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Intravenous and Oral Tranexamic Acid Are Equivalent at Reducing Blood Loss in Thoracolumbar Spinal Fusion

A Prospective Randomized Trial

Yu, Charles C., MD; Kadri, Omar, MD; Kadado, Allen, MD; Buraimoh, Morenikeji, MD; Pawloski, Jacob, BS; Bartol, Stephen, MD; Graziano, Gregory, MD

doi: 10.1097/BRS.0000000000002954
RANDOMIZED TRIAL
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Study Design. A prospective randomized trial of patients enrolled at a university affiliated tertiary medical center between February and December 2017.

Objective. To compare perioperative blood loss in patients undergoing elective posterior thoracolumbar fusion who were treated with intravenous (IV) versus oral (PO) tranexamic acid (TXA).

Summary of Background Data. The use of antifibrinolytic agents such as TXA to decrease operative blood loss and allogenic blood transfusions is well documented in the literature. While evidence supports the use of IV and topical formulations of TXA in spine surgery, the use of PO TXA has not been studied.

Methods. Eighty-three patients undergoing thoracolumbar fusion were randomized to receive 1.95 g of PO TXA 2 hours preoperatively or 2 g IV TXA (1 g before incision and 1 g before wound closure) intraoperatively. The sample was further stratified into three categories based on number of levels fused (1–2 level fusions, 3–5, and >5). The primary outcome was the reduction of hemoglobin. Secondary outcomes included calculated blood loss, drain output, postoperative transfusion, complications, and length of hospital stay. Equivalence analysis was performed with a two one-sided test (TOST). A P-value of <0.05 suggested equivalence between treatments.

Results. Fourty three patients received IV TXA and 40 patients received PO TXA. Patient demographic factors were similar between groups except for body mass index (BMI). The mean reduction of hemoglobin was similar between IV and PO groups (3.36 g/dL vs. 3.43 g/dL, respectively; P = 0.01, equivalence). Similarly, the calculated blood loss was equivalent (1235 mL vs. 1312 mL, respectively; P = 0.02, equivalence). Eight patients (19%) in IV TXA group received a transfusion compared with five patients in PO TXA group (13%) (P = 0.44). One patient (2% and 3% in IV and PO, respectively) in each group experienced a deep venous thrombosis/pulmonary embolism (P = 0.96).

Conclusion. Patients treated with IV and PO TXA experienced the same perioperative blood loss after spinal fusions. Given its lower cost, PO TXA represents an excellent alternative to IV TXA in patients undergoing elective posterior thoracolumbar fusion and may improve healthcare cost-efficiency in the studied population.

Level of Evidence: 1

Tranexamic acid (TXA) is widely utilized to decrease operative blood loss and allogenic blood transfusions. This prospective randomized trial compares perioperative blood loss in patients undergoing elective posterior thoracolumbar fusion who were treated with intravenous (IV) versus oral (PO) TXA. Not only is it cheaper, PO TXA was equivalent to IV TXA in reducing blood loss after spinal fusions.

Department of Orthopaedic Surgery, Henry Ford Health System, Detroit, Michigan

Department of Orthopaedic Surgery, University of Maryland, Baltimore, Maryland

Wayne State University School of Medicine, Detroit, Michigan.

Address correspondence and reprint requests to Charles C. Yu, MD, Department of Orthopaedic Surgery, Henry Ford Health System, 2799 West Grand Blvd, Detroit, MI 48202; E-mail: cyu1@hfhs.org

Received 27 July, 2018

Revised 14 October, 2018

Accepted 19 November, 2018

The manuscript submitted does not contain information about medical device(s)/drug(s).

No funds were received in support of this work.

Relevant financial activities outside the submitted work: grants.

Elective thoracolumbar spinal fusion surgery is associated with significant perioperative blood loss frequently requiring allogeneic blood transfusions, thereby increasing the risks of infection, blood incompatibility, and allergic reactions. Historically, several methods of blood conservation have been utilized, such as autologous blood predonation, antifibrinolytic drugs, and red blood cell salvage.1 Tranexamic acid (TXA) is a synthetic amino acid derivative that prevents the activation of plasminogen, stabilizing fibrin clots.2 Clinically, TXA has been shown to reduce perioperative blood loss, as well as the risk of blood transfusion after spinal fusions.3,4 As a result, the use of TXA in spinal fusion surgeries has been increasing in popularity.5–7

TXA can be given intravenously (IV), topically, and orally (PO). Much of the orthopedic literature focuses on the IV formation. There is evidence supporting the use of PO TXA in the gynecologic and recently the adult reconstruction literature.8 Although IV TXA is effective in reducing blood loss,9 it is a costly medication, ranging from $47 to $108 depending on formulation.10 To our knowledge, there is no prospective study comparing perioperative blood loss in patients undergoing elective thoracolumbar spine surgery treated with IV versus PO TXA. Potential advantages of the oral formulation include lower medication cost and ease of administration.

Therefore, the objective of this prospective randomized study was to compare the efficacy of IV and PO routes of TXA on perioperative blood loss and allogeneic blood transfusion rate in adult patients undergoing posterior thoracolumbar instrumented fusion surgery.

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MATERIALS AND METHODS

Study Design and Patients

This study was a single-center, randomized, prospective trial designed to test equivalence between IV and oral TXA in the setting of elective thoracolumbar fusion between February and December 2017. Our institutional review board approved the present study, and it was registered with the public ClinicalTrials.gov registry (NCT03037515). After obtaining informed consent, adult patients (age ≥ 18 yrs old) undergoing elective posterior thoracolumbar instrumented spinal fusions were enrolled in the study. Exclusion criteria included known allergy to TXA, history of renal failure or kidney transplant, history of arterial thromboembolic event (e.g., myocardial infarction, stroke) within the past year, placement of an arterial stent within the past year, a history of thromboembolic event, coagulopathy, or refusal to receive blood products.

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Intervention

Enrolled patients were randomly assigned between the two treatment groups of IV and oral TXA using a random number algorithm. Because the number of fusion levels can influence blood loss, the sample was sub-categorized by the number of vertebral levels arthrodesed (1–2 levels, 3–5 levels, >5 levels). Serum and pharmacokinetic studies have demonstrated that IV TXA reaches therapeutic concentration rapidly but falls below the threshold after 5 hours; PO TXA reaches therapeutic levels after 2 hours and maintains levels above the therapeutic threshold for 6 hours after administration.11 Based on pharmacokinetic data, the oral TXA group received 1950 mg TXA (three tablets of 650 mg) approximately 2 hours before incision. The IV TXA group received the standard dosing for our institution of 1 g TXA (diluted in 100 mL normal saline) given as an IV bolus immediately before incision and another 1 g TXA given before closure.

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Surgical Technique and Postoperative Care

Posterior instrumented spinal fusions were performed prone on a Jackson table with the abdomen free. A forced-air warming device was used to maintain normothermia. A standard open midline approach was utilized, intertransverse fusion beds were prepared uniformly, and pedicle screws were inserted in the standard fashion. When indicated, transforaminal lumbar (TLIF) and direct lateral interbody (DLIF) fusions were also performed per surgeon preference. Before wound closure, hemostasis was achieved and drains were placed routinely. All cases were performed by surgeons with over 25 years experience in spine surgery.

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Blood Management

An autologous blood recovery system (Cell Saver, Haemonetics, MA) was used when requested by the surgeon and salvaged red blood cells (RBCs) were returned to the patient. Suctioned blood from the surgical field was processed and given back to the patient if estimated blood loss (EBL) was greater than 500 mL or at the surgeon's discretion. As a result, not every patient may have been given salvaged RBCs. Intraoperative blood transfusion was given if hemoglobin (Hgb) dropped below 7.0 g/dL or at the anesthesiologist's discretion, such as if patient was unstable despite fluid resuscitation and salvaged RBC replacement. The postoperative transfusion protocol required transfusion for a Hgb level below 7.0 g/dL or if Hgb was between 7.0 and 8.0 g/dL and patients had symptomatic anemia including tachycardia, hypotension, or pallor.

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Data Collection

Patient demographic and preoperative characteristics were documented for comparison between the treatment groups. All patients had postoperative labs including a complete blood count (CBC). Drain outputs were recorded three times a day (per 8 h shift). Drains were discontinued if output was below 30 mL per shift or by the end of postoperative day 2. The recorded characteristics included the following: age, sex, American Society of Anesthesiologists’ physical status classification (ASA), weight, height, body mass index (BMI), and pertinent preoperative laboratory values (prothrombin time/international normalized ratio, creatinine, platelet count, hematocrit, and hemoglobin).

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Outcome Measures

The primary outcome was reduction of Hgb, which was the difference between preoperative and the lowest postoperative Hgb values. Secondary outcomes included calculated blood loss, reduction of hematocrit, drain output, rate of postoperative transfusion, thromboembolic event, infections and length of hospital stay. In addition, intraoperative measures such as case length, calculated blood loss, intravenous fluid received and number receiving intraoperative cell saver, and blood transfusion were investigated. Blood loss was calculated as a function of patient characteristics including sex, weight, and height as well as preoperative and postoperative hemoglobin balance.12–14

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Sample Size and Statistical Analysis

A pretest power analysis determined that 30 patients in each group were needed to show a 1.0 g/dL difference in hemoglobin drop, assuming an equivalence margin of ±1.0 g/dL, 5% alpha error, and 80% power. The primary outcome of Hgb drop and the secondary outcome of calculated blood loss were tested for equivalence using a two one-sided test (TOST). The remaining secondary outcomes and covariates were compared using traditional t tests. Ordinal scale outcome variables were tested using nonparametric methods such as chi-square, Fisher exact test, or Wilcoxon rank sum test. A P-value of <0.05 suggests statistical significance. All data were analyzed by Microsoft Excel 2011 (Microsoft, Seattle, WA) and XLSTAT 2017: Data Analysis and Statistical Solution for Microsoft Excel (Addinsoft, Paris, France).

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RESULTS

During the period of study enrollment from February and December 2017, 100 patients were scheduled for elective thoracolumbar fusion surgery. Seventeen patients were ineligible due to meeting exclusion criteria, refusal to participate or missing pertinent lab values (Figure 1). Among the 83 enrolled study participants who underwent randomization, 43 had IV TXA and 40 had PO TXA. No patient was lost or excluded during the follow-up period. Two orthopedic spine surgeons performed the operations: Gregory Graziano performed majority of the surgeries (89% of total, 93% and 85% for IV and PO, respectively), and Stephen Bartol performed the rest. Standard posterior approach was utilized in all cases except for one DLIF that was performed in the PO group.

Figure 1

Figure 1

The average age of an enrolled patient was 63 ± 13 years (mean ± SD). There were 49 females and 34 males. There were no statistical differences in the patient characteristics and preoperative measurements pertaining to age, sex, weight, height, ASA, estimated blood volume, preoperative anticoagulant use, and pertinent preoperative laboratory values including hemoglobin, hematocrit, international normalized ratio, and creatinine (Table 1). BMI was higher in the PO TXA group (32.1 ± 5.8 kg/m2) than in the IV TXA group (28.5 ± 5.7 kg/m2) (P = 0.006). Furthermore, preoperative platelet count was higher in PO group (240 ± 53 × 103/mm3) than in IV group (205 ± 61 × 103/mm3) (P = 0.008). Revision cases comprised of 59% of the total sample (65% and 53% for IV and PO, respectively). A single level pedicle subtraction osteotomy (PSO) was performed for 12 patients (six in each group) by Gregory Graziano. TLIF was performed for 22 patients (7 and 15 for IV and PO, respectively), and chi-square analysis showed a statistically significant difference (P = 0.03). Intraoperative measures between the treatment groups demonstrated no statistical difference in anesthesia time, surgery time, EBL, IVF, percentage of patients receiving cell saver, and percentage of patients receiving blood transfusion. Overall, the patients within the two treatment groups were considered similar in regard to the measured independent variables (Table 2).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Primary Outcome Measure

The reduction in Hgb was statistically equivalent between IV and PO TXA (Table 3). The reduction in hemoglobin for the IV TXA group was 3.36 ± 1.82 g/dL while the drop in Hgb for the PO TXA group was 3.43 ± 1.75 g/dL (P = 0.01, equivalent).

TABLE 3

TABLE 3

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Secondary Outcome Measures

The calculated blood loss between the IV and PO TXA groups was equivalent (Table 3). On average, the volume of blood loss for the IV and PO TXA groups was 1235 ± 672 mL and 1312 ± 748 mL (P = 0.02, equivalent), respectively. Hematocrit drop between IV and PO TXA groups was also equivalent (Table 3). The change in hematocrit for IV and PO groups was calculated to be 10.0 ± 5.4 and 10.2 ± 5.4 (P = 0.009, equivalent), respectively. Postoperative rate of transfusion, drain output, length of hospital stay, and complications demonstrated no statistical difference between IV and PO TXA groups (Table 3). Total drain output for IV and PO TXA groups was similar at 620 ± 499 mL and 655 ± 607 mL (P = 0.77), respectively. Eight patients (19%) in IV TXA group received a transfusion compared with five patients in PO TXA group (13%) (P = 0.44). One patient (2% and 3% in IV and PO, respectively) in each group experienced a deep venous thrombosis/pulmonary embolism (P = 0.96). Three patients (7%) in IV TXA group had superficial surgical site infection (SSSI), and two patients (5%) had deep surgical site infection (DSSI) (P = 0.71). Length of hospital stay was similar between IV and PO groups, 4.5 ± 2.8 days and 4.1 ± 3.4 days (P = 0.64).

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DISCUSSION

Significant blood loss from spine surgery can lead to allogeneic blood transfusion and other significant complications.15,16 Strategies have been designed to reduce perioperative blood loss in complex spine surgery, such as preoperative administration of EPO, autologous blood predonation, intraoperative cell salvage, controlled hypotension, and use of antifibrinolytic agents.17 The antifibrinolytic medication, TXA, especially in its IV form, has been frequently used in the last few decades in pediatric scoliosis,7,8,18,19 adult spinal deformity,20 and degenerative spine cases.9,21–26 Furthermore, IV TXA has been shown to be safe and effective in reducing blood loss and need for transfusion.27 This is the first study in the spine literature that compares IV versus PO formulations of TXA. We found no difference in the efficacy between the two routes of administration in both the primary outcome of hemoglobin drop and secondary outcomes. PO TXA appears to be as safe as IV TXA in regards to postoperative thromboembolic events and infections. The safety profile of PO TXA is consistent with that of other antifibrinolytic agents reported in previous studies.3,27

TXA can be administered intravenously, topically, and orally. Compared with total joint arthroplasty, spine surgery traditionally has had a preference for intravenous over topical administration due to larger exposures and more extensive dissection. On the other hand, proponents of topical TXA argue that it can provide a maximum concentration at the bleeding site while minimizing systemic absorption. Liang et al28 found that topical TXA combined with Gelfoam was effective in decreasing postoperative drain output, drain duration, and hospital stay compared with both Gelfoam alone and control groups in lumbar spine surgery. Multiple studies have reported the efficacy of IV tranexamic acid in reducing blood loss by 25% to 41% while maintaining a safety profile.8,9 However, the efficacy of PO TXA in spinal fusion surgeries has remained largely unknown. To our knowledge, current orthopedic research comparing IV and PO TXA has been limited to total joints arthroplasty literature.10,29 Their findings are consistent with ours in that there is no difference in TXA efficacy between the IV and PO forms.

Given the ever-changing landscape of medical reimbursement, cost effective health care practice is beneficial to patients, providers, the healthcare system, and society at large. The use of TXA in orthopedic surgery has become a routine practice because it has been shown to be safe, clinically beneficial, and cost-effective.30 Allogeneic blood transfusions carry the risk of transfusion reactions, disease transmission, and increased hospital costs.31–33 In primary total knee arthroplasty (TKA) and total hip arthroplasty (THA), TXA offers not only savings from transfusion costs but also all hospital costs including operating room, laboratory and pharmacy costs, totaling $879 per patient.34–37 Given that PO TXA is cheaper and easier to administer than IV TXA, switching to PO can lead to greater cost savings. In our institution, the oral TXA dosage cost $14 compared with $53 for the generic IV formulation alone (not including the cost of pharmacy preparation). As the American population continues to age, the number of spinal fusion surgeries performed in the United States will likely continue to increase from the current annual rate of about 500,000. Consequently, transitioning to PO TXA has potential to can yield cost savings of at least 20 million dollars per year for the health care system.

Several potential limitations exist in this study. First, the study population contains heterogeneity such as varying patient diagnosis and surgical technique/approach. However, heterogeneity was minimized through sub-stratification of the number of fusion levels into three categories. Posterior approach was mostly used (100% and 98% for IV and PO, respectively), and a single surgeon performed most of the cases (93% and 85% for IV and PO, respectively). Second, blood loss calculation was based on the lowest postoperative hemoglobin value, which may be inaccurate due to hemodilution if the patient was discharged before postoperative day 5.38 However, change in hematocrit was similar for IV and PO groups. Lastly, we did not perform individual analysis in the three subgroups (1–2 levels, 3–5 levels, >5 levels) because of lack of adequate statistical power. Despite these limitations, the validity of our results should be maintained, as the same methodology was applied to both treatment arms and length of stay was not different between the two groups.

Another potential limitation is that we did not include a placebo group and assumed that PO TXA was superior to placebo based on arthroplasty literature.5,39 We believe that using the standard IV formulation as a control instead of a pure placebo was more clinically useful. Additionally, because perioperative bleeding during spine surgery is multifactorial and can be more significant than TKA or THA,40 we would put patients at increased risk for blood loss if we did not give TXA. Additionally, administration of TXA in spine surgery is already emerging as the standard of care, and this study is an attempt to optimize current standards. Strengths of this study include that it was completed at a single center and by a single surgeon predominantly.

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CONCLUSION

In conclusion, in the setting of spine thoracolumbar fusions, oral tranexamic acid produced an equivalent reduction in hemoglobin and blood loss compared with its intravenous counterpart. Given the equivalent clinical outcomes, potential cost savings, and the ease of drug administration, oral tranexamic acid is a superior alternative to intravenous tranexamic acid.

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References

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Keywords:

allogeneic blood transfusion; blood loss; healthcare cost efficiency; spinal fusion; tranexamic acid

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