Clinical trial NCT04139655: Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study
Official title: Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study (COPMAN)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Myocardial Infarction
Myocardial Injury
Major Adverse Cardiac Events
Infectious Complications
Keywords: MINS
Colchicine
Myocardial Injury
Major Adverse Cardiac Events
Myocardial Injury after Non-Cardiac Surgery
MACE
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Providence Health & Services
name: Vancouver Coastal Health
First posted: 2019-10-25
Enrollment: 0
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Control Pilot Study
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Patients Recruited
timeFrame: 3 months
Secondary outcomes:
measure: Incidence of Myocardial Injury after Non-Cardiac Surgery (MINS)
timeFrame: From Post-Operatively day one up to 7 days post-operatively
measure: Adverse Events
timeFrame: Duration of hospital admission up to 7 days post-operatively
measure: Incidence of premature discontinuation of the study drug and Reasoning
timeFrame: Post-Operatively until date of study drug discontinuation (up to 7 days post-operatively)
measure: Incidence of infectious complications
timeFrame: Duration of hospital admission up to 7 days post-operatively
Other outcomes:
measure: Medical comorbidities
timeFrame: Duration of hospital admission up to 7 days post-operatively
measure: Clinical risk stratification scores
timeFrame: Duration of hospital admission up to 7 days post-operatively
measure: Neutrophil to lymphocyte ratio (NLR)
timeFrame: Pre-operatively up to 7 days post-operatively
Locations:
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
Study officials:
affiliation: Providence Health Care and UBC
name: Ron Ree, MD
role: PRINCIPAL_INVESTIGATOR
References:
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