Inflammation plays a key role in atherosclerosis. This point gives way to the idea of using anti-inflammatory substances as a treatment for coronary heart diseases for instance acute coronary syndrome [33, 34]. Most studies in the field focused only on CAD or evaluated both ACS and CAD together which due to distinct pathophysiology in some aspects (such as acuteness or chronicity)[35], cast doubt on the validity of results. The present analysis evaluated the effect of colchicine as secondary prevention, specifically on ACS and MI. The results of our meta-analysis revealed that ACS and MI patients who had received colchicine had a similar incidence of primary composite endpoint, MI, and GI adverse events when compared with the non-colchicine group. Of note, the stroke occurrence significantly declined following colchicine administration. Another finding was that colchicine revealed marginally significant effect on the hs-CRP serum level reduction.
hs-CRP is a non-specific inflammatory marker recognized as one of the acute phase reactants which are synthesized and released from the liver [36]. Previous studies have posed predictive effects of the high hs-CRP serum level on adverse clinical outcomes, possibly representative of persistent inflammation [37–40]. Colchicine has pleiotropic inhibitory effects on inflammation including inhibition of microtubule polymerization and also interleukin 1, interleukin 6, and NLRP3 inflammasome activation [41–43]. The key mediator, which controls the synthesis of most acute-phase proteins including hs-CRP, seems to be IL-6 [44]. Therefore, it is theoretically expected and experimentally shown that the colchicine usage decreases the hs-CRP levels which lead to fewer adverse cardiac events. In our current study, although a downward trend was observed for the hs-CRP serum level in the pooled analysis, this effect was non-significant. Apart from statistical heterogeneity which was significant for this analysis, methodological heterogeneity among the included studies should gain attention, too. The included studies were different with regard to the type and severity of diseases, loading dose of colchicine, timing of colchicine administration, follow-up duration, and the number of patients undergoing PCI in each study and even different groups of each study. These all can turn to a misleading conclusion. Another explanation for this result is the low number of studies and subjects. Since p-value closely correlates with the sample size, such that in sufficiently large scale samples almost always significant results are observed [45], considering the effect size for the current study is essential. Interestingly, SMD manifested significant medium-power effect of colchicine on hs-CRP attenuation. In the subgroup analysis, we found that 1mg per day colchicine was associated with a significant reduction in hs-CRP. These are molecular promising results which are recommended to be ascertained by clinical outcomes.
The study conducted by Roubille et al. showed the correlation between hs-CRP and infarct size and also that the peak of hs-CRP could be detected within 3 days post-MI [46]. In another study, the time-to-treatment analysis of colchicine initiation on the COLCOT study population revealed that the start of colchicine administration within 3 days was more greatly linked with a favorable composite of hard clinical outcomes [47]. We might be able to speculate that if a substance with a dampening inflammation mechanism is used for atherosclerosis treatment, the optimal outcome might be achieved through early administration. More evidence is needed to support this claim and also to determine the relationship between hs-CRP and hard clinical outcomes. Indeed, based on the current evidence, we are unable to attribute a more favorable outcome in the given study to hs-CRP attenuation as time-to-treatment analysis for the hs-CRP outcome is lacking for this study [48]. An observational study indicated significant hs-CRP reduction and plaque stabilizing effect of low dose colchicine plus optimal medical treatment in comparison with optimal medical treatment alone. A high linear correlation was found between hs-CRP change and plaque stabilizing effect in this study [49]. Although this point takes us one step closer to linking the molecular results with clinical outcomes, large-scale high-quality randomized controlled trials are needed to confirm it.
The two main hard clinical outcomes which were MI and primary composite endpoint did not change following colchicine administration. Despite the lack of heterogeneity, there are noteworthy points about these analyses. The COLCOT study [48] constituted 90% of the weight of both analyses. In this study, colchicine was started at the median of 13 days after index MI. This, along with the fact that the intervention and control groups were not matched according to culprit lesions or infarct size, could be addressed as confounding factors in the analysis. It was indicated that in the COLCOT the positive effect of colchicine on primary composite endpoint was mostly driven by stroke and urgent hospitalization for angina leading to coronary revascularization which in our study were not counted as components of composite endpoint since they were not reported in most of the studies and the limitations in conducting meta-analysis for such outcomes. Moreover, lack of effect can be partly explained by the study conducted by Tong et al. [50]. Although using colchicine at the time of index hospitalization improved the recurrence of ACS, surprisingly, the number of deaths was significantly higher in the colchicine group. Indeed, 5 out of 8 deaths that occurred in the colchicine group were due to non-cardiovascular reasons; 2 of the deceased patients suffered metastatic cancer or acute myeloid leukemia. The other 2 halted colchicine within the first month and sepsis happened 10 months thereafter. Based on the acute nature of sepsis [51], we can barely attribute the occurrence of sepsis in these cases to colchicine consumption.
One unanticipated finding was the inverse directions that were detected for MI and ACS patients regarding the primary composite endpoint. This could suggest that the more acute the inflammatory condition is, the more efficient the colchicine would be. As mentioned above, colchicine has shown better clinical outcomes when applied within the three days post-MI simultaneous with the most acute phase of the inflammation. The last-mentioned finding of our study might emphasize the consistent point, which is colchicine consumption for acute inflammation, in another way. Although the detected trend was statistically non-significant in the current study, it is worth evaluating in future research by resolving the limitations of previous studies.
In line with previous studies, in the current study colchicine consumption significantly decreased the occurrence of stroke. Khandkar et al.[52] in their meta-analysis included the studies which reported stroke as an outcome and used colchicine as the intervention. They concluded that colchicine consumption reduced the risk of stroke by about three-times. The result was prominently driven by a cohort study that evaluated colchicine as primary prevention in gout patients. The other meta-analysis conducted by Masson et al.[53] focused specifically on the patients with high cardiovascular risk and colchicine as secondary prevention means that they evaluate the effect of colchicine on ACS, CAD, heart failure, postcardiac surgery, and on those who underwent PCI. They reported three-fold fewer strokes in the colchicine group. Likewise, the meta-analysis conducted by Katsanos et al.[54] with a focus on coronary heart disease and also the current study which specifically included ACS patients have demonstrated this promising result. An explanation for the consistency among the last three is that the COLCOT study made about 70% of the weight of each analysis. Due to the restricted number of articles, further studies are needed to elucidate both the primary and secondary preventive effects of colchicine on stroke. Moreover, the mechanism of the anti-stroke effect of colchicine needs to be determined as in the present study colchicine decreased the risk of stroke contrary to MI while due to similar pathophysiology (which is inflammation), we expected the same result for both. This might be suggestive of a yet unknown colchicine mechanism of action. Improvement of stroke could not be attributed to the hs-CRP reduction in our study due to insufficient information about 2 studies which constituted more than 90% of the weight of the analysis performed for stroke.
As colchicine has a narrow therapeutic window, another subject that should obtain consideration is the adverse effects of this drug. The toxic effect of colchicine on cells has been claimed to be prominently exerted by anti-mitotic activity. Therefore, the GI tract, skin, hair, and bone marrow with high proliferative activity are at greater risk [55]. Consistent with this point, there is strong evidence that the most common adverse effects are gastrointestinal, such as diarrhea, nausea, and vomiting [41, 56]. Our study revealed similar GI adverse events between the colchicine and non-colchicine groups. Besides, we found that colchicine dosage was associated with GI adverse events and the risk of GI events could be avoided by low dose (0.5 mg/d) administration. It should be noted that our results should be treated with caution due to high statistical heterogeneity. A meta-analysis involving 14188 cardiovascular patients found that administration of colchicine was associated with nearly a two-fold rise in GI adverse events that could be avoided by low-dose application of colchicine [57]. In addition, Ullah et al. [58] in their meta-analysis reported the significantly greater harmful effect of colchicine on CAD patients. To sum up, while the current research did not indicate a higher risk of GI-related side effects, additional trials with long-term follow-up are certainly required regarding the opposite view of high-quality studies with greater number of participants. Besides, other than GI, there are more extreme side effects that need more attention, such as sepsis, myelotoxicity, etc. Sufficient evidence does not exist to conduct meta-analysis. In future long-term studies, these should be further elucidated, too.
Although the current study focused specifically on ACS patients for more reliable outcomes, there are several limitations to acknowledge. First, it is possible that the methodological heterogeneity among the included studies has affected our results. For instance, the colchicine onset, duration, daily dosage, and loading dose altogether were not completely the same in any of the two included studies. Second, hard clinical outcomes were mostly driven by the COLCOT study as this study made about 70% or more of the weight of these analyses. Indeed, COLCOT is the only multinational large-scale study on this topic. Third, we were unable to conduct a meta-analysis for some clinical outcomes as they were evaluated in only one or two studies. These include atrial fibrillation, hospitalization leading to revascularization, unstable angina, deep vein thrombosis, and pulmonary embolism. It is possible that considering these outcomes as components of MACE would change the result of the present study.
New strategies for the treatment and prevention of coronary heart disease may be identified with the understanding that inflammation plays a pathological function in atherosclerosis. Colchicine appears to have some benefits on stroke. MI and primary composite endpoint did not change following colchicine consumption in our study. Nevertheless, a better result might be achieved by consumption in more acute inflammatory conditions; it means colchicine application for more acute conditions like MI rather than all ACS which includes unstable angina and also consumption as immediate as possible following index MI. Moreover, colchicine revealed marginally significant efficacy for lowering CRP level, which is a prognostic factor for cardiovascular complications. Colchicine, especially in low doses, seems to be relatively safe in the clinical setting. However, this result should be treated with more caution, due to high statistical and methodological heterogeneity and inconsistency with the results of a larger meta-analysis.