, and then received the same LMWH treatment as the control group. In contrast, the 4-dose TXA group received 1.0 g TXA intravenously 30 min before surgery and additional 1.0-g doses at 3, 6, and 9 h after surgery, along with identical LMWH treatment. All patients were prescribed oral rivaroxaban following hospital discharge to prevent DVT. Blood transfusions were administered based on specified criteria: (1) Hemoglobin level lower than 7 g/dL; (2) Hemoglobin dropped more than 4 g/dL postoperatively; and (3) Serious symptoms of anemia such as fatigue, weakness, and shortness of breath. During their hospital stay, all patients routinely underwent Doppler ultrasound for both lower limbs at the first day and every 3 days after surgery, including the discharge day, to diagnose and exclude DVT. Regular follow-up appointments took place at 1, 3, 6, and 12 months postoperatively. All patients underwent standard IMN procedures by senior orthopedic surgeons. The procedure involves placing a metal rod running along the femur’s length through a small incision near the hip into the femur’s marrow canal. Screws are then placed through the rod into the femur’s head and neck to firmly secure the broken bones.

DATA COLLECTION:

All data were retrieved from clinical records. Demographic and clinical data included age, gender, height, weight, BMI (Body Mass Index), AO fracture type, American Society of Anesthesiologists (ASA) score, preoperative coagulation function (FG, APTT, PT), and operation time. The primary outcomes were total blood loss (TBL), hidden blood loss (HBL), maximum preoperative hemoglobin (Hb) drop, maximum preoperative hematocrit (HCT) drop, the number and rate of blood transfusions, number and incidence rates of DVT. Total blood volume was calculated using Nadler’s formula as follows: Total blood volume=k1×height (m3)+k2×weight (kg)+k3. For male patients, k1=0.3669, k2=0.0322, k3=0.6041; and for female patients, k1=0.3561, k2=0.0331, k3=0.1833 [15]. TBL was estimated with the Gross linear formula as follows: TBL=Total blood volume×(HCT pre-op - HCT post-op)×2/(HCT pre-op + HCT post-op) [21]. Intraoperative visible blood loss=(volume in suction bottles during surgery - irrigation volume)+gauze net increase. The postoperative HBL=TBL - intraoperative visible blood loss. Postoperative complications were observed and recorded, which included pulmonary embolism, cardiovascular accidents, wound hematoma, postoperative infections, and other bleeding events such as gastrointestinal bleeding and hematuria. To achieve double-blind experiments, saline was used as an alternative to TXA with the same injection time in the 4-dose group. Data collection was performed by clinical doctors, and the anonymous data were then analyzed by nonclinical professionals.

STATISTICAL ANALYSIS:

To determine the required sample size, we referred to a previous study that reported the mean HBL in the intravenous TXA and placebo groups as 640 ml (SD 421 ml) and 1010 ml (SD 398 ml), respectively [22]. With a power of 80%, a two-sided alpha level of 0.05, and a 1: 1 allocation ratio, we calculated the required sample size to be 20 patients per treatment group. In total, 79 patients were enrolled: 22 received 4-dose of TXA, 25 received 1-dose of TXA, and 35 did not receive TXA. All enrolled patients (n=79) were included in the final analysis (Figure 1).

Descriptive statistics are presented as mean ± standard deviation for continuous data and as frequencies (%) for categorical data. Between-group differences were assessed using one-way ANOVA for continuous data and Fisher’s exact test or Pearson’s chi-square test for categorical data. P<0.05 was considered statistically significant. Data were analyzed using SPSS version 23.0 (Chicago, IL).

Results

All data were from standardized measurements across all patients. There were no significant differences observed among the different groups in terms of age, sex, BMI, AO fracture type, ASA score, preoperative Hb, preoperative HCT, preoperative coagulation function, preoperative D-dimer levels, total blood volume, operation duration, mean DVT diagnosed time, and length of stay (Table 1).

Patients receiving 4 doses of TXA (4-dose TXA) exhibited significantly lower TBL (640.86±337.22 ml) compared to the single-dose TXA group (1-dose TXA) (971.74±511.14 ml, P<0.05) and the control group (1226.27±458.22 ml, P<0.05). Additionally, the 1-dose TXA group also demonstrated a significant reduction in TBL compared to the control group (P<0.05). These trends were similarly observed in HBL (4-dose TXA 583.13±318.08 ml, 1-dose TXA 902.94±509.99 ml, control 1154.39±452.06 ml, P<0.05). Regarding the maximum perioperative HCT drop, the 4-dose TXA group showed a significant decrease compared to both the 1-dose TXA group (P<0.05) and the control group (P<0.05), while the 1-dose TXA group was significantly lower than the control group (P<0.05) (4-dose TXA 5.26±1.99, 1-dose TXA 7.04±2.99, control 9.03±2.94). However, when comparing the maximum perioperative Hb drop, the results were different – the 4-dose TXA group demonstrated a significant reduction compared to the control group (4-dose TXA 15.64±8.63, control 30.78±10.53, P<0.05). The 1-dose TXA group also exhibited a significant reduction compared to the control group (1-dose TXA 20.76±8.89, P<0.05). However, there was no significant difference between the 4-dose TXA and the 1-dose TXA groups (P>0.05), with only the 4-dose TXA group showing a lower Max Hb drop value. This may be attributed to statistical bias resulting from a small sample size (Figure 2).

When comparing the transfusion rates among the 3 groups, the 4-dose TXA group had the lowest transfusion rate (13.64%), followed by the 1-dose TXA group (28.00%), while the control group had the highest transfusion rate (28.12%). However, no significant differences were observed between the groups (P>0.05). The incidence of DVT also did not show any significant differences and was only reflected in the number of cases (4-dose TXA 22.73%, 1-dose TXA 24.00%, control 25.00%, P>0.05) (Table 2). Complications observed postoperatively during follow-up were 1 case of wound hematoma in the control group and 1 case of postoperative infection in the 4-dose TXA group (Table 3).

Discussion

Results showed that the 4-dose group had the least variation in perioperative HCT and HB levels, followed by the 1-dose group. This aligns with changes observed in TBL and HBL. Administering TXA 4 times within 10 h postoperatively significantly reduced postoperative hidden blood loss. We hypothesized that factors such as marrow expansion and surgical trauma make the first 12 postoperative hours the peak periods for blood loss. Previous research indicates that intravenous 1.0 g TXA can maintain effective blood concentrations for up to 2.9 h [23]. Thus, administering TXA at 3-h intervals postoperatively can sustain its effective concentration for an extended period, reinforcing coagulation functions during peak blood loss periods. Zhou et al [10] and Jiang et al [20] demonstrated the clinical efficacy of TXA appliances in reducing blood loss in IF, while ignoring the possibility of perioperative multiple doses of TXA. In our study, we compared the 3 different regimens and found 4-dose TXA therapy had excellent clinical effects in reducing perioperative blood loss compared to the single-dose group and control group.

With the aging population, the incidence of hip fractures is steadily increasing. Studies have shown that the lifetime morbidity rate for hip fractures is 20% in females and 10% in males, with IF being the most common [24]. Proximal femoral nail anti-rotation (PFNA), the standard form of IMN, has emerged as the preferred treatment for most IF [25,26]. However, PFNA treatment often results in continuous perioperative hemoglobin loss, mainly due to intraoperative bleeding and hidden blood loss. This can lead to a higher transfusion rate and a longer postoperative recovery period, especially in older patients with chronic anemia and poor nutritional status [25]. Additionally, hip injuries and prolonged bed rest are significant risk factors for postoperative DVT [26]. To prevent DVT, clinicians often use anticoagulants, which can, in turn, increase hemoglobin loss. In line with the Enhanced Recovery After Surgery (ERAS) approach, investigating blood management during PFNA treatment for IF has become critical, and the combined use of TXA and LMWH has shown promise [27].

TXA is a synthetic amino acid analog known to reduce bleeding and transfusion needs by competitively inhibiting plasminogen activation and the binding of plasmin to fibrin [26–29]. Previous research has demonstrated that intravenous TXA significantly reduces blood loss and transfusion volume in joint replacement patients [30–34]. Similarly, for IF, perioperative intravenous TXA reduces overall and hidden blood loss [10,24]. However, the optimal dose and timing of TXA usage for elderly intertrochanteric fracture patients remain contentious. Nikolaou et al demonstrated that a single preoperative dose of 15 mg/kg TXA benefits older patients undergoing IMN treatment for these fractures [35]. Other studies have reported the effectiveness of different TXA administration strategies in reducing postoperative bleeding for elderly hip fracture patients [36]. For example, Zhang et al reported that administering 1 g of intravenous TXA 10 min before incision and 3 h after significantly reduces HBL and the need for allogeneic red blood cell transfusion, without increasing thrombotic events, including DVT [22]. Tian’s research indicated that administering 2 doses of 10 mg/kg intravenous TXA before and 5 h after surgery could significantly reduce postoperative hidden blood loss [37].

However, early TXA use may potentially increase preoperative DVT and related events. Zufferey et al reported a 3-fold increase in thrombo-thrombotic events in hip fracture patients after using TXA [38]. Given the inherent high DVT risk with hip fractures, often exacerbated by patient age and other risk factors, immediate TXA administration upon hospital admission could amplify these risks. Any resultant complications might adversely impact surgical treatment, with severe consequences. Therefore, in this study, patients did not receive TXA upon admission, but rather received their first dose of TXA 30 min preoperatively. In accordance with the principles of ERAS, our goal was to promptly assess surgical eligibility for elderly hip fracture patients upon admission and initiate surgery within 48 h of the injury [39]. This strategy helps minimize the effects of preoperative blood loss, both overt and concealed, on the overall outcome. Given the high DVT risk with IF, clinical guidelines universally recommend postoperative anticoagulation. In this study, we administered LMWH within 24 h postoperatively, which can significantly reduce postoperative DVT after hip fractures, with high safety and efficacy [18,19]. Patients were divided into 2 experimental groups: those receiving 4 intravenous doses of TXA+LMWH (the 4-dose group) and those receiving a single intravenous dose of TXA+LMWH (the 1-dose group). The control group received LMWH perioperatively without TXA. This design allowed us to examine the effects of different dosages TXA+LMWH on perioperative blood loss, thrombosis occurrence rate, and transfusion rate. Due to the challenges in achieving a stable high TXA concentration when locally administered to IF, our study opted for intravenous TXA application to enhance repeatability and maintain a relatively stable blood–drug concentration. To achieve the optimal postoperative anticoagulation state, while ensuring clinical safety, we administered the same LMWH dose across all groups.

Balancing anticoagulation and hemostasis in hip fracture patients is a pressing concern to reduce perioperative bleeding without increasing DVT-associated risks. Our study found no significant differences in DVT rates among groups, suggesting that multiple TXA applications do not increase perioperative DVT risks. This could be attributed to postoperative LMWH usage. Combining both drugs at different perioperative stages addresses primary clinical challenges (hemostasis within 12 h after surgery and anticoagulation after 12 h), promoting faster post-injury recovery.

This study was an attempt and to determine the optimal application of TXA and LMWH perioperatively, validating the safety of 4-dose intravenous TXA in IF. Considering the simplicity and repeatability of use of TXA and LMWH, this method can be promoted in primary hospitals.

However, there are still some limitations to this study. This was a single-center study, which may have introduced certain biases; multi-center participation is recommended for broader validation and to minimize statistical biases. In addition, the relatively small sample size constrained our capacity to detect significant differences in transfusion rates and incidence of DVT among groups. Therefore, larger-scale studies are imperative to substantiate the clinical benefits of the 4-dose TXA therapy in treatment of IF.

Conclusions

Using TXA 4 times during the perioperative period, combined with LMWH, significantly reduces perioperative blood loss after IMN operation for IF patients. The 4-dose TXA therapy had better clinical efficacy in decreasing PBL than a single dose or no TXA. In our study, the regimen of 4-dose TXA with LMWH did not increase the incidence of DVT.