Effect of Colchicine on Coronary Reperfusion in Patients With Acute Coronary Syndrome

Sponsor

Pontificia Universidad Catolica de Chile (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05472337

Collaborator

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile (Other)

Enrollment

Arms

14.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This randomized clinical trial will determine the treatment effect of colchicine (1.5 mg loading dose and 0.5 mg daily thereafter) for 6 weeks on microvascular coronary reperfusion and infarct size in patients with acute coronary syndrome.

Condition or Disease	Intervention/Treatment	Phase
Acute Coronary Syndrome	Drug: Colchicine	Phase 2

Detailed Description

Despite significant advances in the treatment of coronary artery disease, acute coronary syndromes (ACS) remain one of the leading causes of mortality and morbidity worldwide. In Chile, it is estimated that cardiovascular disease is responsible for one out of every four deaths Moreover, the consequences of an infarction, i.e., myocardial damage and death, lead to disability, loss of productivity, and economic costs.

Based on the knowledge that ACS occurs as a consequence of the atheroma plaque complication (rupture or erosion) and the consequent thrombosis at that level, current therapy in patients admitted for ACS includes :

(i) acute inhibition of thrombosis by means of antiplatelet and anticoagulant drugs.

Coronary revascularization for severe stenosis by means of coronary angioplasty or bypass surgery.

These therapies have resulted in marked patient benefit, however, in many cases fail to reduce myocardial damage and to achieve adequate myocardial reperfusion.

In fact, in up to 50% of patients with ACS undergoing angioplasty inadequate myocardial reperfusion is observed, despite achieving correct repermeabilization of the coronary artery.

The complication of an atheromatous plaque leading to ACS results from the presence of inflammatory cells, which weaken the vessel wall and promote thrombosis. Both monocytes and neutrophils are key in these phenomena. By intervening in the plaques by means of angioplasty

which includes balloon and implantation of high-pressure stents - both plaque debris, thrombi, and inflammatory cells are released into microcirculation.

This triggers an inflammatory response at this level, which promotes endothelial and tissue edema, myocardial hemorrhage, and direct occlusion of these microvessels.

The result is that even with an adequate recanalization of the epicardial coronary artery (which has the complicated plaque) tissue reperfusion is insufficient, complicating proper recovery of the affected myocardium.

Colchicine is a low-cost, safe, widely available, anti-inflammatory drug, with multiple uses in cardiovascular pathology.

It is recommended in patients with acute pericarditis, including those post-infarction, and has recently been shown to be useful in preventing new cardiovascular events in patients with ACS. Previous studies have shown that during coronary angioplasty in patients with ACS, inflammatory cytokines, neutrophil-derived microparticles, and Neutrophil Extracellular Traps (NETS) are released into the microcirculation.

These are recognized as key agents in the No-Reflow phenomena, by promoting inflammation facilitating thrombosis, and occluding microvessels. Our studies have also shown that the use of Colchicine in a single dose 6 to 24 hours prior to coronary angioplasty results in a dramatic reduction in the release of these inflammatory cytokines and NETs at the time of coronary angioplasty.

It is possible then, that Colchicine is potentially a new strategy to prevent No-Reflow associated with coronary angioplasty in patients with ACS.

In addition, a recent sub-analysis of the Colchicine Cardiovascular Outcomes Trial (COLCOT study, which assessed the use of colchicine vs. placebo in patients with ACS) showed that the use of colchicine mainly benefited those patients who initiated it within the first 3 days of their event and resulted in significantly fewer cardiovascular (CV) episodes (cardiovascular death, infarction, stroke, or emergency hospitalization for angina) at 2-year follow-up, compared with those who initiated it later.

IMR has been shown to have prognostic implications in ACS patients undergoing angioplasty.

The higher the value, the higher the microvascular obstruction, resulting in less myocardial recovery. Index of Microvascular Resistance (IMR) can, in fact, independently predict left ventricular function and infarct size and it is considered a therapeutic target and a relevant measurement in determining the prognosis of patients. Therefore, measurement of IMR before and after angioplasty, makes it possible to determine changes in microcirculation related to the procedure.

Therefore, investigators aim to conduct an open-label randomized controlled trial to evaluate the effects of adding colchicine to standard care among patients with acute coronary syndrome in terms of microvascular obstruction after coronary angioplasty in patients with ACS, as measured by the IMR.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective randomized comparison between colchicine versus no colchicine in terms of microvascular coronary reperfusion and infarct size in patients with acute coronary syndrome.Prospective randomized comparison between colchicine versus no colchicine in terms of microvascular coronary reperfusion and infarct size in patients with acute coronary syndrome.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effect of Colchicine on Coronary Reperfusion in Patients With Acute Coronary Syndrome

Anticipated Study Start Date :

Aug 1, 2022

Anticipated Primary Completion Date :

Oct 30, 2023

Anticipated Study Completion Date :

Oct 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Colchicine Subjects allocated to the intervention group will receive colchicine + standard of care for 6 weeks.	Drug: Colchicine Oral colchicine (1 mg loading dose followed by 0.5 mg 1 hour later, administered 6 to 24 hours before angioplasty, followed by 0.5 mg (1 comp.) per day for 6 weeks.
No Intervention: Standard of Care - Control Subjects allocated to the control group will receive only standard of care for 6 weeks.

Arm

Intervention/Treatment

Experimental: Colchicine

Subjects allocated to the intervention group will receive colchicine + standard of care for 6 weeks.

Drug: Colchicine

Oral colchicine (1 mg loading dose followed by 0.5 mg 1 hour later, administered 6 to 24 hours before angioplasty, followed by 0.5 mg (1 comp.) per day for 6 weeks.

No Intervention: Standard of Care - Control

Subjects allocated to the control group will receive only standard of care for 6 weeks.

Outcome Measures

Primary Outcome Measures

Change in Index of Microcirculatory resistance (IMR) between pre and post-coronary angioplasty. [baseline ( pre-angioplasty) and at the end of the procedure (angioplasty)]
Invasive assessment of Index of Microvascular Resistance (IMR) before and after angioplasty in both colchicine and control group.

Secondary Outcome Measures

Average value of endpoint IMR. [at the end of the procedure (angioplasty)]
Comparison of IMR obtained post- angioplasty between colchicine and control group
Change in cardiac enzyme levels (troponin) before and after angioplasty in both colchicine and control group. [baseline (pre-angioplasty) and 24 h post-angioplasty]
Measurement of Troponin before and after angioplasty in both colchicine and control group
Change in level of inflammatory markers ( Ultra-sensible C-reactive protein and IL-6) at baseline and 6 week follow-up. [baseline (prior to Colchicine administration) and at 6 weeks after discharge]
Measurement of Ultra-sensible C-reactive protein and Interleukin-6 before and after angioplasty in both colchicine and control group
Percent of salvaged myocardium. [baseline (two - four days post-angioplasty and at 6 weeks after discharge]
Measurement of salvaged myocardium using cardiac magnetic resonance imaging in both colchicine and control group

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years.
Adults hospitalized at the Clinical Hospital of the Catholic University for an ACS condition, defined as:

Presence of chest pain, associated with enzymatic elevation (increase of ultrasensitive troponin above normal value (99th percentile)) with or without electrocardiographic changes.

Patients undergoing coronary angiography with the intention of angioplasty in the next few days (during the index hospitalization).
Ability and willingness to provide written informed consent.

Exclusion Criteria:

ST-segment elevation myocardial infarction (undergoing emergency angioplasty therefore not allowing time for the administration and effect of colchicine).
Severe left main stenosis.
Advanced heart failure, left ventricular ejection fraction <35%.
Related to colchicine use: known intolerance, previous use for another condition (e.g., gout), severe liver disease (e.g., severe liver disease).
Severe liver disease (transaminase elevation 3 times above normal), blood dyscrasia (leukocyte or platelet count lower than normal), glomerular filtration rate (MDRD), use of CYP3A4 or calcineurin inhibitors, active autoimmune disease or the use of chronic anti-inflammatory therapy, concomitant infection, pregnancy or concomitant infection, pregnancy or lactation.
Any other disease that limits life expectancy to <1 year.
Medical history of a disorder that could, in the opinion of the treating physician, place the participant at significant risk if they were to participate in the trial.