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

November 11, 2021 updated by: Ron Ree, University of British Columbia

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

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.

Study Overview

Detailed Description

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.

Study Type

Interventional

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • British Columbia
      • Vancouver, British Columbia, Canada, V6Z 1Y6
        • St. Paul's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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:

    1. Age 70 years or greater
    2. Undergoing intraperitoneal, retroperitoneal, intrathoracic, or major orthopaedic surgery
    3. History of heart failure
    4. History of transient ischemic attack
    5. History of diabetes requiring insulin or oral hypoglycemic medications
    6. Hypertension
    7. Serum creatinine greater than 170 mmol/mL
    8. History of smoking within 2 years of surgery
    9. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Colchicine Group
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.
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.
Placebo Comparator: Placebo Group
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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients Recruited
Time Frame: 3 months
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)
Time Frame: From Post-Operatively day one up to 7 days post-operatively
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
Time Frame: Duration of hospital admission up to 7 days post-operatively
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
Time Frame: Post-Operatively until date of study drug discontinuation (up to 7 days post-operatively)
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
Time Frame: Duration of hospital admission up to 7 days post-operatively
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Medical comorbidities
Time Frame: Duration of hospital admission up to 7 days post-operatively
Based on patient charts.
Duration of hospital admission up to 7 days post-operatively
Clinical risk stratification scores
Time Frame: Duration of hospital admission up to 7 days post-operatively
Revised cardiac risk index (RCRI) scores based on patient charts. RCRI score is used and recommended by Canadian Cardiovascular Society as an evidence-based 30-day perioperative cardiovascular mortality and morbidity risk stratification tool. The tool is composed of 6 yes or no questions and provides a score from 0/6 to 6/6 which is interpreted as a percentage of 30-day risk of death, MI, or cardiac arrest. The lowest risk percentage is 3.9% and the highest percentage risk is 15%. A higher percentage indicates a higher risk of death, MI, or cardiac arrest in 30-days post-operatively.
Duration of hospital admission up to 7 days post-operatively
Neutrophil to lymphocyte ratio (NLR)
Time Frame: Pre-operatively up to 7 days post-operatively
Based on patient charts, to be obtained from patient's pre-operative bloodwork. NLR is a marker of neutrophil predominant inflammatory state that is associated with Major Adverse Cardiac Events (MACE) in a systemic review
Pre-operatively up to 7 days post-operatively

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Ron Ree, MD, Providence Health Care and UBC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 1, 2020

Primary Completion (Anticipated)

September 1, 2021

Study Completion (Anticipated)

October 1, 2021

Study Registration Dates

First Submitted

September 25, 2019

First Submitted That Met QC Criteria

October 23, 2019

First Posted (Actual)

October 25, 2019

Study Record Updates

Last Update Posted (Actual)

November 19, 2021

Last Update Submitted That Met QC Criteria

November 11, 2021

Last Verified

November 1, 2021

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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