Tranexamic acid reduces hidden blood loss in the treatment of intertrochanteric fractures with PFNA: a single-center randomized controlled trial

Globally, hip fracture is a frequent cause of morbidity and mortality, especially in elderly people [1, 2]. Intertrochanteric fracture is one of the three major types of hip fracture, comprising approximately half of all hip fractures. Intertrochanteric fracture usually occurs in patients with a history of falls or bone disease, and results from a low-energy mechanism such as a fall from standing [3]. Patients typically present with pain and difficulty walking.

Types of intertrochanteric fracture [4] and treatment [5] affect functional outcomes and mortality in patients with hip fracture. Patients with intertrochanteric fractures incur more blood loss than those with femoral neck fractures and have a higher rate of transfusion [6]. In addition, perioperative hemoglobin and hematocrit levels have implications for outcomes, as patients with hip fracture are usually frail and elderly and particularly prone to anemia and hypovolaemia [7‐9]. Evidence suggests that total blood loss during hip fracture surgery may be much greater than that observed intraoperatively. One study showed that overall blood loss was 1473 mL greater than that observed intraoperatively in patients undergoing hip surgery [6], and another study [10] reported 277.2 ± 7.6 mL hidden blood loss in patients undergoing proximal femoral nail anti-rotation (PFNA) for intertrochanteric fractures. Hidden blood loss could aggravate functional outcomes and increase mortality in patients with hip fracture by lowering hemoglobin levels. Hidden blood loss should be minimized during surgery for intertrochanteric fracture.

Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine, with antifibrinolytic properties that competitively inhibit lysine-binding sites on plasminogen molecules. TXA has been used for hemostasis in orthopedic surgery [11‐16]. Previous studies have shown that TXA reduced total blood loss and the need for transfusion in hip arthroplasty and hip fracture surgery [14, 15, 17]. However, the majority of these studies focused on the hemostatic effect of TXA on visible blood loss in hip fracture surgery, rather than on postoperative hidden blood loss [18]. One study showed that TXA decreased external blood loss by 30%, but not hidden blood loss, in total knee replacement [19]. Other reports in total knee arthroplasty show that TXA significantly reduced hidden blood loss and total blood loss [20‐22], but there have been few studies investigating whether TXA can reduce hidden blood loss in surgery for intertrochanteric fractures [18, 23].

In this study, we hypothesized that TXA administration would lead to decreased postoperative hidden blood loss in patients with intertrochanteric fractures. The objective of this study was to investigate whether intravenous (i.v.) administration of 1 g TXA could reduce postoperative hidden blood loss in patients with intertrochanteric fractures.

Between December 2015 and July 2016, 215 patients with intertrochanteric fractures were admitted to our institution through the emergency department. Seventy-seven patients who met all of the inclusion criteria and none of the exclusion criteria were randomized to the TXA (n = 37) and NS groups (n = 40) (Fig. 1). Patients’ demographic and clinical characteristics were similar between the two groups as summarized in Table 1. Most patients (81.81%) were female aged 64 to 93 years. Upon admission, the hemoglobin level in 16 patients was <90 g/L; these patients received a total of 48.0 U of packed RBC by intravenous infusion. Four patients in the TXA group and four patients in the NS group each received 4 U packed RBC. Before surgery, hemoglobin level in most patients was between 91 and 137 g/L and hematocrit was between 27.6 and 34.6%.

All surgeries were successful. Mean operative time and mean length of hospital stay were not significantly different between the TXA and NS groups. There was less surgical blood loss in the TXA group compared to the NS group (128.85 ± 123.18 vs. 98.30 ± 59.10; P = 0.31), but the difference was not significant. However, the postoperative transfusion rate was significantly lower in the TXA group compared to the NS group (TXA, 28.20% [2.0 U packed RBC in 10 patients, 4.0 U packed RBC in 1 person] vs. NS, 56.09% [2.0 U packed RBC in 18 patients, 4.0 U packed RBC in 5 patients]; P = 0.01). In the NS group, three patients >90 years of age received an intraoperative transfusion of 2 U packed RBC each.

As shown in Table 2, on postoperative day 1, both mean hematocrit and mean hemoglobin levels were not significantly different in the TXA group compared to the NS group. Postoperative drainage at postoperative day 2 was also not significantly different between the TXA and NS group (89.50 ± 44.77 mL vs. 89.73 ± 33.30 mL, P = 0.98). On postoperative day 3, mean hemoglobin and mean hematocrit levels were comparable. But the calculated hidden RBC loss (210.09 ± 202.14 mL vs. 359.35 ± 290.12 mL, P = 0.049) and total RBC loss (279.35 ± 209.11 mL vs. 417.89 ± 289.56 mL, P = 0.049) were significantly less in the TXA group compared to the NS group (Table 2).

There were no systematic complications related to TXA administration. The incidence of adverse events in the TXA and NS group were not significantly different (Table 3). Patients with hematoma and infection at the surgical site were treated conservatively, but one patient required surgical debridement.

All patients were followed up for 30 days after surgery. Three patients were lost to follow-up due to death (2 of pulmonary embolism and 1 of renal failure). Deep vein thrombosis resolved spontaneously.

Hip fracture surgery may result in substantial blood loss in elderly and frail patients, exposing them to postoperative anemia, which could negatively impact clinical outcomes and mortality. Previous studies have shown that TXA reduced hidden blood loss associated with total knee arthroplasty [22]. However, it is not clear whether TXA decreases hidden blood loss in patients undergoing PFNA for intertrochanteric fractures. Our results showed that both postoperative hidden blood loss and total blood loss were significantly reduced in patients with intertrochanteric fractures treated with TXA, suggesting TXA administration is an efficacious approach to reducing blood loss in patients undergoing PFNA for intertrochanteric fractures.

Our results showed that compared to NS, TXA administration reduced postoperative RBC loss to 279.35 mL and hidden blood loss to 700.3 mL (assuming 30% hematocrit) in patients with intertrochanteric fractures. These results are consistent with previous studies reporting on total knee arthroplasty [12], periacetabular osteotomy [11], extracapsular fracture of the hip [13], and total shoulder arthroplasty [16]. Our data also suggests that TXA administration has the potential to decrease the number of orthopedic patients requiring transfusion; administration of 1 g of TXA decreased the transfusion rate from 56.09 to 28.20%. This would contribute to a substantial reduction in healthcare costs and resource utilization for these patients.

TXA competitively blocks a lysine-binding site of plasminogen and thereby inhibits its conversion to the active enzyme plasmin. Plasmin binds to fibrinogen or fibrin structures and promotes fibrinolysis [29]. Additional evidence suggests that plasmin is pro-inflammatory [30]. Currently, it is debatable whether TXA benefits trauma patients through reversal of fibrinolysis or modulating the inflammatory response [31, 32].

In this study, we chose to administer 1 g of TXA or NS i.v. after anesthetization and before surgery. We used a low dose and systemic administration, as reported by Wingerter et al. [33]. In contrast, Drakos et al. [23] administered 3 g of TXA around the fracture site at the end of the surgical procedure in patients undergoing surgery for intertrochanteric fracture, and Tengberg et al. [13] administered 1 g of TXA as an intravenous bolus prior to surgery followed by a postoperative 24-h infusion of 3 g TXA in 1 L of isotonic saline in patients undergoing surgery for extracapsular hip fracture.

The most common complication associated with TXA administration is ischemic cerebral infarction at postoperative 1 month after operation. However, there was no ischemic cerebral infarction in our study and there were no significant differences in the incidence of adverse events between the TXA and NS groups. TXA is a synthetic derivative of the amino acid lysine and may, therefore, be associated with thrombotic complications; however, recent large studies and meta-analyses have not consistently reported an increased risk for thrombosis [34‐36]. The overall complication rate in our study was comparable with previous reports [13, 23].

To our knowledge, this is the first randomized controlled trial of TXA vs. NS for postoperative hidden blood loss in patients undergoing PFNA for intertrochanteric fractures. Only patients eligible for PFNA were included; therefore, the demographic and clinical characteristics of the TXA and NS groups were comparable.

The study has some limitations. First, the sample size is relatively small. Second, this study was not double-blind. Third, the fracture type was limited to intertrochanteric fractures. Future studies using larger sample sizes and a variety of fracture types are warranted to confirm our findings.

This study demonstrated that TXA could effectively reduce postoperative hidden blood loss in patients undergoing PFNA for intertrochanteric fractures and may decrease the number of patients needing transfusion.