Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study

Study Overview
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Brief Summary
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Perioperative Myocardial Infarction (PMI) is a major contributor to perioperative mortality and morbidity with overall incidence of 5-16%. It is associated with increased 30-day mortality of 11.6% vs 2.2% of patients without PMI in non-cardiac surgical patients. However, its recognition and diagnosis remains challenging as the typical symptoms and findings of ischemic MI may be masked by post-operative changes and pain management. In this study, the investigators hope to determine if colchicine decreases the incidence of MINS in high risk surgical patients undergoing non-cardiac surgery and optimally establish colchicine as a viable therapy to improve perioperative cardiovascular outcome in those patients.

Detailed Description
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Perioperative Myocardial Infarction (PMI) is a major contributor to perioperative mortality and morbidity with overall incidence of 5-16%. It is associated with increased 30-day mortality of 11.6% vs 2.2% of patients without PMI in non-cardiac surgical patients. However, its recognition and diagnosis remains challenging as the typical symptoms and findings of ischemic MI may be masked by post-operative changes and pain management. To support early detection and diagnosis of myocardial injury in the perioperative setting, myocardial injury after non-cardiac surgery (MINS) has been recognized as an important prognostic marker independently associated with mortality and significant morbidity in the perioperative period. MINS is defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. Perioperative screening and monitoring of MINS is recommended by the most recent 2016 Canadian Cardiovascular Society (CCS) Guidelines. One study found of the MINS patients, only 41.8% of which filled universal definition of MI. This may suggest that screening for MINS in the Perioperative setting by detecting post-operative troponin rise is an important marker to prompt further investigation and closer monitoring. However, despite efforts in recognition and establishment of MINS, there is still no consensus for the optimal management of MINS in addition to routine cardiac risk stratification. Common MI management options may be complicated by post-operative changes such as anemia, hypotension, hypoxemia, and use of routine anti-platelet and anticoagulation agents and invasive intervention is associated with high risk of complication and mortality in the perioperative period. Colchicine is an alkaloid anti-inflammatory drug with well-established safety and adverse effect profile in various clinical settings including pericarditis and gout flare. Pharmacologically, colchicine inhibits beta-tubulin polymerization into microtubules, preventing activation and migration of neutrophils to achieve its anti-inflammatory effect. Clinically in the cardiac surgery patient population, colchicine has been shown in multiple meta-analyses to be efficacious in preventing post-operative atrial fibrillation, in treatment and prevention of pericarditis and post-pericardiotomy syndrome. In patients who are high risk for cardiovascular events, systemic review has shown reduction in cardiovascular mortality and myocardial infarction in some studies. Colchicine is an ideal agent in the perioperative period as it does not increase the risk of major bleeding, hepatic and renal toxicity, and there is only gastrointestinal discomfort at high doses. In this study, the investigators hope to determine if colchicine decreases the incidence of MINS in high risk surgical patients undergoing non-cardiac surgery and optimally establish colchicine as a viable therapy to improve perioperative cardiovascular outcome in those patients. Research Question: In the current clinical setting, is a larger, multi-centre randomised controlled trial comparing effect of perioperative oral colchicine administration versus placebo on incidence of MINS feasible? This pilot study will inform many aspects of the future multi-centre trial. The pilot study will provide information on the recruitment rate of eligible patients and incidence of MINS on the recruited patient, which will allow the investigators to determine the sample size required in the large multi-centre trial to detect clinically relevant differences. The pilot study will also provide information on the operational aspect of clinical trial, including initial patient enrolment and consent processes, data collection from electronic chart review. This will help refine the process and improve efficiency of the larger trial. Lastly, information collected on side-effects of study drug (colchicine) would improve timely detection and treatment of the associated side effects (GI, myopathies, and blood dyscrasias), as well as expected drop-out rate from the larger trial due to intolerance of these side effects.

Official Title
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Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study (COPMAN)

Conditions
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Myocardial Infarction, Myocardial Injury, Major Adverse Cardiac Events, Infectious Complications

Intervention / Treatment
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* Drug: Colchicine 0.6 mg
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient undergoing non-cardiac surgery is eligible if (s)he is: Aged 45 years of age or older Expected to be admitted for >48 hours Have a preoperative Brain natriuretic peptide (BNP) value of 92 or higher, or a N-terminal prohormone brain natriuretic peptide (NT-proBNP) value of 300 or higher, If a BNP or NT-proBNP is not available, then the patient must fulfill at least one of the criteria for moderate to high risk of perioperative myocardial injury (see below): Moderate to high risk for perioperative myocardial injury criteria: History of coronary artery disease History of peripheral artery disease History of stroke Undergoing major vascular surgery Any 3 of the following 9 criteria: Age 70 years or greater Undergoing intraperitoneal, retroperitoneal, intrathoracic, or major orthopaedic surgery History of heart failure History of transient ischemic attack History of diabetes requiring insulin or oral hypoglycemic medications Hypertension Serum creatinine greater than 170 mmol/mL History of smoking within 2 years of surgery Undergoing urgent or emergent surgery Exclusion Criteria: Patients will be ineligible for the study if (s)he has: An allergy to colchicine Myelodysplastic syndrome An estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73m2 Anticipated post-operative administration of cyclosporine, ketoconazole, itraconazole, protease inhibitors, or clarithromycin

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: Parallel Assignment
Interventional Model Description: Randomized Control Pilot Study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colchicine Group<br>Administration of oral colchicine at 0.6 mg 1 hour prior to surgery, then 0.6 mg twice daily starting on the night after surgery for 7 days or until discharge from hospital, whichever occurs earlier. For patient under 60kg in body weight, daily dose will be 0.6 mg once daily. Medical and surgical management of the participant will be carried out under each institute's standard clinical practice. | Drug: Colchicine 0.6 mg<br>* Oral colchicine given at 0.6 mg 1 hour prior to surgery, then 0.6 mg twice daily starting on the night after surgery for 7 days or until discharge from hospital, whichever occurs earlier. For patient under 60kg in body weight, daily dose will be 0.6 mg once daily. Medical and surgical management of the participant will be carried out under each institute's standard clinical practice.<br>|
| Placebo Comparator: Placebo Group<br>Participants allocated to the control group will receive a placebo pill at the same dosing regimen as with treatment group. Perioperative and surgical care will not be different from standard clinical practice. | Drug: Placebo oral tablet<br>* Placebo oral tablet given at 0.6 mg 1 hour prior to surgery, then 0.6 mg twice daily starting on the night after surgery for 7 days or until discharge from hospital, whichever occurs earlier. For patient under 60kg in body weight, daily dose will be 0.6 mg once daily. Medical and surgical management of the participant will be carried out under each institute's standard clinical practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Recruited | The number of eligible subjects recruited in 3 months after 2 weeks of run-in period in participating centres | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Myocardial Injury after Non-Cardiac Surgery (MINS) | The incidence of MINS in the treatment versus placebo group, as defined by high sensitivity troponin T level > 65 ng/L or Troponin level > 0.03 ng/mL. The incidence of MINS will be determined upon review of the troponin assay on post-operative day 0, 1, 2 and 3rd (or according to each participating institution's own MINS pathway) and electrocardiogram (ECG) on post-operative day 1, or as otherwise clinically indicated and ordered by the perioperative team. Information will be obtained by review of blood work results and ECG on institution's electronic health record and patient's bedside chart if necessary by our research team member. | From Post-Operatively day one up to 7 days post-operatively | 
| Adverse Events | We will collect adverse effects, whether or not associated with study drug through review of patient's bedside chart and discharge summary. | Duration of hospital admission up to 7 days post-operatively | 
| Incidence of premature discontinuation of the study drug and Reasoning | Incidence of premature discontinuation of the study drug will be recorded. If the subject chooses to discontinue the study drug and withdraw from the study, the duration of treatment before withdraw as well as reasons of withdraw will be recorded. | Post-Operatively until date of study drug discontinuation (up to 7 days post-operatively) | 
| Incidence of infectious complications | Incidence of infectious complications will also be recorded with review of chart and discharge summary. The determination of the complication will depend on patient's chart review, history and physical assessment by the primary care provider team, and associated imaging and laboratory investigations as clinically indicated. Complications include, but are not limited to: including but not limited to: pneumonia, surgical site infection, urinary tract infection, and sepsis during the hospital admission. | Duration of hospital admission up to 7 days post-operatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MACE, MINS, Colchicine, Myocardial Injury, Major Adverse Cardiac Events, Myocardial Injury after Non-Cardiac Surgery