In recent years, several meta-analyses have been published on the use of TXA in hip fractures. Luo [21] included 5 RCTs with 540 cases to analyze the role and safety of TXA in intramedullary nailing for the treatment of geriatric intertrochanteric fractures. It was concluded that TXA reduced TBL, IBL, and HBL, decreased transfusion ratio and transfusion units and did not increase the risk of thrombosis. Xing's meta-analysis [27], which included 5 RCTs with 539 cases, analyzed the role of TXA in intramedullary nailing of the proximal femur for the treatment of geriatric intertrochanteric fractures. TXA was effective in reducing TBL, IBL, HBL, transfusion rate, hospital stay, and wound hematoma rate without increasing operative time, postoperative mortality, thrombotic events, wound infection, cerebrovascular accident, respiratory infection, or renal failure. A meta-analysis by Yu [23], investigating the use of TXA in geriatric intertrochanteric fractures, included 11 RCTs with 1202 cases. TXA reduced IBL, HBL, TBL, hospital stay, transfusion ratio, and risk of wound complications. Patients in the TXA group had higher HB levels at 1, 2, and 3 days postoperatively. There was no difference in thrombotic risk and mortality. A meta-analysis by Masouros [22] included 10 randomized controlled studies containing 1123 cases to evaluate the role of intravenous TXA in hip fractures in the elderly. The results concluded that TXA was found to be effective in reducing TBL, transfusion ratio, and transfusion units without increasing the risk of thrombotic events. Also, the results of a single dose of 15 mg/kg were comparable to the effect of multiple doses.
However, there was significant clinical heterogeneity among the studies included in the preceding meta-analysis. These randomized controlled studies were selected with different TXA application methods, patient age, fracture type, and surgical option. To reduce the unreliability of results due to clinical heterogeneity, we limited the objective of this study to the intravenous application of TXA. Because the effect of topical application for intertrochanteric fractures is uncertain [28], some studies suggest that topical application does not achieve less blood loss [29, 30]. It would be inappropriate to synthesize the study with articles using different methods of application. We limited the population to geriatric intertrochanteric fractures and excluded femoral neck fractures because the two surgical options are completely different and not comparable. We limited the surgical option to the proximal femoral intramedullary nailing technique because it is used more frequently compared to dynamic hip screw for more types of fractures, shorter operative time, less blood, fewer complications, and better function [9, 10]. Finally, six high-quality randomized controlled studies [17–20, 25, 26] were included in our study. The results of the meta-analysis showed that intravenous application of TXA to intramedullary nailing in geriatric patients with intertrochanteric fractures was effective in reducing TBL, IBL, and HBL, decreasing transfusion rates and transfusion units, and not increasing thrombotic events or mortality, which were consistent with previous studies [21–23, 27].
With the deepening of the concept of enhanced recovery, the importance of blood management has become increasingly prominent [31]. Without proper blood management measures to reduce perioperative blood loss, early and rapid recovery of patients cannot be achieved, which is especially important in elderly patients. We use TBL, IBL, and HBL as our primary observations. The calculation of blood loss is mostly based on the Nadler [32] and Gross [33] formula mentioned in the literature. The calculation of TBL is related to blood volume and preoperative and postoperative hematocrit. The calculation of IBL is the intraoperative suction flow plus the blood volume on the gauze. HBL is equivalent to TBL minus IBL. If there was an intraoperative or postoperative blood transfusion, then the transfusion volume should be added to TBL. This formula was used in all of our studies. Our study showed a statistically significant decrease in TBL of about 232.82 ml (p < 0.00001), IBL of about 36.33 ml (p < 0.00001), and HBL of about 189.23 ml (p < 0.0001) in the TXA group compared with the control group. However, we also found significant heterogeneity in the 3 pooled analyses, consistent with previous meta-analyses [23]. Using the leave-one-out technique, the I2 value of the heterogeneity test for the TBL results would decrease from 51–17%. If Zhang's findings [19] were excluded, the I2 value for HBL results would decrease from 62–0%. One of the sources of heterogeneity may be the calculation of TBL and HBL. Although they both used the Nadler and Gross formula, there were differences in the specific calculation strategies. Also, there were differences in the measurement time of blood tests. Preoperative blood tests were performed at admission [19, 25] or one day before surgery [17, 18, 20] in some studies and on the morning of surgery day in others[26]. Postoperative blood data in some studies were the lowest values on postoperative day 1 and 3 [17, 19–21, 25], and some were the values on day 2 [26]. Different times of measurement may lead to bias in TBL calculations, resulting in heterogeneity in the results of the meta-analysis. If the results of Zhou’s study [20] were excluded, the I2 value for IBL results would decrease from 50–0%. The IBL calculation was not related to blood tests and the methodology was essentially the same. We attempted subgroup analysis to identify the cause of heterogeneity but were unsuccessful. The final statistical results are still significantly different, even if we exclude the study with significant heterogeneity.
The reduction in transfusion rate is another important indicator of the bleeding-reducing effect of TXA. Our study found that the perioperative transfusion rate was 33.45% in the TXA group and 57.79% in the control group. There was a statistical difference between them (RR = 0.53; 95% CI 0.33 to 0.85; p = 0.008), indicating that the TXA group had a 47% lower transfusion risk than the control group. Transfusion units also decreased, on average by 0.58 units per patient (WMD = -0.58; 95% CI -0.75 to -0.41; p < 0.01). However, we noted significant heterogeneity among the combined transfusion rate data (χ2 = 33.82, df = 5, I2 = 85%, p < 0.00001). Even after adopting the leave-one-out technique to omit any of the trials, heterogeneity persisted. The only factor we could pinpoint was the variation in transfusion strategy across studies.
Despite the evidence that TXA is effective in reducing blood loss in patients, there are concerns about increased thrombotic events and mortality. Thrombotic events include DVT, PE, and cardiovascular and cerebrovascular accidents. Zufferey [34] and Schiavone [35] reported that the thrombotic events and mortality of patients in the TXA group were three times higher than those in the control group, but there was no statistical difference. Franchini's meta-analysis [36] examining the safety of intravenous application of TXA in orthopedic surgery included 73 RCTs containing 4174 cases in the TXA group and 2779 cases in the control group. The final pooling concluded that the risk of thrombosis in the TXA and control groups were comparable and not statistically different. A large retrospective study by Zak [37], which included 26,808 patients with coronary artery disease or coronary stenting who underwent total knee or total hip replacement, concluded that TXA was safe and did not increase the risk of thrombosis after 8 years of follow-up. Meanwhile, intravenous application of TXA was more recommended and appears to have a lower risk of thrombosis compared to topical application, but there was no statistical difference. A retrospective study by Porter [38] found that TXA applied to intertrochanteric fractures with a high risk of thrombosis according to a scoring scale still had an excellent safety profile. There were no statistically significant differences in thrombotic events or mortality compared to controls. Our results are consistent with the previous studies.
Our study still has several limitations. First, although we more strictly limited the study criteria to reduce clinical heterogeneity, some differences between research methods cannot be completely avoided. For example, preoperative waiting time, blood test time points, TXA dose, use of low-molecular heparin, and transfusion strategy may all have an impact on the study results. Second, the detailed calculation of BL still varies, making the data less comparable among studies, and BL was the primary outcome in this study. Third, fewer studys were included, and the total number of cases was low. Finally, some studies had a follow-up period of only one month, and long-term follow-up data were not available. Despite the aforementioned shortcomings, our study included the most recent RCTs. All RCTs were of high methodological quality. There was strong statistical evidence for the study results.