In Noncardiac Surgery, Reduced Bleeding Events With Tranexamic Acid

Originally published by our sister publication Anesthesiology News

The largest trial of tranexamic acid (TXA) ever performed has shed much-needed light on the drug’s cardiovascular effects in patients undergoing major noncardiac surgery, and the results are somewhat surprising.

The POISE-3 (PeriOperative ISchemic Evaluation-3) trial concluded that patients treated with TXA not only had significantly fewer serious bleeding events than those treated with placebo, but also did not suffer more cardiovascular injury.

“There is no question that TXA reduces bleeding,” explained Daniel I. Sessler, MD, the Michael Cudahy Professor and Chair of the Department of Outcomes Research at Cleveland Clinic, “but whether the drug also prevents serious bleeding complications was less obvious. An equally important question is whether the drug promotes cardiovascular complications.

“The most common perioperative cardiovascular complication is myocardial injury, which is thought to result from supply–demand mismatch and coronary clotting,” he said. “A drug that promotes clotting—including clotting in coronary arteries—might therefore worsen myocardial injury. If TXA worsens cardiovascular outcomes, reduced bleeding might not be a good trade-off in many patients.”

Multicenter International Trial

The trial comprised 9,535 noncardiac surgery inpatients presenting at 114 hospitals in 22 countries between June 2018 and July 2021, all of whom were at least 45 years of age and at risk for perioperative bleeding and cardiovascular complications. Patients were excluded if scheduled for intracranial neurosurgery, TXA administration was planned by the surgeon, or had serious renal disease.

Participants were randomized to receive either a 1-g IV bolus of TXA or placebo before and after surgery. The study’s primary efficacy outcome was a composite of life-threatening bleeding, major bleeding or bleeding into a critical organ at 30 days. Its primary safety outcome was a composite of myocardial injury, nonhemorrhagic stroke, peripheral arterial thrombosis or symptomatic proximal venous thromboembolism at 30 days.

Reporting in The New England Journal of Medicine (2022;386[21]:1986-1997), the investigators revealed that a composite bleeding event occurred in 433 of the 4,757 patients (9.1%) treated with TXA, compared with 561 of the 4,778 (11.7%) who received placebo (hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.001 for superiority).

“This is a highly statistically significant and clinically meaningful outcome,” Sessler said.

Comparable results were found for major bleeding (HR, 0.72; 95% CI, 0.63-0.83) and bleeding into a critical organ (HR, 0.57; 95% CI, 0.28-1.16), although not for life-threatening bleeding (HR, 0.99; 95% CI, 0.73-1.36).

Composite cardiovascular events occurred in 649 of 4,581 patients (14.2%) in the TXA group and 639 of 4,601 (13.9%) who received placebo (HR, 1.02; 95% CI, 0.92-1.14; P=0.04 for noninferiority).

“Although the trial did not formally establish noninferiority, the absolute difference between the groups was trivial and not clinically meaningful,” Sessler noted. “TXA did not worsen cardiovascular outcomes, most of which were myocardial injury.”

Indeed, the incidence of nonhemorrhagic stroke, peripheral arterial thrombosis and symptomatic proximal venous thromboembolism was less than 1% in both the treatment and control groups.

Analyses of secondary outcomes found that bleeding independently associated with death after surgery was less common among TXA patients (8.7% vs. 11.3%; HR, 0.76), while the incidence of myocardial infarction was more common in TXA patients (1.4% vs. 1.1%; HR, 1.27). Finally, a net risk–benefit outcome event—defined as a composite of death from cardiovascular causes, nonfatal life-threatening bleeding, major bleeding, bleeding into a critical organ, myocardial injury, stroke, peripheral arterial thrombosis and symptomatic proximal venous thromboembolism—occurred in 20.7% of TXA patients and 21.9% of controls (HR, 0.94).

As Sessler noted, one of the primary strengths of POISE-3 was its size. “The effect of TXA on cardiovascular outcomes would not show up in a small study,” he said. “The strength of POISE-3 is that it was large enough to robustly evaluate cardiovascular complications. POISE-3 shows that tranexamic acid reduces bleeding-related complications without worsening cardiovascular outcomes.”

Given these findings, the investigators encouraged its use in noncardiac surgical patients.

“TXA should probably be used more often than it currently is,” Sessler explained. “The drug is safe and it’s inexpensive, and our results suggest that a fair fraction of surgical patients should get it.

“A lot of bleeding is predictable,” he continued. “For example, there are operations like spine surgery where bleeding is predictable. But one thing you might conclude from POISE-3 is that major bleeding and bleeding into critical organs is often unpredictable, yet life-threatening when it does occur.”

Large Trial With Many Surgeries

Steven M. Frank, MD, said the study offers the first “solid evidence” that TXA is effective in reducing bleeding and transfusion—outside of cardiac, orthopedic and trauma surgery—or postpartum hemorrhage.

“This study included a huge number of patients having a wide variety of surgeries, both of which are important for assessing safety outcomes,” commented Frank, the director of the Johns Hopkins Health System Blood Management Program and director of the Center for Bloodless Medicine and Surgery at Johns Hopkins Medicine, in Baltimore. “It is therefore reassuring that the impact of TXA in promoting cardiovascular events was not clinically significant.

“We should all recognize, however, that surgical procedures have become more and more minimally invasive, with robotic and laparoscopic approaches dramatically reducing blood loss and transfusion rates,” Frank added. “Thus, clinical judgment should prevail when deciding whether the bleeding risk for a given surgery justifies using TXA.”

—Michael Vlessides

Frank and Sessler reported no relevant financial disclosures. The POISE-3 trial was led by P.J. Devereaux, MD, PhD, the director of cardiology at the Population Health Research Institute of McMaster University, in Hamilton, Ontario.