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evident
Original paper
2022NEJMSurgery/Perioperative

POISE-3

Tranexamic Acid in Patients Undergoing Noncardiac Surgery

RCTPerioperative medicine

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Overview

In noncardiac surgery, TXA reduced 30-day composite bleeding versus placebo; cardiovascular noninferiority was not established.

Clinical takeaway

TXA lowered the 30-day composite bleeding outcome. The composite cardiovascular safety outcome was close between groups, but the trial did not establish noninferiority on that safety end point.

Key result

Composite bleeding occurred in 9.1% with TXA vs 11.7% with placebo (HR 0.76, 95% CI 0.67-0.87; P<0.001 for superiority). Composite cardiovascular events were 14.2% vs 13.9% (HR 1.02, 95% CI 0.92-1.14); noninferiority was not established.

Practice impact

TXA can reduce a 30-day composite bleeding outcome in noncardiac surgery; do not treat cardiovascular safety as proven noninferior.

Evidence

Study design

Randomized trial of tranexamic acid versus placebo at the start and end of noncardiac surgery, with a partial factorial hypotension-avoidance versus hypertension-avoidance comparison that is not reported here.

Enrollment

9,535

Follow-up

30 days.

Geography

Not listed

Clinical question

Does perioperative tranexamic acid reduce a 30-day composite bleeding outcome in noncardiac surgery, and is it noninferior to placebo for a 30-day composite cardiovascular outcome?

Population

  • Patients undergoing noncardiac surgery.

Intervention

Tranexamic acid 1 g intravenous bolus at the start and end of surgery.

Comparator

Placebo at the start and end of surgery.

Primary outcome

Primary efficacy outcome: composite of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days. Primary safety outcome: composite of myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism at 30 days.

Tranexamic acid reduced the 30-day composite bleeding outcome versus placebo. Noninferiority for the 30-day composite cardiovascular safety outcome was not established (HR 1.02, 95% CI 0.92-1.14; upper one-sided 97.5% CI 1.14).

Hazard ratio / 0.76 / 95% CI 0.67-0.87 / p<0.001

Key results

  • Among 9535 randomized patients, a composite bleeding event occurred in 433 of 4757 (9.1%) with tranexamic acid vs 561 of 4778 (11.7%) with placebo; hazard ratio 0.76 (95% CI 0.67-0.87); absolute difference -2.6 percentage points (95% CI -3.8 to -1.4); two-sided P<0.001 for superiority.
  • A composite cardiovascular event occurred in 649 of 4581 (14.2%) with tranexamic acid vs 639 of 4601 (13.9%) with placebo; hazard ratio 1.02 (95% CI 0.92-1.14); upper boundary of the one-sided 97.5% CI 1.14; absolute difference 0.3 percentage points (95% CI -1.1 to 1.7); one-sided P=0.04 for noninferiority.
  • Noninferiority for the cardiovascular composite required the upper boundary of the one-sided 97.5% CI for the hazard ratio to be below 1.125 and a one-sided P value below 0.025; those criteria were not met, so noninferiority was not established.

Harms

  • The primary safety outcome was the 30-day composite cardiovascular event, analyzed in 4581 patients assigned to tranexamic acid and 4601 assigned to placebo, a smaller set than the 9535 randomized patients used for the bleeding comparison.
  • The cardiovascular composite was 14.2% with tranexamic acid vs 13.9% with placebo (HR 1.02, 95% CI 0.92-1.14). The between-group difference was small, but noninferiority was not established.

Clinical Use

Practice impact

  • Tranexamic acid at the start and end of noncardiac surgery reduced a 30-day composite bleeding outcome versus placebo.
  • Do not cite POISE-3 as proof that tranexamic acid is noninferior for the composite cardiovascular safety outcome; that bar was not met.

Applicability

  • Most applicable to patients undergoing noncardiac surgery in whom a 1 g intravenous bolus of tranexamic acid can be given at the start and end of surgery.

Limitations

  • The hypotension-avoidance versus hypertension-avoidance factorial comparison is not reported in this paper.
  • The cardiovascular composite was assessed in 4581 and 4601 patients, not in all 9535 who underwent randomization.
  • Noninferiority required an upper one-sided 97.5% CI for the hazard ratio below 1.125 and a one-sided P value below 0.025; the observed upper bound was 1.14 and the one-sided P value was 0.04.

Common misinterpretations

  • A small absolute difference in the cardiovascular composite is not the same as established noninferiority.
  • The bleeding result is a superiority finding on the efficacy composite; it does not settle the safety question the trial set for itself.

Related evidence

POISE - Earlier TrialPOISE-2 - Earlier TrialCRASH-2 - Same Drug Class

Citation

Devereaux PJ, Marcucci M, Painter TW, et al. Tranexamic Acid in Patients Undergoing Noncardiac Surgery. N Engl J Med. 2022;386(21):1986-1997. doi:10.1056/NEJMoa2201171

Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established.