Clinical trial NCT01082874: PeriOperative ISchemic Evaluation-2 Trial
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiovascular Disease
Keywords: Randomized Controlled Trial
Blinded
Clonidine
acetyl-salicylic acid (ASA)
Perioperative vascular complications
Noncardiac surgery
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: McMaster University
First posted: 2010-03-09
Enrollment: 10010
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Composite of All-cause Mortality and Nonfatal MI
timeFrame: 30 days
measure: All-cause Mortality and Nonfatal MI
timeFrame: 1 year
Secondary outcomes:
measure: Composite of All-cause Mortality, Nonfatal MI, and Nonfatal Stroke
timeFrame: 30 days
measure: Individual Secondary Outcomes
timeFrame: 30 days
measure: Composite Outcome by ASA Stratum
timeFrame: 30 days
measure: Safety Outcomes in ASA Trial
timeFrame: 30 days
measure: Safety Outcomes in Clonidine Trial
timeFrame: 30 days
measure: Composite Outcome at 1 Year
timeFrame: 1 year
measure: Individual Secondary Outcomes at 1 Year
timeFrame: 1 year
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: National Coordination Office
state: Ohio
city: Rosario
country: Argentina
facility: National Coordination Office
city: Parkville
country: Australia
facility: National Coordination Office Australia and New Zealand
state: Victoria
city: Vienna
country: Austria
facility: National Coordination Office
city: Brussels
country: Belgium
facility: National Coordination Office
city: Sao Paulo
country: Brazil
facility: National Coordination Office
city: Hamilton
country: Canada
facility: National Coordination Office
state: Ontario
city: Santiago
country: Chile
facility: National Coordination Office
city: Bucamaranga
country: Colombia
facility: National Coordination Office
city: Herlev
country: Denmark
facility: National Coordination Office
city: Boulogne-Billancourt
country: France
facility: National Coordination Office
city: Bonn
country: Germany
facility: National Coordination Office
city: Hong Kong
country: Hong Kong
facility: National Coordination Office
city: Bangalore
country: India
facility: National Coordination Office
city: Milan
country: Italy
facility: National Coordination Office
city: Kuala Lumpur
country: Malaysia
facility: National Coordination Office
city: Auckland
country: New Zealand
facility: National Coordination Office
city: Islamabad
country: Pakistan
facility: National Coordination Office
city: Lima
country: Peru
facility: National Coordination Office
city: Durban
country: South Africa
facility: National Coordination Office
city: Barcelona
country: Spain
facility: National Coordination Office
city: Basel
country: Switzerland
facility: National Coordination Office
city: Hull
country: United Kingdom
facility: National Coordination Office
Study officials:
affiliation: Population Health Research Institute
name: P.J. Devereaux, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Population Health Research Institute
name: Salim Yusuf, DPhil
role: STUDY_CHAIR
References:
citation: Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt G, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse G, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir M, Eikelboom J, Mizera R, Torres D, Wang CY, VanHelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Baigent C, Chow C, Pettit S, Chrolavicius S, Yusuf S; POISE-2 Investigators. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014 Apr 17;370(16):1494-503. doi: 10.1056/NEJMoa1401105. Epub 2014 Mar 31.
citation: Devereaux PJ, Sessler DI, Leslie K, Kurz A, Mrkobrada M, Alonso-Coello P, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt G, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse G, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir M, Eikelboom J, Mizera R, Torres D, Wang CY, Vanhelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Chow C, Pettit S, Chrolavicius S, Yusuf S; POISE-2 Investigators. Clonidine in patients undergoing noncardiac surgery. N Engl J Med. 2014 Apr 17;370(16):1504-13. doi: 10.1056/NEJMoa1401106. Epub 2014 Mar 31.
citation: Garg AX, Kurz A, Sessler DI, Cuerden M, Robinson A, Mrkobrada M, Parikh C, Mizera R, Jones PM, Tiboni M, Rodriguez RG, Popova E, Rojas Gomez MF, Meyhoff CS, Vanhelder T, Chan MT, Torres D, Parlow J, de Nadal Clanchet M, Amir M, Bidgoli SJ, Pasin L, Martinsen K, Malaga G, Myles P, Acedillo R, Roshanov P, Walsh M, Dresser G, Kumar P, Fleischmann E, Villar JC, Painter T, Biccard B, Bergese S, Srinathan S, Cata JP, Chan V, Mehra B, Leslie K, Whitlock R, Devereaux PJ; POISE-2 Investigators. Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial. BMJ Open. 2014 Feb 25;4(2):e004886. doi: 10.1136/bmjopen-2014-004886.
citation: Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.
citation: Biccard BM, Sigamani A, Chan MTV, Sessler DI, Kurz A, Tittley JG, Rapanos T, Harlock J, Szalay D, Tiboni ME, Popova E, Vasquez SM, Kabon B, Amir M, Mrkobrada M, Mehra BR, El Beheiry H, Mata E, Tena B, Sabate S, Zainal Abidin MK, Shah VR, Balasubramanian K, Devereaux PJ. Effect of aspirin in vascular surgery in patients from a randomized clinical trial (POISE-2). Br J Surg. 2018 Nov;105(12):1591-1597. doi: 10.1002/bjs.10925. Epub 2018 Jul 18.
citation: Graham MM, Sessler DI, Parlow JL, Biccard BM, Guyatt G, Leslie K, Chan MTV, Meyhoff CS, Xavier D, Sigamani A, Kumar PA, Mrkobrada M, Cook DJ, Tandon V, Alvarez-Garcia J, Villar JC, Painter TW, Landoni G, Fleischmann E, Lamy A, Whitlock R, Le Manach Y, Aphang-Lam M, Cata JP, Gao P, Terblanche NCS, Ramana PV, Jamieson KA, Bessissow A, Mendoza GR, Ramirez S, Diemunsch PA, Yusuf S, Devereaux PJ. Aspirin in Patients With Previous Percutaneous Coronary Intervention Undergoing Noncardiac Surgery. Ann Intern Med. 2018 Feb 20;168(4):237-244. doi: 10.7326/M17-2341. Epub 2017 Nov 14.
citation: Garg AX, Kurz A, Sessler DI, Cuerden M, Robinson A, Mrkobrada M, Parikh CR, Mizera R, Jones PM, Tiboni M, Font A, Cegarra V, Gomez MF, Meyhoff CS, VanHelder T, Chan MT, Torres D, Parlow J, Clanchet Mde N, Amir M, Bidgoli SJ, Pasin L, Martinsen K, Malaga G, Myles P, Acedillo R, Roshanov PS, Walsh M, Dresser G, Kumar P, Fleischmann E, Villar JC, Painter T, Biccard B, Bergese S, Srinathan S, Cata JP, Chan V, Mehra B, Wijeysundera DN, Leslie K, Forget P, Whitlock R, Yusuf S, Devereaux PJ; POISE-2 Investigators. Perioperative aspirin and clonidine and risk of acute kidney injury: a randomized clinical trial. JAMA. 2014 Dec 3;312(21):2254-64. doi: 10.1001/jama.2014.15284.
citation: Devereaux PJ; POISE-2 Investigators. Rationale and design of the PeriOperative ISchemic Evaluation-2 (POISE-2) trial: an international 2 x 2 factorial randomized controlled trial of acetyl-salicylic acid vs. placebo and clonidine vs. placebo in patients undergoing noncardiac surgery. Am Heart J. 2014 Jun;167(6):804-9.e4. doi: 10.1016/j.ahj.2014.01.007. Epub 2014 Feb 22.
citation: Chludzinski A, Irani C, Mascha EJ, Kurz A, Devereaux PJ, Sessler DI. Protocol understanding and anxiety in perioperative clinical trial patients approached for consent on the day of surgery. Mayo Clin Proc. 2013 May;88(5):446-54. doi: 10.1016/j.mayocp.2012.12.014.