For the antifibrinolytic agent tranexamic acid, doses varying between 5 and 15 mg/kg failed to produce a dose-dependent drop in hemoglobin after total knee (TKA) or total hip arthroplasty (THA), leading study investigators to recommend using the lowest of these doses in orthopedic patients.
“At my institution, we reviewed quite a bit of data while trying to create a joint replacement surgery protocol,” said Robert B. Maniker, MD, assistant professor of anesthesiology at NewYork-Presbyterian Hospital/Columbia University Medical Center, in New York City. “We realized that, although various drug-timing regimens have been compared, there were really no good dose-finding studies in the orthopedic surgery literature.” Furthermore, although there is evidence that administering two perioperative doses is superior to a single bolus, no dose-finding study exists using a two-bolus regimen for joint replacement.
Three Doses Tested
In this study, the investigators evaluated three doses of tranexamic acid administered for THA and TKA performed under spinal anesthesia. They hypothesized that increasing the dose of the agent would correlate with a smaller drop in hemoglobin.
A total of 84 adult patients participated in the trial, 51 of whom underwent primary unilateral THA and 33 primary unilateral TKA. Each patient received a standardized spinal anesthetic with 15 mg plain isobaric bupivacaine. Patients were then randomly assigned to receive one of three tranexamic acid doses 20 minutes before incision and again at wound closure: 5, 10 and 15 mg/kg.
The study’s main outcome was absolute change in hemoglobin preoperatively to postoperative day 1. Several secondary outcomes were analyzed, including hemoglobin change from preoperative to immediately after surgery and postoperative day 2; intraoperative crystalloid volume; estimated blood loss; postoperative mobility; pain and well-being scores; and incidence of adverse events.
“Currently, a typical dosing regimen for tranexamic acid is two doses of 10 mg/kg,” Dr. Maniker said in an interview with Anesthesiology News. “That’s what we used as our baseline, then evaluated a higher and lower dose using the same two-bolus technique. In the grand scheme of things, that’s still a pretty narrow dose range, but we thought it was a good place to start.”
No Dose Effect
As Dr. Maniker reported at the 2016 annual meeting of the American Society of Regional Anesthesia and Pain Medicine (abstract 1512), the average baseline hemoglobin level for all patients before surgery was 13.0 g/dL. The average hemoglobin level immediately after surgery and on postoperative days 1 and 2 was 11.8, 10.9 and 10.5 g/dL, respectively (P<0.01).
Two patients were converted to general anesthesia for reasons unrelated to the study intervention; they remained in the study and data analysis under the intention-to-treat principle.
The average drop in hemoglobin from before surgery to postoperative day 1 was 2.15 g/dL for the 5-mg/kg dose group, 2.06 g/dL for the 10-mg/kg group and 2.11 g/dL for the 15-mg/kg group (P=0.87).
Similarly, no differences were found between groups in hemoglobin reduction from the preoperative level to immediately after surgery or postoperative day 2, or when stratified on surgery type or surgeon.
“We were a bit surprised by these results,” Dr. Maniker said. “What proved even more surprising was the lack of even a trend toward a dose effect between the three groups.”
No differences were found between groups in estimated blood loss; crystalloid volume; postoperative mobility; or pain and well-being scores. A pulmonary embolus occurred in a patient receiving 15 mg/kg tranexamic acid.
“We can’t make any conclusions about that since it’s just one isolated case and is a known complication of this surgery, even in patients who do not receive the drug,” Dr. Maniker explained. “This population is at fairly high risk for blood clots.”
No myocardial events, cerebrovascular events, seizure or isolated deep venous thrombosis occurred. A THA patient in the 5-mg/kg dose group was transfused one unit of red blood cells on postoperative day 1 for a hemoglobin value of 6.3 g/dL. No other patients were transfused a blood product.
Higher Dose Unnecessary
Given these results, Dr. Maniker suggests starting these patients on the lowest tranexamic acid dose possible. “There really isn’t much evidence to support higher doses in this population; hopefully we’ll have even more literature in the future to determine the optimal dose. But starting with something in the range of 5 to 10 mg/kg in two doses perioperatively is reasonable, especially if you’re concerned about cost and a little gun-shy about the drug. The goal is to get the effect you want at the lowest possible dose.”
Stavros G. Memtsoudis, MD, PhD, said he found the results of the study interesting, although not particularly surprising.
“Given the at least theoretical concern that tranexamic acid may increase the risk of prothrombotic events like [deep venous thrombosis, pulmonary embolism, myocardial infarction] and strokes, it is imperative to try to minimize risk by reducing doses to the minimum effective dose,” he pointed out. “Of course, this assumes that the risk of tranexamic acid–mediated prothrombotic events is both significant in clinical terms and dose dependent.”
Dr. Memtsoudis, clinical professor of anesthesiology and public health at Weill Cornell Medical College, New York City, noted that other approaches to minimizing blood levels of tranexamic acid have been tested with great success. “For example,” he said, “the topical application of tranexamic acid in the wound has been shown to be as effective as IV administration, with the advantage of maximizing local concentrations of the drug and minimizing systemic absorption.”
What is missing at this time, he added, is a clear link between systemic drug concentrations and risk for prothrombotic events. “The problem is that the population at highest risk for these events, such as patients with previous [myocardial infarctions] and strokes, may also be the one that would most benefit from reduced blood loss.”