ORIGINAL ARTICLE
Role of Colchicine in Reducing Reperfusion Injury in STEMI Patients Who Undergo Primary Percutaneous Coronary Intervention: A Randomized Clinical Trial Birry Karim1,2.
Idrus Alwi2.
Mohammad Yamin2.
Merci Monica Pasaribu3.
Kuntjoro Harimurti4.
Nafrialdi5.
Taufik Indrajaya6.
Rivaldo7 Doctoral Program in Medical Sciences.
Faculty of Medicine Universitas Indonesia.
Jakarta.
Indonesia.
Division of Cardiology.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Department of Clinical Pathology.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo National Referral Hospital.
Jakarta.
Indonesia.
Division of Geriatric.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Department of Pharmacology and Therapeutic.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Division of Cardiology.
Department of Internal Medicine.
Faculty of Medicine Universitas Sriwijaya - Mohammad Hoesin Hospital.
Palembang.
Indonesia.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
*Corresponding Author:
Birry Karim.
MD.
PhD.
Division of Cardiology.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jl.
Diponegoro no.
Jakarta 10430.
Indonesia.
Email: drbirrykarim@ ABSTRACT Background: Inflammation plays a role in ST-segment elevation myocardial infarction (STEMI), especially in reperfusion injury (RI).
Colchicine, an anti-inflammatory drug, can suppress inflammation during RI.
assessed the effectiveness of administering colchicine to STEMI patients undergoing primary percutaneous coronary intervention (PPCI) in suppressing RI events.
Methods: This study was a randomized, double-blind, placebo-controlled clinical trial conducted in a multicenter manner at two hospitals in Jakarta with IKPP facilities from December 2022 to April 2023.
STEMI patients that underwent PPCI received 2 mg of colchicine as a loading dose and a maintenance dose of 0.
5 mg every 12 hours for two days or amylum at a similar dose.
Patients were observed for RI events .
ow-flow thrombolysis in myocardial infarction .
Ae.
during angiography procedure, reperfusion arrhythmia, cardiogenic shock, or persistent chest pai.
Results: Seventy-seven STEMI patients with a mean age of 55.
2 A 9.
9 years underwent PPCI.
Of these patients, 37 received colchicine, and 40 received a placebo.
Most subjects were male .
5%), suffered three-vessel disease .
15%), and occlusion in left anterior descending coronary artery .
24%).
Colchicine was found to fail to reduce the incidence of ischemia-RI .
5% vs.
p = 0.
Analysis of comorbidities .
ypertension, chronic kidney disease, diabetes mellitus, and obesit.
and angiography results .
essel disease, lesion diameter, and culprit arter.
failed to demonstrate a statistical difference in RI.
Side effects were similar in the colchicine and placebo groups .
6% vs.
15%).
Conclusion: Colchicine administration in STEMI patients undergoing PPCI failed to reduce RI.
Keywords: Colchicine, inflammation, reperfusion injury.
PPCI.
STEMI.
Acta Med Indones - Indones J Intern Med A Vol 57 A Number 1 A January 2025
Birry Karim
INTRODUCTION
ST-segment elevation myocardial infarct (STEMI) is one form of acute coronary syndrome (ACS) that occurs when coronary artery occlusion results in prolonged cardiomyocyte ischemia and, subsequently, necrosis of myocardium.
The prevalence of cardiovascular disease in Indonesia, according to the 2018 National Heart Survey, is 1.
5%,1 a figure that increased from the 63% of 2013.
2 The global prevalence of STEMI varied from 3.
8% in individuals <60 years of age to 9.
5% in the Ou 60 years of age 3 STEMI incidence from South Asia.
Latin America, and Eastern Europe exhibit rising trends attributable to smoking, obesity, and physical inactivity.
Despite significant advances and innovations in STEMI management, including the development of the STEMI code, double antiplatelet therapy, fibrinolytic, and primary percutaneous coronary intervention (PPCI).
STEMI-associated mortality remains high.
The in-hospital case fatality rate ranges from 9.
7 to 13.
5%, whereas 30-day, 1-year, and 5-year all-cause mortality rates for STEMI patients undergoing PPCI were 7.
4%, and 23.
3%, respectively.
5,6 However, when STEMI patients experienced cardiogenic shock, admission to an intensive cardiac care unit (ICCU) and 30-day mortality reached 43.
7% and 50.
High mortality rates in STEMI patients may be associated with reperfusion injury (RI), manifested as reperfusion arrhythmia, myocardial stunning, microvascular obstruction, and intramyocardial hemorrhage.
8 RI is mediated by various proinflammatory cytokine or biological agents, such as IL .
IL-1.
IL-6, tumor necrosis factor-alpha (TNF-), eicosanoids, and nitric oxide.
9,10 One of the main intracellular effectors of RI is the NLRP3-ASC-caspase inflammasome pathway, which is stimulated by DAMP and PAMP and increases IL-1 synthesis.
Despite numerous pharmacological agents and various interventions developed to reduce RI, an effective treatment has not yet been established.
Colchicine is an anti-inflammatory drug extracted from the Colchicum plant.
Colchicine anti-inflammatory effects are exerted through various mechanisms, such as disruption of Acta Med Indones-Indones J Intern Med microtubule formation in inflammatory cells, anti-mitotic effect, inhibition of neutrophil chemotaxis, adhesion, recruitment, and mobilization, inhibition of reactive oxygen species (ROS) formation, and inhibition of the NLRP3 inflammasome pathway.
12 Colchicine has been effectively used in the treatment of pericardial disease and prevention of postoperation atrial fibrillation.
Colchicine also significantly reduces the rate of major adverse cardiovascular events in stable coronary artery Nevertheless, data on the efficacy of colchicine in ACS are still conflicting.
13 Our study aims to analyze colchicineAos effect on RI in STEMI patients undergoing PPCI.
METHODS
This randomized double-blind controlled clinical trial was conducted from December 2022 to April 2023 in Cipto Mangunkusumo Hospital (CMH) and Jantung Jakarta Hospital (JJH).
The eligibility criteria for the patients enrolled in this trial were a STEMI diagnosis based on clinical signs and electrocardiography findings, 18Ae80 years of age.
PPCI in the catheterization laboratory at CMH or JJH, and written informed consent by patients and their families to enroll in this clinical Patients with a history of malignancy, allergy to contrast media, stroke in the last three months, coronary artery bypass graft in the last three years, inflammatory bowel disease, chronic diarrhea, chronic kidney disease (CKD) with eGFR < 30 ml/minute, chronic liver disease, autoimmune, or steroid usage were excluded.
The study subject was divided into two arms: the intervention arm and the placebo arm.
Each arm received standard medical therapy for STEMI treatment .
xygen, double antiplatelet therapy, and stati.
and underwent PPCI.
The intervention arm received 2 mg of colchicine as the initial loading dose .
our tablet.
ne table.
every 12 hours for two days.
The placebo arm received 2 mg of amylum as the initial dose .
our tablet.
and 500 mg of amylum .
ne table.
every 24 hours for two After PPCI was performed, subjects were monitored for two days to observe the incidence of RI.
The patient was admitted to the ICCU for 48 hours and assessed clinically and through an Vol 57 A Number 1 A Jnauary 2025 Role of Colchicine in Reducing Reperfusion Injury in STEMI Patients ICCU monitor.
The subject was assessed for RI as the primary outcome, including reperfusion arrhythmia, cardiogenic shock, persistent chest pain, or low flow TIMI 0Ae2 during the angiography procedure.
Demographic data, including age, sex, body mass index, onset of STEMI, history of diabetes, hypertension, dyslipidemia, coronary artery disease, smoking, and CKD, were collected at the initial evaluation.
Results of PPCI, including culprit artery and number of vessels affected, were also retrieved.
A computer-assisted randomization technique of random block allocation technique with a combination of four blocks was used by the Epidemiology Unit of the Internal Medicine Department.
Until the end of the study, the assignment of patients to each arm remained blinded to patients, investigators, nurses, pharmacists, emergency medical officers, field officers, and attending physicians who performed PPCI.
Both arms received drug pills of the same size, number, and appearance.
Data analysis was carried out using the SPSS 20 program.
Descriptive data are displayed in table form.
The KolmogorovAeSmirnov test was carried out to determine the normality of the data.
Differences in the proportion of RI events between the two intervention groups were calculated using the Chi-square test.
The implementation of this research complied with the principles of the AuDeclaration of HelsinkiAy and the principles outlined in the AuGuideline for Good Clinical PracticeAy from the ICH Tripartite Guideline (ICH-GCP) as well as local regulations applicable in Indonesia.
This research has received a letter of passing ethical review from the Permanent Committee for Medical Research Ethics.
FKUI-RSCM.
Jakarta.
No.
KET-1057/UN2.
F1/ETIK/PPM.
02/2022.
This study was registered in the clinical trials database registry at w.
gov with the identification number NCT05734612.
RESULTS
This study enrolled 104 patients with STEM.
Among them, 20 patients were excluded based on exclusion criteria.
three declined to participate, and the attending physician of one patient refused to collaborate.
The remaining 80 patients were evenly randomized into two groups: the intervention arm .
= .
and the placebo arm .
= .
Unfortunately, three patients in the intervention group inadvertently received incorrect drugs.
Thus, 37 patients in the intervention arm and 40 in the placebo arm successfully completed the study without The recruitment, allocation, follow-up, and analysis process are illustrated in Figure 1.
104 STEMI patients screened .
Excluded .
- Refuse to participate .
- Falls into exclusion criteria .
- Attending physician refuse to participate .
Recruitment Randomization .
= Allocation Colchicine Allocation Received drugs .
Placebo Allocation Received drugs .
Follow-Up Drop out .
, wrong drugs Drop out .
Followed-Up .
Followerd-Up .
Analysis Analyzed .
Analyzed .
Figure 1.
Study subject recruitment, randomization, allocation, follow-up, and analysis flow chart.
Birry Karim Acta Med Indones-Indones J Intern Med The mean age of the participants was 55.
A 9.
9 years, with the majority being male .
6%).
There were no statistically significant differences in demographic characteristics between the intervention and control arms (Table .
Each participant had comorbidities, such as diabetes, hypertension, dyslipidemia, a history of smoking, obesity.
CKD, and coronary artery disease.
Smoking history was the most prevalent comorbidity .
42%).
The majority of subjects had two risk factors .
27%).
considerable number of participants .
experienced three-vessel disease .
VD), with the left anterior descending artery (LAD) being the most frequently affected infarct-related artery .
24%).
RI was observed in 18 .
6%) of the subjects of the intervention arm and 17 .
of the placebo arm (Table .
, which was not statistically significant .
= 0.
Analysis of the relationship between various comorbidities, such as diabetes mellitus, hypertension, smoking, obesity.
CKD, and RI incidence shows no difference .
> 0.
Subsequent analysis of the angiography results reports, such as culprit artery, number of the lesions, and lesion diameter, also shows no statistical difference .
> 0.
During follow-up, adverse events were No serious adverse events occurred.
Non-serious adverse events were found in a total of eight subjects in the colchicine drug intervention group, as listed in Table 3.
Of the eight side effects, the most common complaint was diarrhea in six patients .
%).
Meanwhile, other side effects include gastrointestinal bleeding in the form of melena .
7%) and hematemesis .
7%).
Table 1.
Baseline Subject Characteristics Colchicine n = 37 3 A 10.
Placebo n = 40 15 A 9.
STEMI onset .
ean A SD) 0 A 2.
19 A 3.
Comorbidities, n (%) Diabetes mellitus Dyslipidemia Hypertension Smoking Obesity Chronic kidney disease Coronary artery disease 15 .
Subject characteristics Age .
ean A SD) Sex, n (%) Male
Female Coronary angiography, n (%) CAD 1VD
CAD 2VD
CAD 3VD
Infarct location, n (%) LAD
LCx
RCA
p-value *= Chi-square test.
A= Independent t-test.
SD= standard deviation.
CAD = coronary artery disease.
VD= vessel disease.
LAD = left anterior descending artery.
LCx = left circumflex artery.
RCA= right coronary artery Vol 57 A Number 1 A Jnauary 2025 Role of Colchicine in Reducing Reperfusion Injury in STEMI Patients Table 2.
Relation of Intervention.
Comorbidities, and Angiography Results and Reperfusion Injury Reperfusion injury, n = 35 No reperfusion injury, n = 42 18 .
Intervention, n (%) Colchicine Placebo
Comorbidities, n (%) Diabetes mellitus No diabetes mellitus Hypertension No hypertension Obesity No obesity CKD
No CKD
Smoking No smoking Angiography results Culprit artery, n (%) LAD
LCX
RCA
Vessel disease (VD), n (%) Lesion diameter, n (%) < 3 mm Ou 3 mm p-value *= Chi-square test, **= Fisher exact test.
CKD = Chronic kidney disease Table 3.
Colchicine Side Effects Side effects Colchicine .
= .
Placebo .
= .
Diarrhea, n (%) Hematemesis, n (%) Bloating, n (%) Nausea and vomiting, n (%) Melena, n (%) 6 .
DISCUSSION