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

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ClinicalTrials.gov Identifier: NCT05472337

Recruitment Status : Recruiting

First Posted : July 25, 2022

Last Update Posted : September 9, 2022

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Sponsor:

Collaborator:

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

Information provided by (Responsible Party):

Pontificia Universidad Catolica de Chile

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

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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.

ii) 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

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Study Type :	Interventional (Clinical Trial)
Estimated 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.
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Effect of Colchicine on Coronary Reperfusion in Patients With Acute Coronary Syndrome
Actual Study Start Date :	August 1, 2022
Estimated Primary Completion Date :	October 30, 2023
Estimated Study Completion Date :	October 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angioplasty

Drug Information available for: Colchicine

Genetic and Rare Diseases Information Center resources: Acute Graft Versus Host Disease

U.S. FDA Resources

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.

Outcome Measures

Primary Outcome Measures :

Change in Index of Microcirculatory resistance (IMR) between pre and post-coronary angioplasty. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05472337

Contacts

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Contact: Gonzalo Martínez, MD	56 223543218	gmartinezr@med.puc.cl
Contact: Maria Paz Orellana	011 56 979683630	mporella@uc.cl

Locations

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Chile
Hospital Clínico Pontificia Universidad Catolica de Chile	Recruiting
Santiago, Chile, 8330024
Contact: Gonzalo Martinez, Dr. 56 2 23543633 gmartinezr@med.puc.cl

Sponsors and Collaborators

Pontificia Universidad Catolica de Chile

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

Investigators

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Principal Investigator:	Gonzalo Martínez, MD	Pontificia Universidad Catolica de Chile

More Information

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Responsible Party:	Pontificia Universidad Catolica de Chile
ClinicalTrials.gov Identifier:	NCT05472337
Other Study ID Numbers:	210507002
First Posted:	July 25, 2022 Key Record Dates
Last Update Posted:	September 9, 2022
Last Verified:	July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Pontificia Universidad Catolica de Chile:


Colchicine Myocardial Infarction Myocardial Ischemia Heart Diseases	Cardiovascular Diseases Acute Coronary Syndrome Myocardial Reperfusion Anti-Inflammatory Agents

Additional relevant MeSH terms:

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Acute Coronary Syndrome Syndrome Disease Pathologic Processes Myocardial Ischemia Heart Diseases Cardiovascular Diseases Vascular Diseases	Colchicine Gout Suppressants Antirheumatic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents

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