Abstract
Introduction
Myocardial infarction (MI) is associated with a significant post-event inflammatory response which further contributes to post-MI prognosis. Colchicine, an anti-inflammatory agent, exhibits potential benefits in various cardiovascular conditions such as coronary artery disease, pericarditis and atrial fibrillation. This meta-analysis predominantly aimed to provide an up-to-date evaluation of the efficacy and safety of colchicine in reducing adverse cardiovascular events in patients following acute MI.
Methods
A Comprehensive search was conducted on PubMed, Cochrane Library, Scopus, Google Scholar and clinicaltrials.gov for randomized controlled trials (RCTs) investigating the effect of colchicine on patients with MI from inception till May 2024. Our primary outcome was a composite of adverse cardiovascular events, while secondary outcomes included all-cause mortality, incidence of stroke, incidence of cardiac arrest, hospitalization urgency, incidence of recurrent MI, adverse gastrointestinal events and levels of high-sensitivity C – reactive protein (Hs-CRP). Risk ratios (RR) and mean differences (MD) were pooled under the random-effects model.
Results
Eleven trials with 7161 patients were included in our analysis out of which 3546 (49.51 %) were allocated to colchicine and 3591 (50.14 %) received placebo. Colchicine demonstrated statistically significant reduction in the composite of adverse cardiovascular events (RR = 0.75, 95 % CI: 0.60-0.94, P = 0.01, I 2 = 47 %), and hospitalization urgency (RR = 0.46, 95 % CI: 0.31-0.68, P = 0.0001, I 2 = 0 %) but statistically significant increment in adverse gastrointestinal events (RR = 1.86, 95 % CI: 1.14-3.02, P = 0.01, I 2 = 79 %). However, all-cause mortality (RR = 1.00, 95 % CI: 0.72-1.39, P = 0.98, I 2 = 0 %), incidence of cardiac arrest (RR = 0.81, 95 % CI: 0.33-1.95, P = 0.63, I 2 = 0), incidence of stroke (RR = 0.45, 95 % CI: 0.17-1.19, P = 0.11, I 2 = 36 %), incidence of recurrent MI (RR = 0.78, 95 % CI: 0.57-1.06, P = 0.11, I 2 = 11 %) and the levels of hs-CRP (MD= -0.87, 95 %CI: -1.80-0.06, P=0.07, I 2 =67 % remained comparable across the two groups.
Conclusion
The use of colchicine post-MI reduces the composite of adverse cardiovascular events, and hospitalization urgency but increases adverse gastrointestinal events. However, colchicine does not impact all-cause mortality, cardiac arrest, stroke incidence, incidence of recurrent MI and the levels of hs-CRP. Large scale multicenter RCTs especially with longer follow-up duration are warranted to validate these findings.
Graphical abstract
Central Illustration highlighting key findings on effect of colchicine on patients with myocardial infarction
Introduction
Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide, with inflammation significantly contributing to the development of MI and prognosis post-MI. Following MI, the inflammatory response initially plays a protective role by removing necrotic debris and promoting tissue repair. However, sustained inflammation can lead to adverse outcomes such as detrimental cardiac remodeling, fibrosis and impaired contractility and ultimately worsening prognosis marked by elevated C-reactive protein (CRP) and interleukin-6 (IL-6). , Among the anti-inflammatory medications in circulation, colchicine stands out due to its established safety and efficacy in managing other inflammatory disorders such as gout, familial Mediterranean fever and pericarditis. , Clinical trials have explored its effectiveness in managing other cardiovascular conditions including atrial fibrillation following surgery or ablation, coronary artery disease (CAD), percutaneous coronary interventions and cerebrovascular disease.
Colchicine disrupts cellular functions by binding to tubulin and inhibiting its polymerization, particularly affecting neutrophils. , It ultimately reduces immune migration to damaged areas, decreases immune cell adhesion to the endothelium and suppresses the secretion of inflammatory molecules. , Additionally, colchicine inhibits the NLRP3 inflammasome causing a reduction in IL-1β and IL-18. These cytokines drive inflammation and are linked to increased levels of Hs-CRP and IL-6, both of which are markers of inflammation. , Moreover, colchicine reduces cardiac fibrosis and vascular stenosis by inhibiting the proliferation of myofibroblasts and smooth muscle cells and reduces cardiac remodeling by lowering Matrix metalloproteinase 9 (MMP-9), NADPH oxidase 2 (NOX2) and TGF-β1 (Transforming growth factor beta-1). ,
Formerly published meta-analyses conducted on the following topic recruited a restricted number of trials and also proved to be ineffective in interpreting heterogeneity due to insufficient evidence. Hence, we sought to perform an updated systematic review and meta-analysis to demonstrate the efficacy and adverse effect of colchicine in MI while incorporating recently published randomized control trials. This study will encourage to better guide clinical decisions, optimize treatment strategies and pave the way for further research in this respective area.
Methods
This review was prospectively registered with Prospero ( CRD42024540702 ). It has been conducted in agreement with the guidelines established in the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Compliance with these guidelines ensures transparent and coherent reviews allowing for global interpretation and reliance.
Searching of databases
A comprehensive literature search was performed across major electronic databases including PubMed, Scopus, Cochrane Library, Google Scholar, clinical trials.gov. Eligible randomized controlled trials were recognized from beginning through May 2024 by two authors (T.K, Z.A) using the following MeSH (Medical Subject Headings) terms: Myocardial infarction [Mesh] and Colchicine; [Mesh]. Acquired articles were subsequently transferred onto Rayyan.ai. Further information on the comprehensive search results is accessible in the supplementary file. Furthermore, the citation lists of pertinent meta-analyses were manually examined to ensure thorough inclusion of evidence.
Screening and selection
A transparent evaluation process was established using Rayyan.ai. comprising both initial and subsequent evaluations. A total of 93 articles were retrieved from the databases searched. Following the elimination of 10 duplicates, 83 articles advanced to primary screening. After assessing the title and abstracts, 28 articles remained for additional consideration. A subsequent full-text screening recognized 17 articles for exclusion due to either the lack of intended outcomes or the inclusion of unsuitable population. Subsequently, 11 RCTs satisfied our inclusion criteria ( Fig. 1 ).
Eligibility criteria
We included adult participants in randomized controlled trials (RCTs) that examined the effects of colchicine treatment, regardless of dosage or mode of administration for certain time duration. The treatment was compared to a placebo or no treatment. Our group of interest included patients who experienced MI, regardless of the type or their diabetic status. More specifically, our main inclusion criteria were as follows: (1) study design: Randomized controlled trials (RCTs); (2) patient population: Patients with MI (both STEMI and NSTEMI) diagnosed by coronary angiography with a follow-up duration of 1 month or more; (3) intervention: colchicine, irrespective of the type, dosing regimen or route of administration; (4) comparator: placebo or standard of care; (5) Outcome: outcomes of interest included; and (6) studies that exclusively discuss MI.
The exclusion criteria were as follows: (1) all study designs other than RCTs, such as quasi-randomized trials and observational studies; (2) studies conducted on animals or children; (3) studies that included patients with any ischemic heart disease rather than specifically focusing on MI; (4) studies with only abstract available; and (5) studies that did not report the specific outcomes of interest. No language or date restrictions were applied.
Outcomes
A composite of adverse cardiovascular events was our primary outcome. Secondary outcomes included all-cause mortality, adverse gastrointestinal effects, incidence of stroke, incidence of cardiac arrest, incidence of recurrent MI, incidence of urgent re-hospitalization and hs-CRP levels.
Risk of bias assessment
Two authors (A.Y and Z.A) independently evaluated the risk of bias in the included studies using the revised Cochrane Risk of Bias Tool for RCTs (RoB 2.0). Bias was assessed using the following five domains: (1) bias from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in the measurement of the outcome; and (5) bias in the selection of the reported result. Risk of bias for each included study was categorized as either high, low or some concerns of bias. Any discrepancies regarding the risk of bias were settled by consensus ( Fig. 2 ).
Data extraction
Two authors were involved in creating a standardized data extraction form to collect relevant data from the included studies. Study information extracted included: author names, study design, and sample size. Baseline characteristics were recorded and included age, body mass index (BMI), smoking status, hypertension, diabetes, dyslipidemia, follow-up duration for colchicine. Outcomes extracted included adverse cardiovascular events, adverse gastrointestinal events, all-cause mortality, incidence of stroke, incidence of cardiac arrest, incidence of recurrent MI, hs-CRP levels and hospitalization urgency.
Statistical analysis
Statistical analysis were performed using Review Manager (RevMan) version 5.4.1, in line with recommendations from the Cochrane Collaboration and the PRISMA guidelines. Outcomes were analyzed using a random effects model (DerSimonian and Laird) and summary estimates were reported as pooled risk ratios (RR) and mean differences (MD) with 95 % confidence intervals (CI). Statistical heterogeneity was quantified with Higgin I 2 statistics. Heterogeneity was defined as low, moderate or high based on I 2 values of 25 %, 50 % and 75 % respectively. The value of analysis was performed on an intention-to-treat basis. A two-sided p-value of 0.05 was considered significant. Publication bias for the primary outcome was visually assessed with funnel plots. Moreover, due to limited number of studies (fewer than 10) for each outcome, we excluded the application of Egger’s regression test to analyze publication bias.
Certainty of evidence assessment
Certainty of evidence was assessed using the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluations) which evaluates five key considerations: risk of bias, inconsistency, indirectness, imprecision and publication bias. Each body of evidence was rated as being of high, moderate, low or very low certainty. ,
Results
Eleven RCTs exactly matched our PICOS and inclusion criteria ( Fig. 1 PRISMA flowchart). In these RCTs, 7161 patients with MI were involved in the randomization process out of which 3546 (49.51 %) were allocated to colchicine and 3591 (50.14 %) received placebo. There was a considerable variation in terms of follow-up duration, ranging from 5 days to greater than 1 year. Characteristics of the included trials and patient baseline characteristics are summarized in Table 1 .
| Author name | TYPE | Parameters | Sample Size | Age, years | Smoking, n% | Diabetes mellitus, n (%) | Hypertension, n (%) | Dyslipidemia, n (%) | BMI, n (%) | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|---|---|
| Bouleti C et al. | RCT | Colchicine | 101 | 59.0 ± 10.6 | 44(43.6) | 12/101 (11.9) | 30(29.7) | 29/101 (28.7) | 27.3 ± 5.0 | 12 months |
| Placebo | 91 | 60.9 ± 10.4 | 39(42.9) | 13/91 (14.3) | 29 (31.9) | 34/91 (37.4) | 26.9 ± 4.4 | |||
| Tardif JC et al. | RCT | Colchicine | 2366 | 60.6 ± 10.7 | 708 (29.9) | 462 (19.5) | 1185 (50.1) | NA | 28.2 ± 4.8 | NA |
| Placebo | 2379 | 60.5 ± 10.6 | 708 (29.8) | 497 (20.9) | 1236 (52.0) | NA | 28.4 ± 4.7 | |||
| Roubille F et al. | RCT | Colchicine | 462 | 62.5 ± 10.4 | 127(27.5) | 462 | 337(72.9) | NA | 29.7 ± 5.1 | NA |
| Placebo | 497 | 62.4 ± 10.7 | 122(24.5) | 497 | 381(76.7) | NA | 30.2 ± 5.2 | |||
| Hennessy et al. | RCT | Colchicine | 111 | :61 ± 13.6 | 77 (65 %) | 27(23 %) | 64 (54 %) | NA | 28(25-30) | 1 months |
| Placebo | 113 | 61 ± 12.5 | 67 (57 %) | 25 (21 %) | 48(41 %) | NA | 28(26-30) | |||
| akodad et al. . | RCT | Colchicine | 23 | 60.1 ± 13.1 | 17 (73.9) | 3 (13.0) | 9 (39.1) | 8 (34.8) | NA | 1 Month |
| Placebo | 21 | 59.7 ± 11.4 | 14 (66.7) | 3 (14.3) | 10 (47.6) | 8 (38.1) | NA | |||
| Wasyanto et al. | RCT | Colchicine | 16 | 57.87 | 13 (41) | 3(9) | 8 (25) | 3(9) | NA | 5 Days |
| Placebo | 16 | 52.87 | 10 (31) | 4(13) | 7(22) | 1(3) | NA | |||
| .Deftereos et al. | RCT | Colchicine | 74 | 58 ± 12.72 | 13 (17) | 13 (17) | 31 (40) | 44 (57) | 27.1 (25.3–30.7) | 5 Days |
| Placebo | 77 | 58 ± 8.98 | 19 (26) | 19 (26) | 29(39) | 35 (47) | 27.1 (24.6–30.8) | |||
| Gholoobi et al. | RCT | Colchicine | 75 | 60.87 ± 7.9 | 40 (53.3 %) | 40 (53.3 %) | NA | 197.58 ± 35.56 | NA | 1 Month |
| Placebo | 75 | 61.97 ± 5.4 | 34(45.3 %) | 40 (53.3 %) | NA | 219.46 ± 37.74 | NA | |||
| Mewton et al. | RCT | Colchicine | 101 | 59.0 ± 10.6 | 12/101 (11.9) | 12/101 (11.9) | 30(29.7) | 29/101 (28.7) | 27.3 ± 5.0 | 2 Month |
| Placebo | 91 | 60.9 ± 10.4 | 13/91 (14.3) | 13/91 (14.3) | 29(31.9) | 34/91 (37.4) | 26.9 ± 4.4 | |||
| Caesario et al. | RCT | Colchicine | 92 | 56.43 ± 8.96 | 32 (34.8 %) | 32 (34.8 %) | 53 (57.6 %) | 78 (84.7 %) | 1.73 ± 0.32 | 3 Month |
| Placebo | 104 | 55.47 ± 9.68 | 43 (41.3 %) | 43 (41.3 %) | 69 (66.3 %) | 83 (79.8 %) | 1.69 ± 0.24 | |||
| Akrami et al. | RCT | Colchicine | 122 | 56.9 ± 7.56 | 27 (22.5) | 27 (22.5) | 52(43.3) | 37 (30.8) | NA | 6 Month |
| Placebo | 129 | 56.89 ± 7.45 | 32 (24.8) | 32 (24.8) | 59(45.7) | 36 (27.9) | NA |
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