Colchicine is associated with a decreased Risk for myocardial infarction in patients with GoutA systematic review and meta-analysis

Objective: This meta-analysis aimed to identify the effects of Colchicine on myocardial infarction (MI) in patients with Gout. Methods: In July 2018, a systematic computer-based search was conducted in PubMed, EMBASE, and Cochrane Database of Systematic Reviews. Data on patients with Gout that compared Colchicine versus others (non-used Colchicine) were retrieved. The endpoints were the incidence rate for MI. After testing for heterogeneity between studies, data were aggregated for random-effects models when necessary. Results: Three clinical studies with 114371 patients (Colchicine group=1063, control group=113308) were finally included in the meta-analysis. Colchicine was associated with a decreased Risk for myocardial infarction (95% CI, 0.25, 0.33, P=.000). Conclusions: Colchicine was efficacious in the reduction of the incidence rate for MI in patients with Gout.


Background
Myocardial infarction (MI) is the main cause of death in some chronic diseases, especially in patients with inflammatory diseases [1]. Gout, the common types of inflammatory arthritis caused by deposits of monosodium urate (MSU) crystals, is associated with the increasing of cardiovascular disease (especially MI) morbidity and mortality [2]. Gout causes cardiovascular diseases (CVD) mainly due to hyperuricemia and serum uric acid induced inflammatory response [3]. Therefore, the main treatment of this disease is antiinflammatory and uric acid lowering [4]. Recently, several studies and a meta-analysis have illustrated a protective effect of urate-lowering therapies (febuxostat and allopurinol) against MI [5][6][7]. However, early use of anti-inflammatory drugs (such as: colchicine) therapy for gout patients weather can also reduce cardiovascular events [8].
3 Colchicine is derived from the bulb-like corms of the Colchicum autumnale plant, also known as autumn crocus, and is widely used for treatment of acute gout flares, prophylaxis against gout flare [9,10]. Several retrospective observed studies have assessed the efficacy of Colchicine in the reduction of the incidence rate for MI in patients with Gout [11][12][13]. Other trials contained non-controlled observational studies and demonstrated inconsistent results [8,14]. Additionally, large sample clinical studies are emerging, and it is necessary to reevaluate the efficacy of Colchicine for reducing the incidence rate for MI in patients with Gout. The aim of this meta-analysis was to assess whether Colchicine can decrease the incidence rate for MI in patients with Gout.

Methods
This systematic review and meta-analysis was reported according to the previous reporting items as follow PRISMA guidelines [15]. The following studies were excluded: (a) reviews, (b) case report, (c) no reports associated with gout and MI, (d) data cannot be extracted.
Data extraction and quality assessment Two searchers (ZX and LY), collected data on the study design, sample size, treatments, research group and control group according to the previous formulation. Cochran's Q test, at p<0.05 and the I² statistic were used to evaluate the statistical 5 heterogeneity of the study. High values indicated that the study had high heterogeneity.
Significant heterogeneity of meta-analyses used a random-effects model. Statistical analysis was performed by RevMan V.5.3. p <0.01 was as statistically significant.
Publication bias was performed by funnel plots and Egger's test.

Eligible studies
In the preliminary search, finally, 64 studies were searched from the electronic databases (EMBASE = 4, Web of Science = 55, Cochrane Library = 5). In order to delete duplicate papers, all papers were imported into Endnote X9 (Thomson Reuters Corp., USA) software.
A total of 63 papers were reviewed and 61 papers were removed according to the inclusion criteria at abstract and title levels. Finally, 3 papers (including an additional records identified through other sources) with 114371 patients (Colchicine group = 1063, control group = 113308) were included in the meta-analysis [11][12][13].

Study characteristics
The flow diagram for the included studies can be seen in Fig 1. The general characteristics of the included studies can be seen in Table 1

Outcomes of the meta-analysis
We included three studies comparing MI incidence between colchicine ever users and never users (see Table 1) [11][12][13]. In a nested case-control research, presented as an abstract from the 2014 ACR annual meeting, incidence of MI was not decreased among patients with RA with colchicine use (RR 0.28 (95% CI 0.24 to 0.32)) [11]. In a retrospective, cross-sectional study, MI risk was reduced with colchicine treatment (RR 0.46 (95%CI 0.19 to 1.06)) [12]. In a retrospective research of an incident Gout cohort, colchicine use relative to the decreased incidence of MI (RR 0.40 (95% CI 0.23 to 0.68) 6 [13]. MI incidence was lower for colchicine ever users than never users (pooled RR 0.29 (95% CI 0.25 to 0.33, p 0.00001)) (Fig 3).

Discussion
By searching literature, this is the first systematic review with meta-analysis of the correlation between Colchicine using and a decreased incidence of MI in patients with Gout. According to our results, Colchicine has a positive impact on reducing incidence of MI in patients with Gout.
Our meta-analysis showed lower incidence of MI in patients with Gout for Colchicine users than Colchicine non-users. Our literature search highlighted two other studies consistent with this findings but data could not be extracted for meta-analysis[18]. This finding was confirmed in several publications [12,13,18], reporting reduced MI/CVE incidence with Colchicine use among patients with Gout. However, Dubreuil, M. [11]also reported that colchicine use was not associated with a reduced risk of MI among persons with gout, which could be related to not rule out some potential confounding factors.
So, according to our results, early using Colchicine could have significant benefit for reducing the MI incidence in patients with Gout. Yet, RCT studies are lacking, and Future studies should identify a larger sample of continuous colchicine users to clarify its potential cardio-protective role in Gout.

Conclusion
In conclusion, gout patients who took colchicine may reduce incidence of MI versus those who did not take colchicine.

Limitations
Several limitations as follow up: First, no specialized RCTs about this topic to date, Only part data from observational studies was extracted, which certainly was bound to produce 7 some unavoidable bias, comprising: namely design bias, selection bias, treatment bias and publication bias. Moreover, patients with history of CVD were from these observational studies. Finally, By summarizing some published studies, we can find out the incidence of cardiac infarction in each study take the place of individual patient-level data, so producing confounding and selection bias could not be avoided in these studies.   Figure 1 Elaborated searching strategies of the systematic literature review with metaanalysis.

Abbreviations
12 Figure 2 Risk of bias of all included trials.
13 Figure 3 Forest plots of RR for MI incidence among Colchicine ever users and never users.