Cardiovascular Disease
Conditions
Keywords
Randomized Controlled Trial, Blinded, Clonidine, acetyl-salicylic acid (ASA), Perioperative vascular complications, Noncardiac surgery
Brief summary
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
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.
Interventions
DRUGActive Clonidine
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.
DRUGPlacebo Clonidine
Pre-op (goal 2-4 hours): 2 oral placebo tablets and transdermal placebo patch. Patch to be removed 72 hours post-op.
DRUGActive ASA
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
DRUGPlacebo ASA
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
Sponsors
McMaster University
Hamilton Health Sciences Corporation
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Are undergoing noncardiac surgery; 2. Are ≥ 45 years of age; 3. Are expected to require at least an overnight hospital admission after surgery; AND 4. 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
1. Consumption of ASA within 72 hours prior to surgery 2. Hypersensitivity or known allergy to ASA or clonidine 3. Systolic blood pressure \< 105 mm Hg 4. Heart rate \< 55 beats per minute in a patient who does not have a permanent pacemaker 5. Second or third degree heart block without a permanent pacemaker 6. Active peptic ulcer disease or gastrointestinal bleeding within previous 6 weeks 7. 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 8. 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 9. Drug-eluting coronary stent in the year prior to randomization 10. Bare-metal coronary stent in the 6 weeks prior to randomization 11. 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; 12. Planned use - during the first 3 days after surgery - therapeutic dose anticoagulation or a therapeutic subcutaneous or intravenous antithrombotic agent 13. Undergoing intracranial surgery, carotid endarterectomy, or retinal surgery 14. Not consenting to participate in POISE-2 prior to surgery 15. Previously enrolled in POISE-2 Trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Composite of All-cause Mortality and Nonfatal MI | 30 days |
| All-cause Mortality and Nonfatal MI | 1 year |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Outcome by ASA Stratum | 30 days | Composite outcome of all-cause mortality, nonfatal MI, cardiac revascularization procedure, nonfatal pulmonary emboli, and nonfatal deep venous thrombosis. |
| Safety Outcomes in ASA Trial | 30 days | Stroke, congestive heart failure, life-threatening bleeding, and major bleeding. |
| Composite of All-cause Mortality, Nonfatal MI, and Nonfatal Stroke | 30 days | — |
| Composite Outcome at 1 Year | 1 year | All-cause mortality, nonfatal MI, and nonfatal stroke. |
| Individual Secondary Outcomes at 1 Year | 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. |
| Safety Outcomes in Clonidine Trial | 30 days | Stroke, clinically important hypotension, clinically important bradycardia, and congestive heart failure. |
| Individual Secondary Outcomes | 30 days | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Denmark, France, Germany, Hong Kong, India, Italy, Malaysia, New Zealand, Pakistan, Peru, South Africa, Spain, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Clonidine and Active ASA Active Clonidine: 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.
Active ASA: 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 | 2,499 |
| Active Clonidine and Placebo ASA Active Clonidine: 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.
Placebo ASA: 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 | 2,510 |
| Placebo Clonidine and Active ASA Placebo Clonidine: Pre-op (goal 2-4 hours): 2 oral placebo tablets and transdermal placebo patch. Patch to be removed 72 hours post-op.
Active ASA: 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 | 2,499 |
| Placebo Clonidine and Placebo ASA Placebo Clonidine: Pre-op (goal 2-4 hours): 2 oral placebo tablets and transdermal placebo patch. Patch to be removed 72 hours post-op.
Placebo ASA: 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 | 2,502 |
| Total | 10,010 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 10 | 10 | 6 | 10 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo Clonidine and Active ASA | Placebo Clonidine and Placebo ASA | Total | Active Clonidine and Active ASA | Active Clonidine and Placebo ASA |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1663 Participants | 1636 Participants | 6599 Participants | 1626 Participants | 1674 Participants |
| Age, Categorical Between 18 and 65 years | 836 Participants | 866 Participants | 3411 Participants | 873 Participants | 836 Participants |
| Age, Continuous | 68.7 years STANDARD_DEVIATION 10.2 | 68.5 years STANDARD_DEVIATION 10.3 | 68.6 years STANDARD_DEVIATION 10.3 | 68.4 years STANDARD_DEVIATION 10.4 | 68.6 years STANDARD_DEVIATION 10.3 |
| Gender Female | 1188 participants | 1160 participants | 4724 participants | 1212 participants | 1164 participants |
| Gender Male | 1310 participants | 1340 participants | 5283 participants | 1287 participants | 1346 participants |
| Region of Enrollment Argentina | 3 participants | 3 participants | 11 participants | 3 participants | 2 participants |
| Region of Enrollment Australia | 113 participants | 118 participants | 470 participants | 119 participants | 120 participants |
| Region of Enrollment Austria | 42 participants | 46 participants | 176 participants | 44 participants | 44 participants |
| Region of Enrollment Belgium | 46 participants | 47 participants | 184 participants | 44 participants | 47 participants |
| Region of Enrollment Brazil | 16 participants | 16 participants | 57 participants | 13 participants | 12 participants |
| Region of Enrollment Canada | 872 participants | 873 participants | 3498 participants | 875 participants | 878 participants |
| Region of Enrollment Chile | 38 participants | 39 participants | 153 participants | 38 participants | 38 participants |
| Region of Enrollment Colombia | 164 participants | 162 participants | 649 participants | 162 participants | 161 participants |
| Region of Enrollment Denmark | 80 participants | 81 participants | 321 participants | 80 participants | 80 participants |
| Region of Enrollment France | 24 participants | 20 participants | 89 participants | 21 participants | 24 participants |
| Region of Enrollment Germany | 11 participants | 7 participants | 31 participants | 6 participants | 7 participants |
| Region of Enrollment Hong Kong | 69 participants | 68 participants | 276 participants | 69 participants | 70 participants |
| Region of Enrollment India | 151 participants | 146 participants | 595 participants | 149 participants | 149 participants |
| Region of Enrollment Italy | 38 participants | 38 participants | 154 participants | 39 participants | 39 participants |
| Region of Enrollment Malaysia | 30 participants | 32 participants | 120 participants | 30 participants | 28 participants |
| Region of Enrollment New Zealand | 11 participants | 10 participants | 46 participants | 14 participants | 11 participants |
| Region of Enrollment Pakistan | 44 participants | 44 participants | 175 participants | 43 participants | 44 participants |
| Region of Enrollment Peru | 43 participants | 44 participants | 172 participants | 41 participants | 44 participants |
| Region of Enrollment South Africa | 89 participants | 90 participants | 353 participants | 87 participants | 87 participants |
| Region of Enrollment Spain | 131 participants | 135 participants | 538 participants | 133 participants | 139 participants |
| Region of Enrollment Switzerland | 25 participants | 23 participants | 96 participants | 24 participants | 24 participants |
| Region of Enrollment United Kingdom | 22 participants | 20 participants | 86 participants | 22 participants | 22 participants |
| Region of Enrollment United States | 437 participants | 440 participants | 1760 participants | 443 participants | 440 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 2,499 | 0 / 2,510 | 0 / 2,499 | 0 / 2,502 |
| serious Total, serious adverse events | 46 / 2,499 | 52 / 2,510 | 45 / 2,499 | 39 / 2,502 |
Outcome results
Primary
All-cause Mortality and Nonfatal MI
Time frame: 1 year
Primary
Composite of All-cause Mortality and Nonfatal MI
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Clonidine and Active ASA | Composite of All-cause Mortality and Nonfatal MI | 173 participants |
| Active Clonidine and Placebo ASA | Composite of All-cause Mortality and Nonfatal MI | 194 participants |
| Placebo Clonidine and Active ASA | Composite of All-cause Mortality and Nonfatal MI | 178 participants |
| Placebo Clonidine and Placebo ASA | Composite of All-cause Mortality and Nonfatal MI | 161 participants |
Secondary
Composite of All-cause Mortality, Nonfatal MI, and Nonfatal Stroke
Time frame: 30 days
Secondary
Composite Outcome at 1 Year
All-cause mortality, nonfatal MI, and nonfatal stroke.
Time frame: 1 year
Secondary
Composite Outcome by ASA Stratum
Composite outcome of all-cause mortality, nonfatal MI, cardiac revascularization procedure, nonfatal pulmonary emboli, and nonfatal deep venous thrombosis.
Time frame: 30 days
Secondary
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.
Time frame: 30 days
Secondary
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.
Time frame: 1 year
Secondary
Safety Outcomes in ASA Trial
Stroke, congestive heart failure, life-threatening bleeding, and major bleeding.
Time frame: 30 days
Secondary
Safety Outcomes in Clonidine Trial
Stroke, clinically important hypotension, clinically important bradycardia, and congestive heart failure.
Time frame: 30 days