POISE-3

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Devereaux PJ, et al. "Tranexamic Acid in Patients Undergoing Noncardiac Surgery". NEJM. 2022. :.
PubMedFull textClinicalTrials.gov

Clinical Question

In adults with known risk factors for bleeding and cardiovascular complication receiving noncardiac surgery, did tranexamic acid bolus before and after surgery decrease risk of bleeding without increasing risk of myocardial or thrombotic complications within 30 days.

Bottom Line

Incidence of bleeding outcomes was significantly lower when patients received tranexamic acid, however, the non-inferior margin for cardiovascular outcomes was not met.

Major Points

A common issue, perioperative bleeding may increase risk of morbidity, mortality, and impacts to the rest of the healthcare system. Tranexamic acid, an antifibrinolytic through inhibition of proteolytic activity of plasmin and displacement of plasminogen from fibrin, has evidence to support its use in trauma CRASH-2, nose bleedsTXA for Epistaxis, topically,[1] or gynecological bleeding. [2]

In the PeriOperative ISchemic Evaluation-3 (POISE-3) study, a multicentered, double-blind, RCT, set in 114 sites across 22 countries from 2018-2021, the randomized patients to receive either 1g IV bolus of tranexamic acid (TXA) at the beginning and end of surgery (n=4757) or matched placebo (n=4778). The primary outcome of a composite of life-threatening bleeding, major bleeding, and bleeding into a critical organ at 30 days, occurred less in the TXA (9.1%) as compared to the placebo (11.7%) group (HR 0.76; 95% CI 0.67-0.87; p < 0.001). The composite safety outcome of myocardial infarction, isolated ischemic troponin elevation, non-hemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism at 30 days also occurred more often in the TXA exposed group (14.2% vs. 13.9% [HR 1.02; 95%CI 0.92–1.14; p = 0.04]).

This trial was stopped early due to challenges with recruitment from the COVID-19 pandemic, with a revised power calculation decreasing to 90%, the investigators met their new sample size calculation. With a relatively short half-life (2-11 hours) the drug is primarily renally excreted. Whereas patients with severe renal dysfunction were excluded, analysis based on renal function may have offered deeper understanding of the risk and outcomes.

Guidelines

As of April 2022, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, randomized, controlled trial
  • N=9535
    • Peri-operative Tranexamic Acid (n=4757)
    • Placebo (n=4778)
  • Setting: 114 sites in 22 countries
  • Enrollment: June 2018 – July 2021
  • Follow-up: 30 day
  • Analysis: Per-protocol
  • Primary Outcome: composite of life-threatening bleeding, major bleeding, and bleeding into a critical organ at 30 days

Population

Inclusion Criteria

  • age ≥ 45 years
  • inpatient non-cardiac surgery
  • risk of bleeding / cardiovascular complications:
    • known atherosclerotic disease
    • undergoing major surgery
    • age ≥70 years
    • serum creatinine >175 μmol/L [2.0 mg/dL]

Exclusion Criteria

  • cardiac or intracranial surgery
  • physician planned administration of study drug during surgery
  • eGFR <30 mL/min (Cockcroft–Gault equation)
  • receiving long-term dialysis.

Baseline Characteristics

Tranexamic Acid Group displayed

  • Demographics: mean age 69.5 years, 43.9% female
  • Medical history: 14% Heart failure, 29.6% CAD, 8.4%Stroke, 5.9% TIA, 90.2% Hypertension, 10% Atrial fibrillation, 27.6% Active cancer
  • Surgery: 37% general, 22.9% orthopedic, 14.8% vascular, 12.6% urologic, 5% spinal, 3.4% gynecologic, 2.7% thoracic, 0.3% plastic
  • Medications taken within 24hrs of surgery: 0.5% Therapeutic DOAC, 0.1% vitamin-K antagonist, 1.2% therapeutic parenteral antithombotic, 15.8% prophylactic anticoagulant
    • 13.4% ASA, 1.8% P2Y12 inhibitor, 5.6% NSAID, COX-2 inhibitor 2.8%
  • Post-surgery thromboembolism prophylactic medication: 64.2%

Interventions

  • Tranexamic acid 1g IV bolus both at beginning and end of surgery
  • Matched placebo

Outcomes

Comparisons are Tranexamic Acid vs. Placebo.

Primary Outcomes

Composite of life-threatening bleeding, major bleeding, and bleeding into a critical organ at 30 days
9.1% vs. 11.7% (HR 0.76; 95% CI 0.67-0.87) p < 0.001

Secondary Outcomes

Life threatening bleeding at 30 days
1.6% vs. 1.7% (HR 0.99; 95% CI 0.73–1.36)
Major bleeding at 30 days
7.6% vs. 10.4% (HR 0.72; 95% CI 0.63–0.83)
Bleeding into critical organ
0.3% vs. 0.4% (HR0.57; 95% CI 0.28–1.16)
Bleeding independently associated with death after noncardiac surgery
8.7% vs. 11.3% (HR 0.76; 95%CI 0.67–0.87)
Net risk–benefit outcome, composite of death from cardiovascular causes, nonfatal life-threatening bleeding, major bleeding, bleeding into a critical organ, myocardial injury after noncardiac surgery, stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism
20.7% vs. 21.9% (HR 0.94; 95%CI 0.86–1.02)

Adverse Events

Composite of myocardial infarction, isolated ischemic troponin elevation, non-hemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism at 30 days
14.2% vs. 13.9% (HR 1.02; 95%CI 0.92–1.14) p = 0.04

Criticisms

  • recruitment was stopped early due to slow enrollment associated with COVID-19 pandemic
  • analysis of renal function may have given deeper understanding of risk straticification

Funding

  • Canadian Institutes of Health Research Foundation Grant (FDN-143302)
  • Australian National Health and Medical Research Council Project Grant (1162362)
  • General Research Fund Grant (14104419)
  • Hong Kong Research Grant Council
  • Population Health Research Institute

Further Reading