Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization: The Peri-OPerative COlchicine to Reduce Negative Events (POPCORN) Trial

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Not yet recruiting

CT.gov ID

NCT05618353

Collaborator

NYU School of Medicine (Other)

700

Enrollment

Locations

Arms

Anticipated Duration (Months)

140

Patients Per Site

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Heart disease remains the leading cause of death in Veterans. Inflammation in the arteries of the heart may increase the risk of cardiac death. Patients with heart disease undergoing major surgery are at increased risk of complications after surgery, including heart attack, stroke, and death. The proposed research seeks to better understand the role of inflammation in the damage to the heart and blood vessels after major surgery. This research also seeks to identify the potential beneficial role of a safe medication, colchicine, which has direct effects on inflammatory cells and has been used in the treatment of inflammatory diseases for more than 2000 years, on reducing the rate of complications after surgery. With its quick onset of action and excellent safety profile, colchicine may have the potential to reduce risk of heart injury, stroke, or death after major surgery.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Colchicine Drug: Placebo	Phase 4

Detailed Description

Patients with prior coronary revascularization have a high risk of major adverse cardiovascular events (MACE) after major surgery, up to more than 2-fold when compared to patients without prior coronary revascularization. The pro-inflammatory and hypercoagulable states induced by surgery and the hemodynamic changes caused by fluid shifts and anesthesia are all important triggers of perioperative myocardial ischemia. Indeed, peri-operative systemic inflammation is associated with a nearly 4-fold increase in the risk of perioperative MACE. Neutrophils, the most abundant of inflammatory cells, adhere to inflamed or injured endothelium, migrate into the vessel wall, release proteolytic enzymes that can lead to erosion or rupture of plaque. Peri-operative cytokine generation may also activate the inflammasome and, thereby, macrophage-mediated synthesis of interleukin (IL)-1 , a known target for therapy for secondary prevention of MACE, particularly in the setting of high C-reactive protein (CRP) concentration.

Colchicine is a safe, well-tolerated anti-inflammatory agent that preferentially accumulates in neutrophils compared with other inflammatory cells. Colchicine inhibits chemotaxis, endothelial adhesion, and extravasation of neutrophils at sites of endothelial injury or inflammation; suppresses the inflammasome-mediated production of IL-1 by macrophages; and reduces inflammation and MACE in patients with cardiovascular disease. The Colchicine Cardiovascular Outcomes Trial and Low Dose Colchicine 2 Trial demonstrated a reduction in MACE with colchicine in about 4000 patients with prior myocardial infarction and about 5000 patients with stable coronary artery disease, respectively. The Colchicine-PCI trial demonstrated for the first time that administration of colchicine prior to injury dampens the inflammatory response measured by CRP. The effects of colchicine on peri-operative MACE in patients with prior coronary revascularization undergoing major surgery, remains unknown.

The aims of this trial are to 1) assess the effect of colchicine compared to placebo on peri-operative MACE in response to intermediate- or high-risk non-cardiac surgery in patients with prior coronary revascularization; 2) characterize the level of systemic inflammation and profile of peri-operative neutrophils in this population; and 3) determine the clinical and genetic predictors of peri-operative MACE and examine factors that determine heterogeneity of treatment response in this population. This prospective, double-blinded, placebo-controlled, randomized trial will enroll 700 participants with prior coronary revascularization who undergo intermediate- or high-risk non-cardiac surgery across five VA medical centers that serve as cardiovascular referral centers for their VISNs. Following referral for surgery, and confirmation that the patient meets all study entry criteria, participants will be consented and randomized 1:1 within center to a loading dose of colchicine or placebo one day before surgery and twice daily dosing for 14 days post-operation. DNA will be collected at baseline, while measures of systemic inflammation will be collected at baseline, one day, two days, and at 14 days post-operation (or hospital discharge, whichever occurs earlier). Follow-up for all randomized participants who undergo surgery will occur at 30 days + 7 days.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

700 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days. If a patient is unable to take oral medications (by mouth or nasogastric tube) post-operatively (e.g., post abdominal surgery), colchicine will be held until the clinically treating physician allows resumption of oral medications if still within 14 days post-operation.One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days. If a patient is unable to take oral medications (by mouth or nasogastric tube) post-operatively (e.g., post abdominal surgery), colchicine will be held until the clinically treating physician allows resumption of oral medications if still within 14 days post-operation.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Matching placebo at the same time points as the intervention

Primary Purpose:

Treatment

Official Title:

Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients With Prior Coronary Revascularization

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Apr 1, 2027

Anticipated Study Completion Date :

Dec 31, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Colchicine One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days.	Drug: Colchicine 0.6 mg tablets Other Names: Colcrys
Placebo Comparator: Placebo Matching placebo at same time points as active comparator	Drug: Placebo Matching placebo

Arm

Intervention/Treatment

Active Comparator: Colchicine

One day before surgery: Colchicine 1.2 mg with 0.6 mg PO one hour later. This load will be followed by colchicine 0.6 mg twice daily for a total of 14 days.

Drug: Colchicine

0.6 mg tablets

Other Names:

Colcrys

Placebo Comparator: Placebo

Matching placebo at same time points as active comparator

Drug: Placebo

Matching placebo

Outcome Measures

Primary Outcome Measures

Major adverse cardiovascular events [30 days post-operation]
Defined as a composite rate of myocardial injury, non-fatal MI, non-fatal stroke, and all-cause mortality.

Secondary Outcome Measures

rate of myocardial injury [30 days post-operation]
rate of myocardial injury
rate of non-fatal MI [30 days post-operation]
rate of non-fatal MI
rate of non-fatal stroke [30 days post-operation]
rate of non-fatal stroke
rate of all-cause mortality [30 days post-operation]
rate of all-cause mortality
Unplanned coronary revascularization [30 days post-operation]
Unplanned coronary revascularization
Prognostic threshold of myocardial injury [30 days post-operation]
troponin >30 ng/L (high-sensitivity troponin >65 ng/L or absolute change >14 ng/L or 20-65 ng/L with an absolute change of >5 ng/L)
Change in hsCRP [through 14 days post-operation or at hospital discharge, whichever occurs earlier]
between 1) baseline and one day post-operation, and 2) over time including at two days and 14 days post-operation (or hospital discharge, whichever occurs earlier)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Men and women with prior coronary revascularization (via PCI or coronary artery bypass graft surgery) referred for intermediate- (>3% cardiovascular risk with general abdominal or intraperitoneal surgery) versus high-risk (>5% cardiovascular risk with suprainguinal surgery, peripheral vascular surgery, thoracic surgery) surgery [2,89].
If planned for only a laparoscopic or endovascular approach, at least one component of the Revised Cardiac Risk Index score (history of myocardial infarction, history of congestive heart failure, history of transient ischemic attack or stroke, pre-operative use of insulin, pre-operative creatinine >2 mg/dL) should be present.

Exclusion Criteria:

Colchicine use within one month or history of colchicine intolerance
Inflammatory bowel disease with history of diarrhea as presentation or chronic diarrhea
Pre-existent progressive neuromuscular disease
amyotrophic lateral sclerosis
hereditary muscular disorders
myositis
necrotizing myopathy
myasthenia gravis
lambert-eaton syndrome
Glomerular filtration rate <30mL/minute or on dialysis
History of cirrhosis, chronic active hepatitis or severe hepatic disease
History of myelodysplasia with current evidence of cytopenia
Active infection defined as fever >100.4oF or antibiotic use with white blood cell count greater than the upper limit of normal or lower than the lower limit of normal within 24 hours of randomization (major confounder with increased inflammatory markers)
Undergoing immunosuppressive or immunostimulatory chemo or biologic therapy
Pregnant (as confirmed by urine or serum test), nursing, or planning to become pregnant during study participation
Participating in a competing study or unable to consent
Any significant condition or situation that may put the participant at higher risk, confound the study results, or interfere with adherence to study procedures
Patients on strong CYP3A4 and/or P-glycoprotein inhibitors (e.g., ritonavir, clarithromycin, diltiazem, verapamil) at baseline will also be excluded due to potential drug interactions
However, if one of these medications are started during the post-operative study period, dose adjustments will be made per drug package insert
Participants will also be instructed not to drink grapefruit juice while on study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Long Beach Healthcare System, Long Beach, CA	Long Beach	California	United States	90822
2	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York	United States	10010
3	Durham VA Medical Center, Durham, NC	Durham	North Carolina	United States	27705
4	Louis Stokes VA Medical Center, Cleveland, OH	Cleveland	Ohio	United States	44106
5	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas	United States	75216