No Effect of Tranexamic Acid on Bleeding in Surgery for Liver Cancer

Tranexamic acid (TXA) failed to reduce the need for red blood cell (RBC) transfusion following surgery for liver cancer, including colorectal liver metastases, the placebo-controlled HeLiX trial showed.

RBC transfusion rates were 16.3% with TXA and 14.5% with placebo. Intraoperative and total blood loss also did not differ significantly between the groups. Additionally, patients who received TXA had significantly more complications.

The outcome contrasts with positive results from recent trials of TXA in traumatic brain injury, cardiac surgery, and a variety of noncardiac surgeries, reported Paul J. Karanicolas, MD, PhD, of Sunnybrook Health Sciences Centre in Toronto, and co-authors in JAMA.

“This trial demonstrated no improvement in blood transfusion, bleeding, or other perioperative outcomes in patients undergoing liver resection for a cancer-related indication treated with tranexamic acid versus placebo,” the authors wrote in their conclusions. “Participants treated with tranexamic acid had increased overall complications and major complications in particular. These considerations should give pause to routine use of tranexamic acid in liver resection.”

“The HeLiX trial results further suggest avenues for future research,” they added. “In particular, the effect of tranexamic acid on bleeding and postoperative complications in patients undergoing other operations, such as gastrectomy, pancreatectomy, sarcoma resection, and other major cancer surgery requires investigation.”

The data did not identify any subgroups who benefited from TXA, Karanicolas told MedPage Today. The results conflicted with a retrospective analysis in which he and his colleagues found a beneficial effect of TXA during resection of colorectal liver metastases.

“The retrospective design of the study introduces several potential biases, most importantly the potential for unmeasured confounders,” he said. “The use of TXA in clinical practice has changed over time, and was likely used more in higher-risk patients. Although the association between TXA use and RBC transfusion was compelling in our retrospective study, we were not convinced the relationship was causative, and hence, we proceeded to this definitive randomized trial. The difference seen between these two studies speaks to the strong need for randomized trials even in the setting of compelling observational data.”

Whether the results apply to other types of cancer surgery remains open to speculation.

“There is no question that TXA reduces bleeding and blood transfusion in a wide range of surgical procedures — most notably orthopedic and cardiac surgery,” said Karanicolas. “Very little evidence supports its use in major oncologic surgery, where the mechanisms of bleeding and risk factors for thromboses are different. We hypothesize that TXA may not be effective in operations for other types of cancer, although this needs to be tested in future trials.”

Multiple studies have shown that TXA significantly reduces the probability of receiving a blood transfusion for a variety of surgical procedures. However, most of the data have come from studies involving cardiac and orthopedic surgery wherein “bleeding often occurs as oozing from small vessels in raw surfaces,” the authors noted in their introduction. In contrast, bleeding from major abdominal surgery, such as liver resection, often comes from large blood vessels.

Existing evidence has also suggested no increased risk of thrombotic events, but little information supports use of TXA in patients undergoing surgery for cancer, which carries a higher risk of venous thromboembolism, which might be propagated by TXA, they continued. As a result of the limitations, most patients in North America do not receive TXA prior to liver resection.

The HeLiX trial compared the effects of TXA or placebo on RBC transfusion and perioperative complications in patients undergoing liver resection related to malignancy. Investigators at 11 participating centers enrolled patients scheduled for open or minimally invasive liver resection for a cancer-related indication and randomly allocated them to TXA or placebo. The primary endpoint was RBC transfusion within 7 days of surgery.

Data analysis included 1,245 patients, 56.1% of whom had a diagnosis of colorectal liver metastases. The study population had a mean age of 63.2, and women accounted for 39.8% of the patients. Perioperative characteristics were similar between the two groups.

The primary analysis showed no significant difference in receipt of RBC transfusions (OR 1.15, 95% CI 0.84-1.56). Measured blood loss was 817.3 mL with TXA and 836.7 mL with placebo (P=0.75), and total estimated blood loss over 7 days was 1,504.0 versus 1,551.2 mL, respectively (P=0.38).

Use of TXA was associated with a higher likelihood of complications (OR 1.28, 95% CI 1.02-1.60, P=0.03), but the incidence of venous thromboembolism did not differ significantly between the groups (OR 1.68, 95% CI 0.95-3.07).

Other trials that have shown no effect of TXA on RBC transfusion support the hypothesis that differing sources of bleeding account for differing outcomes among prior studies. The HALT-IT trial, which involved 12,009 randomized patients with acute gastrointestinal bleeding, showed no effect of TXA on bleeding-related death. A recent trial of prophylactic TXA to prevent obstetrical hemorrhage after Cesarean delivery showed no significant impact on the outcome of maternal death or blood transfusion.

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