PeriOperative ISchemic Evaluation-3 Trial

Study Overview
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Brief Summary
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This study is a multicentre, international, randomized controlled trial of tranexamic acid (TXA) versus placebo and, using a partial factorial design, of a perioperative hypotension-avoidance versus hypertension-avoidance strategy.

Detailed Description
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The POISE-3 study is a 10,000 patient, multicentre, international, non-inferiority randomized controlled trial of tranexamic acid (TXA) versus placebo and, using a partial factorial design, of a perioperative hypotension-avoidance versus hypertension-avoidance strategy. The primary objective of the study is to determine; if TXA is superior to placebo for the occurrence of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic event; and to determine the impact of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of vascular death and major vascular events in patients who are followed for 30 days after noncardiac surgery.

Official Title
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PeriOperative ISchemic Evaluation-3 Trial

Conditions
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Perioperative Bleeding, Venous Thrombosis, Arterial Thrombosis

Intervention / Treatment
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* Drug: Tranexamic Acid
* Drug: Placebo (Saline)
* Other: Perioperative hypotension-avoidance strategy
* Other: Perioperative hypertension-avoidance strategy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Undergoing noncardiac surgery; ≥ 45 years of age; Expected to require at least an overnight hospital admission after surgery; Provide written informed consent to participate in the POISE-3 Trial, AND Fulfill ≥1 of the following 6 criteria (A-F): A. NT-proBNP ≥200 ng/L B. History of coronary artery disease C. History of peripheral arterial disease D. History of stroke E. Undergoing major vascular surgery; OR F. Any 3 of 9 risk criteria i. Undergoing major surgery; ii. History of congestive heart failure; iii. History of a transient ischemic attack; iv. Diabetes and currently taking an oral hypoglycemic agent or insulin; v. Age >70 years; vi. History of hypertension; vii. Serum creatinine > 175 µmol/L (> 2.0 mg/dl); viii. History of smoking within 2 years of surgery; ix. Undergoing emergent/urgent surgery. Exclusion criteria: Patients undergoing cardiac surgery Patients undergoing cranial neurosurgery Planned use of systemic TXA during surgery Low-risk surgical procedure (based on individual physician's judgment) Hypersensitivity or known allergy to TXA Creatinine clearance <30 mL/min (Cockcroft-Gault equation) or on chronic dialysis History of seizure disorder Patients with recent stroke, myocardial infarction, acute arterial thrombosis or venous thromboembolism (<3 month) Patients with fibrinolytic conditions following consumption coagulopathy Patients with subarachnoid hemorrhage within the past 30 days Women of childbearing potential who are not taking effective contraception, pregnant or breast-feeding Previously enrolled in POISE-3 Trial

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tranexamic Acid (TXA)<br>Patients will receive a 1g loading dose of intravenous TXA before surgery and a 1g loading dose of intravenous TXA at the end of surgery (wound closure). | Drug: Tranexamic Acid<br>* Within 20 minutes preceding the anticipated skin incision, patients will receive intravenous TXA at a loading dose of 1g over 10 minutes, with a second 1g bolus given at the end of surgery when closing the wound.<br>* Other names: TXA;|
| Placebo Comparator: Placebo (0.9% normal saline)<br>Patients will receive a 1g loading dose of placebo (0.9% normal saline) before surgery and a 1g loading dose of placebo (0.9% normal saline) at the end of surgery (wound closure). | Drug: Placebo (Saline)<br>* Within 20 minutes preceding the anticipated skin incision, patients will receive intravenous placebo (0.9% normal saline) at a loading dose of 1g over 10 minutes, with a second 1g bolus given at the end of surgery when closing the wound.<br>* Other names: saline;|
| Active Comparator: Hypotension-avoidance strategy<br>Aims to avoid hypotension before surgery (preoperative), during surgery (intraoperative) and for the first 2 days after the day of surgery (postoperative). | Other: Perioperative hypotension-avoidance strategy<br>* Perioperative hypotension-avoidance strategy includes: Preoperative algorithm that only continues some antihypertensive medications in a stepwise manner for systolic BP ≥130 mm Hg before surgery, Intraoperative blood pressure targeting a mean arterial pressure (MAP) ≥80 mm Hg Postoperative algorithm that only continues some antihypertensive medications in a stepwise manner for systolic BP ≥130 mm Hg during the first 48 hours after surgery.<br>|
| Placebo Comparator: Perioperative hypertension-avoidance strategy<br>Aims to avoid hypertension before surgery (preoperative), during surgery (intraoperative) and for the first 2 days after the day of surgery (postoperative). | Other: Perioperative hypertension-avoidance strategy<br>* Perioperative hypertension-avoidance strategy (i.e., routine care) continues all antihypertensive drugs before and after surgery and an intraoperative BP strategy targeting a MAP ≥60 mm Hg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A composite of life-threatening bleeding, major bleeding, and critical organ bleeding | Number of patients who have at least one of the following: life-threatening bleeding, major bleeding, and critical organ bleeding | 30 days after randomization | 
| A composite of MINS, non-hemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism. | Number of patients who have at least one of the following: myocardial injury after noncardiac surgery, non-hemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism. | 30 days after randomization | 
| For patients in the blood pressure management arm: A composite of vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest. | Number of patients enrolled in the blood pressure management arm who have at least one of the following: vascular death, non-fatal myocardial injury after noncardiac surgery, non-fatal stroke, and non-fatal cardiac arrest. | 30 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A net risk-benefit outcome as a composite of vascular death, and non-fatal life-threatening,major or critical organ bleeding,MINS,stroke,peripheral arterial thrombosis,and symptomatic proximal venous thromboembolism | Number of patients who have at least one of the following: vascular death, and non-fatal life-threatening, major or critical organ bleeding, myocardial injury after noncardiac surgery, stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism, | 30 days after randomization | 
| BIMS | Number of patients who experience bleeding independently associated with mortality after noncardiac surgery (BIMS) | 30 days after randomization | 
| MINS | Number of patients who experience a myocardial injury after noncardiac surgery (MINS) | 30 days after randomization | 
| MINS not fulfilling the universal definition of myocardial infarction | Number of patients who experience a myocardial injury after noncardiac surgery (MINS) not fulfilling the 3rd universal definition of myocardial infarction | 30 days after randomization | 
| Myocardial infarction | Number of patients who experience a myocardial infarction | 30 days after randomization | 
| For patients in the blood pressure management arm: all-cause mortality | Number of patients who die of any cause | 30 days after randomization | 
| For patients in the blood pressure management arm: MINS | Number of patients who experience a myocardial injury after noncardiac surgery (MINS) | 30 days after randomization | 
| For patients in the blood pressure management arm: Myocardial infarction | Number of patients who experience a myocardial infarction | 30 days after randomization | 
| For patients in the blood pressure management arm: MINS not fulfilling the universal definition of myocardial infarction | Number of patients who experience MINS not fulfilling the universal definition of myocardial infarction | 30 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tranexamic Acid, Noncardiac surgery, Myocardial injury, Perioperative myocardial infarction, Hypotension, Hypertension