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A dose of tranexamic acid to start and end noncardiac surgery reduced important bleeding events, the POISE-3 trial showed, albeit with a question mark hanging over cardiovascular risk.

The antifibrinolytic drug cut life-threatening, major, or critical organ bleeding by a relative 24% at 30 days compared with placebo (9.1% vs 11.7%, P<0.001), reported P.J. Devereaux, MD, PhD, of the Population Health Research Institute at McMaster University in Hamilton, Ontario, at the American College of Cardiology (ACC) meeting, held virtually and in Washington.

The effect size was similar for fatal bleeds, major bleeds based on International Society on Thrombosis and Haemostasis definition, and transfusion of packed red cells, Devereaux's group reported simultaneously in the .

However, the primary safety endpoint -- a composite of myocardial injury, nonhemorrhagic stroke, peripheral artery thrombosis, or symptomatic proximal venous at 30 days -- just missed non-inferiority.

The absolute 0.3 percentage point difference between groups (14.2% tranexamic acid vs 13.9% placebo) didn't meet the non-inferiority criterion for the confidence interval upper bound (1.14 vs <1.125 as required in the statistical plan) or for the P-value (P=0.04 vs the required <0.025).

"Health care providers and patients will have to weigh a clear beneficial reduction in the incidence of composite bleeding outcome events...against the low probability of a small increase in the incidence of composite cardiovascular outcome events," (absolute difference -2.6 percentage points, 95% CI -3.8 to -1.4), the researchers wrote.

However, the 95.6% probability that the primary safety endpoint was within the needed range for non-inferiority was an "adequate safety signal," said ACC discussant Joseph Cleveland, MD, of the University of Colorado in Aurora, at a press conference.

POISE-3 results carry the potential for "large public health and clinical benefits if tranexamic acid becomes standard practice in noncardiac surgery," given that surgical bleeding accounts for some 40% of all transfusions, Devereaux's group noted.

And it adds to evidence from large trials in cesarean section and in that also have shown reduced incidence and severity of bleeding, they added. Small trials had also provided supportive data in .

Orthopedic surgery is the one noncardiac surgical specialty where there has been some uptake, Devereaux noted.

Results were consistent across patient subgroups, including for orthopedic versus nonorthopedic surgery and for each individual type of surgery considered.

The heterogeneity in types of major operations -- intrathoracic, intraabdominal, retroperitoneal, vascular, and orthopedic -- and inclusion of nonmajor surgeries as some 20% of the procedures -- was surprising, commented ACC discussant Michael Mack, MD, of Baylor Scott & White Health System in Plano, Texas.

I would be a little concerned or hesitant to recommend it in the 20% of nonmajor procedures -- plastic surgery, urology, some of these other procedures that aren't really at risk for major bleeding," he said.

Nevertheless, "This should be more widely used in noncardiac surgery," Mack stated.

Devereaux responded that even among the urology procedures in the trial, bleeding was "reasonably common" and reduced by a similar degree with tranexamic acid as in the overall cohort.

"That does not mean that we're talking about a low-risk, day surgery that this has to happen," he said. "I just want to remind people that in the surgical setting, we often are underestimating the true risk of events."

Also, tranexamic acid is such an that the economics of it are important in preventing what can be expensive episodes of care for bleeding events, he added.

The Perioperative Ischemic Evaluation-3 () trial randomly assigned 9,535 patients undergoing noncardiac surgery at 114 hospitals across six continents to double-blind treatment with tranexamic acid (1-g IV bolus) or placebo at the start and end of surgery. Patients were ages 45 or older and deemed at risk of bleeding and vascular complications, with those having intracranial neurosurgery or on chronic dialysis excluded. No nonhospital surgical centers or outpatient procedures were included.

Most of the patients had nonorthopedic surgery (77%) and got prophylaxis for venous thromboembolism after surgery (64%). Average age of the participants was 69; 43.9% were women; and 75.9% were white, with 31% enrolled in North America, 40% in Europe, and the rest in the Asia-Pacific region.

The trial had a partial factorial design to randomize patients on long-term antihypertensive medication to compare strategies aimed to avoid hypotension versus hypertension, the results of which are slated for presentation later at the ACC meeting.

One limitation was that the trial was stopped before the last 4% of the planned sample size could be enrolled "owing to a financial deficit resulting from slowed recruitment during the Covid-19 pandemic," the authors stated.

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