Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Abstract

Background: For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes.

Methods: The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization.

Discussion: Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality.

Trial registration: ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.

Keywords: Cardiovascular complications; Noncardiac surgery; Perioperative bleeding; Perioperative hypotension; Randomized controlled trial; Tranexamic acid.

Conflict of interest statement

ED acknowledges Investigator initiated research grants from Roche Diagnostics, Abbott Laboratories and Boehringer Ingelheim; lecture fee and honoraria for participation in advisory board meeting by Roche Diagnostics; support by a Fonds de Recherche en Sante du Quebec salary award. MJM-Z is supported by a Miguel Servet II research contract from the ISCIII (CP1120/00023), Spain. CSM: has co-founded a start-up company, WARD247 ApS, with the aim of pursuing the regulatory and commercial activities of the WARD-project, an Innovation Fund Denmark funded research project on wireless vital signs. CSM also reports direct and indirect research funding to his department from Ferring Pharmaceuticals, Merck, Sharp & Dohme Corp. and Boehringer Ingelheim outside the submitted work as well as lecture fees from Radiometer. DT received speaker honorarium from 3 M and Pfizer. EB-C received grants from Bayer, Roche, and BMS-Pfizer. AP acknowledges to have provided expertise and have been speaker for Laboratory Edwards, 3 M, and MSD laboratories; to have been speaker for Pfizer. AXG is supported by the Dr. Adam Linton Chair in Kidney Health Analytics. PLG has received speaker fees from Bayer, Bristol-Myers-Squibb, Pfizer, Leo Pharma and Valeo. TR reports grants from UK, NIHR HTA; grants from Australian, NHMRC; grants, personal fees and non-financial support from Pharmocosmos; grants, personal fees and non-financial support from Vifor Pharma; grants from UK, NIHR EME; grants from Australian MRFF; grants from Western Australia FHRF; grants and personal fees from Pfizer Australia; personal fees from BioAge Labs, outside the submitted work; and TR is a regular speaker at national and international conferences on anemia, blood transfusion, wound healing and vascular diseases for which he has received expenses for travel, accommodation and sundries. TR has worked with several agencies promoting meetings or healthcare. TR is a director of The Iron Clinic Ltd and director of Veincare London Ltd & Veincare WA also TR is the Vascular lead for 18-week wait Ltd. All the other co-authors report no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1

The POISE-3 trial flow chart

Fig. 2

Algorithm for management of the patient antihypertensive medications in the hypotension avoidance strategy arm. SBP, systolic blood pressure; ACEi, angiotensin-converting-enzyme inhibitors; ARB, angiotensin II receptor blockers; HR, heart rate; CCB, calcium channel blockers; BP, blood pressure

Fig. 3

SPIRIT figure: participant timeline. Superscript lowercase letter “a” indicates the following: in most centers randomization occurs on the day of surgery prior to the procedure, and always within 24 h before the planned surgery. Superscript lowercase letter “b” indicates the following: in the table, days + 1, + 2, and + 3 refer to days + 1, + 2, and + 3 with respect to the day of surgery. Since randomization most often occurs on the day of surgery prior to the procedure, if surgery is not delayed or canceled, days + 1, + 2, and + 3 after randomization do correspond to postoperative days 1–3