PeriOperative ISchemic Evaluation-2 Trial

Study Overview
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Brief Summary
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Major surgeries not involving the heart are common, and major heart problems during or after such surgeries represent a large population health problem. Few treatments to prevent heart problems around the time of surgery have been tested. There is encouraging data suggesting that small doses of Acetyl-Salicylic Acid (ASA) and Clonidine, which are two medications, given individually for a short period before and after major surgeries may prevent major heart problems. The POISE-2 Trial is a large international study to test if ASA and Clonidine can prevent heart attacks and deaths from heart problems around the time of surgery.

Detailed Description
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POISE-2 is a multicentre, international, blinded, 2x2 factorial randomized controlled trial of acetyl-salicylic acid (ASA) and clonidine. The primary objective is to determine the impact of clonidine versus placebo and ASA versus placebo on the 30-day risk of all-cause mortality or nonfatal myocardial infarction in patients with, or at risk of, atherosclerotic disease who are undergoing noncardiac surgery. Patients in the POISE-2 trial will be randomly assigned to one of four groups: ASA and Clonidine together, ASA and Clonidine placebo, ASA placebo and Clonidine, or a ASA placebo and Clonidine placebo. Research personnel will follow patients at 30 days post-randomization and 1 year post-randomization.

Official Title
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A Large, International, Placebo-controlled, Factorial Trial to Assess the Impact of Clonidine and Acetyl-salicylic Acid (ASA) in Patients Undergoing Noncardiac Surgery Who Are at Risk of a Perioperative Cardiovascular Event

Conditions
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Cardiovascular Disease

Intervention / Treatment
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* Drug: Active Clonidine
* Drug: Placebo Clonidine
* Drug: Active ASA
* Drug: Placebo ASA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are undergoing noncardiac surgery; Are ≥ 45 years of age; Are expected to require at least an overnight hospital admission after surgery; AND Fulfill one or more of the following 5 criteria: History of coronary artery disease History of peripheral vascular disease History of stroke Undergoing major vascular surgery Any 3 of the following 9 criteria: undergoing major surgery (i.e. intraperitoneal, intrathoracic, retroperitoneal or major orthopedic surgery history of congestive heart failure transient ischemic attack diabetes and currently taking an oral hypoglycemic agent or insulin age ≥ 70 years hypertension serum creatinine > 175 µmol/L (> 2.0 mg/dL) history of smoking within 2 years of surgery undergoing urgent/emergent surgery Exclusion Criteria: Consumption of ASA within 72 hours prior to surgery Hypersensitivity or known allergy to ASA or clonidine Systolic blood pressure < 105 mm Hg Heart rate < 55 beats per minute in a patient who does not have a permanent pacemaker Second or third degree heart block without a permanent pacemaker Active peptic ulcer disease or gastrointestinal bleeding within previous 6 weeks Intracranial hemorrhage documented by neuro-imaging, in the 6 months prior to randomization. This does not include petechial hemorrhagic transformation of a primary ischemic stroke Subarachnoid hemorrhage or epidural hematoma unless the event occurred more than 6 months prior to randomization and the offending aneurysm or arterial lesion has been repaired Drug-eluting coronary stent in the year prior to randomization Bare-metal coronary stent in the 6 weeks prior to randomization Thienopyridine (e.g., clopidogrel, ticlopidine, prasugrel) or ticagrelor within 72 hours prior to surgery; or intent to restart a thienopyridine or ticagrelor during the first 7 days post-op; or currently taking an alpha-2 agonist, alpha methyldopa, monoamine oxidase inhibitors or reserpine; Planned use - during the first 3 days after surgery - therapeutic dose anticoagulation or a therapeutic subcutaneous or intravenous antithrombotic agent Undergoing intracranial surgery, carotid endarterectomy, or retinal surgery Not consenting to participate in POISE-2 prior to surgery Previously enrolled in POISE-2 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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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Clonidine and Active ASA<br> | Drug: Active Clonidine<br>* Pre-op (goal 2-4 hours): 2 x 0.1mg oral tablets and transdermal patch (0.2 mg/day). Patch to be removed 72 hours post-op.<br>* Other names: CATAPRES, CATAPRES-TTS;Drug: Active ASA<br>* Pre-op (goal 2-4 hours): 2 x 100mg oral tablets. Post-op: patients ingest one tablet a day (100 mg ASA) for 7 days if patient was were taking ASA chronically prior to surgery or for 30 days if they were not chronically taking ASA prior to surgery<br>* Other names: ASPIRIN;|
| Experimental: Active Clonidine and Placebo ASA<br> | Drug: Active Clonidine<br>* Pre-op (goal 2-4 hours): 2 x 0.1mg oral tablets and transdermal patch (0.2 mg/day). Patch to be removed 72 hours post-op.<br>* Other names: CATAPRES, CATAPRES-TTS;Drug: Placebo ASA<br>* Pre-op (goal 2-4 hours): 2 oral placebo tablets. Post-op: patients ingest one placebo tablet a day for 7 days if patient was were taking ASA chronically prior to surgery or for 30 days if they were not chronically taking ASA prior to surgery<br>|
| Experimental: Placebo Clonidine and Active ASA<br> | Drug: Placebo Clonidine<br>* Pre-op (goal 2-4 hours): 2 oral placebo tablets and transdermal placebo patch. Patch to be removed 72 hours post-op.<br>Drug: Active ASA<br>* Pre-op (goal 2-4 hours): 2 x 100mg oral tablets. Post-op: patients ingest one tablet a day (100 mg ASA) for 7 days if patient was were taking ASA chronically prior to surgery or for 30 days if they were not chronically taking ASA prior to surgery<br>* Other names: ASPIRIN;|
| Placebo Comparator: Placebo Clonidine and Placebo ASA<br> | Drug: Placebo Clonidine<br>* Pre-op (goal 2-4 hours): 2 oral placebo tablets and transdermal placebo patch. Patch to be removed 72 hours post-op.<br>Drug: Placebo ASA<br>* Pre-op (goal 2-4 hours): 2 oral placebo tablets. Post-op: patients ingest one placebo tablet a day for 7 days if patient was were taking ASA chronically prior to surgery or for 30 days if they were not chronically taking ASA prior to surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of All-cause Mortality and Nonfatal MI |  | 30 days | 
| All-cause Mortality and Nonfatal MI |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of All-cause Mortality, Nonfatal MI, and Nonfatal Stroke |  | 30 days | 
| Individual Secondary Outcomes | All-cause mortality, vascular mortality, MI, nonfatal cardiac arrest, cardiac revascularization procedure, pulmonary emboli, deep venous thrombosis, clinically important atrial fibrillation, amputation, peripheral arterial thrombosis, infection/sepsis, rehospitalization for vascular reasons, length of hospital stay, length of intensive care unit / cardiac care unit (ICU/CCU) stay, and new acute renal failure requiring dialysis. | 30 days | 
| Composite Outcome by ASA Stratum | Composite outcome of all-cause mortality, nonfatal MI, cardiac revascularization procedure, nonfatal pulmonary emboli, and nonfatal deep venous thrombosis. | 30 days | 
| Safety Outcomes in ASA Trial | Stroke, congestive heart failure, life-threatening bleeding, and major bleeding. | 30 days | 
| Safety Outcomes in Clonidine Trial | Stroke, clinically important hypotension, clinically important bradycardia, and congestive heart failure. | 30 days | 
| Composite Outcome at 1 Year | All-cause mortality, nonfatal MI, and nonfatal stroke. | 1 year | 
| Individual Secondary Outcomes at 1 Year | All cause mortality, vascular mortality, MI, nonfatal cardiac arrest, cardiac revascularization procedure, stroke, pulmonary emboli, deep venous thrombosis, amputation, peripheral arterial thrombosis, new diagnosis of cancer, diagnosis of recurrent cancer and rehospitalization for vascular reason. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blinded, Randomized Controlled Trial, Clonidine, acetyl-salicylic acid (ASA), Perioperative vascular complications, Noncardiac surgery