a b s t r a c t

Introduction: The efficacy of colchicine administration in patients undergoing percutaneous coronary interven- tion (PCI) remains controversial. We conduct a systematic review and meta-analysis to explore the influence of colchicine administration versus placebo on treatment efficacy for PCI. Methods: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane Library databases through June 2020 for Randomized controlled trials assessing the effect of colchicine administration versus placebo in pa- tients with PCI. This meta-analysis is performed using the random-effect model.

Results: Five RCTs involving 5526 patients are included in the meta-analysis. Overall, compared with control group for myocardial infarction patients undergoing PCI, colchicine intervention can significantly reduce major adverse cardiovascular events (OR = 0.78; 95% CI = 0.62 to 0.97; P = 0.02), but reveals no obvious impact on mortality (OR = 0.89; 95% CI = 0.60 to 1.32; P = 0.57), myocardial infarction (OR = 0.88; 95% CI = 0.67 to

1.17; P = 0.39), serious adverse events (OR = 0.71; 95% CI = 0.31 to 1.61; P = 0.41), or restenosis (OR =

1.02; 95% CI = 0.63 to 1.64; P = 0.95).

Conclusions: colchicine treatment may be effective to reduce major adverse cardiovascular events in patients un- dergoing PCI.

(C) 2021 Published by Elsevier Inc.

1. Introduction

Myocardial infarction has become a leading cause of mortality and morbidity, and percutaneous coronary intervention is widely accepted as the most effective treatment strategy [1-5]. Cardiomyocytes may be injured by acute restoration of Myocardial blood flow [6,7]. Vascular in- jury during PCI results in rapid neutrophil recruitment and subsequent inflammatory cascade which is associated with endothelial dysfunction and microvascular obstruction [8,9]. Inflammation during PCI may also increase the risk of myocardial injury and mortality [10].

Colchicine may have the protective effects on PCI patients via inhibiting neutrophil chemotaxis and activity in response to Vascular injury, active IL (interleukin)-1? and neutrophil-platelet aggregates [11-13]. A 2-dose regimen of colchicine (1.2 mg followed by 0.6 mg ad- ministered over an hour) showed rapid anti-inflammatory effects. 23 In one RCT involving 4745 patients, low-dose colchicine (0.5 mg once daily) after PCI resulted in a significantly lower risk of ischemic cardio- vascular events than placebo [14].

* Corresponding author at: No. 316, Section 2, jiugu Avenue, Jiangyang District, Luzhou City, China.

E-mail address: [email protected] (C. Fu).

Several studies have explored the efficacy of colchicine in PCI pa- tients, but the results have been conflicting [14-16]. With accumulating evidence, we therefore perform a systematic review and meta-analysis of RCTs to investigate the efficacy of colchicine administration versus placebo in patients with PCI.

1. Materials and methods

Ethical approval and patient consent are not required because this is a systematic review and meta-analysis of previously published studies. The systematic review and meta-analysis are conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Re- views and Meta-Analyses) [17].

• 1. Search strategy and study selection

Two investigators have independently searched the following data- bases (inception to June 2020): PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. The electronic search strategy is conducted using the following keywords: colchicine, and myocardial infarction or percutaneous coronary intervention. We also check the reference lists of the screened full-text studies to identify other poten- tially eligible trials.

https://doi.org/10.1016/j.ajem.2021.02.039 0735-6757/(C) 2021 Published by Elsevier Inc.

The inclusive selection criteria are as follows: (i) population: pa- tients undergo PCI; (ii) intervention treatments are colchicine adminis- tration versus placebo; (iii) study design is RCT.

• 1. Data extraction and outcome measures

We have extracted the following information: author, number of pa- tients, age, male, history of myocardial infarction and PCI, detail methods in each group etc. Data have been extracted independently by two investigators, and discrepancies are resolved by consensus. We also contact the corresponding author to obtain the data when necessary.

The primary outcome are mortality and major adverse cardiovascu- lar events (which are defined as repeated revascularization, non-fatal myocardial infarction and cardiac death). Secondary outcomes include myocardial infarction, serious adverse events, and restenosis.

• 1. Quality assessment in individual studies

methodological quality of the included studies is independently evaluated using the modified Jadad scale [18]. There are 3 items for Jadad scale: randomization (0-2 points), blinding (0-2 points), drop- outs and withdrawals (0-1 points). The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score <= 2 is considered to be of low quality. If the Jadad score >= 3, the study is thought to be of high quality [19].

• 1. Statistical analysis

We estimate the odd ratio (OR) with 95% CIs for dichotomous out- comes (mortality, major adverse cardiovascular events, myocardial in- farction, serious adverse events, and restenosis). A random-effects model is used regardless of heterogeneity. Heterogeneity is reported using the I² statistic, and I² > 50% indicates significant heterogeneity [20]. Whenever significant heterogeneity is present, we search for po- tential sources of heterogeneity via omitting one study in turn for the meta-analysis or performing subgroup analysis. Publication bias is not evaluated because of the limited number (<10) of included studies. All statistical analyses are performed using Review Manager Version

5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

1. Results
   1. Literature search, study characteristics and quality assessment

A detailED flowchart of the search and selection results is shown in Fig. 1. 348 potentially relevant articles are identified initially. Finally, five RCTs that meet our inclusion criteria are included in the meta- analysis [14-16,21,22].

The baseline characteristics of the five eligible RCTs in the meta- analysis are summarized in Table 1. The five studies are published be- tween 1992 and 2020, and the total sample size is 5526. Colchicine is administered before or after the PCI, and its doses range from 0.5 mg daily to 2 mg daily.

Among the five studies included here, four studies report mortality [14,15,21,22], two studies report major adverse cardiovascular events, myocardial infarction and serious adverse events, [14,15], as well as two studies report and restenosis [15,22]. Jadad scores of the five in- cluded studies vary from 3 to 5, and all five studies are considered to be high-quality ones according to quality assessment.

• 1. Primary outcomes: mortality, major adverse cardiovascular events

This outcome data is analyzed with the random-effects model, and the pooled estimate of the four included RCTs suggested that compared to control group for PCI, colchicine demonstrates no obvious impact on mortality (OR = 0.89; 95% CI = 0.60 to 1.32; P = 0.57) with no hetero- geneity among the studies (I² = 0%, heterogeneity P = 0.59) (Fig. 2), but can significantly reduce major adverse cardiovascular events (OR = 0.78; 95% CI = 0.62 to 0.97; P = 0.02) with no heterogeneity among the studies (I² = 0%, heterogeneity P = 0.63) (Fig. 3).

• 1. Sensitivity analysis

No heterogeneity is observed among the included studies for the pri- mary outcomes, and thus we do not perform sensitivity analysis via omitting one study in turn to detect the heterogeneity.

• 1. Secondary outcomes

Compared to control group for patients with PCI, colchicine inter- vention reveals no obvious impact on myocardial infarction (OR = 0.88; 95% CI = 0.67 to 1.17; P = 0.39; Fig. 4), serious adverse events

Table 1

Characteristics of included studies

NO. Author Colchicine group Control group Jada scores

		Number	Age (years)	Male (n)	History of myocardial infarction (n)	History of PCI (n)	Methods		Number	Age (years)	Male (n)	History of myocardial infarction (n)	History of PCI (n)	Methods
1	Shah 2020	206	65.9 +- 9.9	193	51	75	preprocedural oral administration of colchicine 1.8 mg		194	66.6 +- 10.2	181	52	75	placebo		5
2 3	Tardif 2019 Akodad	2366 23	60.6 +- 10.7 60.1 +- 13.1	1894 19	370 -	392 1	0.5 mg once daily after the surgery 1 mg colchicine once		2379 21	60.5 +- 10.6 59.7 +- 11.4	1942 16	379 -	406 1	placebo placebo		5 3
4	2017 Zarpelon	71	61.5 +- 10.3	49	15	11	daily after the surgery 1 mg orally, twice daily,		69	60.3 +- 8.1	46	17	9	placebo		4
	2016						preoperatively, and of 0.5 mg, twice daily, until hospital discharge
5	O’Keefe 1992	130	59	111	-	-	0.6 mg twice daily after the surgery		67	62	58	-	-	placebo		4

percutaneous coronary intervention: PCI.

Fig. 1. Flow diagram of study searching and Selection process.

(OR = 0.71; 95% CI = 0.31 to 1.61; P = 0.41; Fig. 5), or restenosis (OR = 1.02; 95% CI = 0.63 to 1.64; P = 0.95; Fig. 6).

1. Discussion

anti-inflammatory therapy remains a promising option to reduce cardiovascular risk in patients undergoing PCI. Preprocedural adminis- tration of high-intensity statin therapy was documented to decrease PCI-related myocardial injury and myocardial infarction in patients

undergoing PCI for acute coronary syndrome [23-25]. Anti-IL-? anti- body, canakinumab was associated with reduced major adverse cardio- vascular events in the setting of lowering IL-6 and hsCRP concentrations in patients with prior myocardial infarction [26]. A rapid-acting anti- inflammatory agent may be beneficial in the settings of urgent PCI pa- tients [27,28].

Colchicine, an anti-inflammatory agent, was traditionally used to treat gout, suppress neutrophil homotypic adhesion, modulate neutro- phil deformability, decrease neutrophil extravasation, suppress an

Fig. 2. Forest plot for the meta-analysis of mortality.

Fig. 3. Forest plot for the meta-analysis of major adverse cardiovascular events.

Fig. 4. Forest plot for the meta-analysis of myocardial infarction.

Fig. 5. Forest plot for the meta-analysis of serious adverse events.

Fig. 6. Forest plot for the meta-analysis of restenosis.

enzymatic component of the inflammasome, as well as reduce IL-1 ? and IL-6 [11]. Decreased levels of neutrophil-platelet aggregates is ob- served after colchicine intervention and is beneficial to improve the out- comes of PCI [29]. Our meta-analysis suggests that colchicine can substantially reduce the major adverse cardiovascular events in PCI pa- tients, but reveals no obvious influence on mortality, myocardial infarc- tion, serious adverse events or restenosis.

Although there is no significant heterogeneity remains in this meta- analysis, different doses and methods of colchicine administration may produce some bias. Colchicine is administered before or/and after the PCI, and its doses range from 0.5 mg daily to 2 mg daily. The benefits of colchicine is found in terms of the decrease in major adverse cardio- vascular events for PCI, but there is lack of benefit of colchicine on mor- tality, which may be attributable to the low dose and only preoperative

use of colchicine. In one RCT involving 140 patients undergoing PCI, col- chicine was used at the dose of 1 mg orally, twice daily, preoperatively, and of 0.5 mg, twice daily, until hospital discharge. The results revealed that colchicine was associated with lower Death rate compared to pla- cebo (5.6% versus 10.1%) [21]. These indicate that high dose, preopera- tive and postoperative use of colchicine may provide better benefits to reduce mortality.

This meta-analysis has several potential limitations that should be taken into account. Firstly, our analysis is based on only five RCTs, and more RCTs with large samples should be conducted to confirm this issue. Next, the doses and methods of colchicine intervention in in- cluded RCTs are different, which may have an influence on the pooling results. Finally, the ideal methods of colchicine intervention remain elu- sive in this meta-analysis.

1. Conclusions

Colchicine intervention may benefit to reduce major adverse cardio- vascular events in patients undergoing PCI.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Funding

Not applicable.

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgements

None.

References

1. Keeley EC, Boura JA, Grines CL. primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised tri- als. Lancet. 2003;361(9351):13-20.
2. Yang HT, Xiu WJ, Zheng YY, Liu F, Gao Y, Ma X, et al. Invasive reperfusion after 12 hours of the symptom onset remains beneficial in patients with ST-segment eleva- tion myocardial infarction: evidence from a meta-analysis of published data. Cardiol

J. 2018;26(4):333-42.

1. Russo JJ, Bagai A, Le May MR, Yan AT. Immediate non-culprit vessel percutaneous coronary intervention (PCI) in patients with acute myocardial infarction and cardio- genic shock: a swinging pendulum. J Thorac Dis. 2018;10(2):661-6.
2. Guo L, Zhong L, Chen K, Wu J, Huang RC. Long-term clinical outcomes of optimal medical therapy vs. successful percutaneous coronary intervention for patients with coronary chronic total occlusions. Hellenic J Cardiol. 2018;59(5):281-7.
3. Echouffo-Tcheugui JB, Kolte D, Khera S, Aronow HD, Abbott JD, Bhatt DL, et al. Dia- betes mellitus and cardiogenic shock complicating acute myocardial infarction. Am J Med. 2018;131(7):778-86.
4. Ottani F, Limbruno U, Latini R, Misuraca L, Galvani M. Reperfusion in STEMI patients: still a role for cardioprotection? Minerva Cardioangiol. 2018;66(4):452-63.
5. Cao B, Zhang C, Wang H, Xia M, Yang X. Renoprotective effect of remote ischemic postconditioning in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Ther Clin Risk Manag. 2018;14: 369-75.
6. Shu J, Ren N, Du JB, Zhang M, Cong HL, Huang TG. Increased levels of interleukin-6 and matrix metalloproteinase-9 are of Cardiac origin in acute coronary syndrome. SCJ. 2007;41(3):149-54.
7. Aggarwal A, Schneider DJ, Terrien EF, Gilbert KE, Dauerman HL. Increase in interleukin-6 in the first hour after coronary stenting: an early marker of the inflam- matory response. J Thromb Thrombolysis. 2003;15(1):25-31.
8. Novack V, Pencina M, Cohen DJ, Kleiman NS, Yen CH, Saucedo JF, et al. Troponin criteria for myocardial infarction after percutaneous coronary intervention. Arch In- tern Med. 2012;172(6):502-8.
9. Paschke S, Weidner AF, Paust T, Marti O, Beil M, Ben-Chetrit E. Technical advance: inhibition of neutrophil chemotaxis by colchicine is modulated through viscoelastic properties of subcellular compartments. J Leukoc Biol. 2013;94(5):1091-6.
10. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated Uric acid crys- tals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-41.
11. Shah B, Allen N, Harchandani B, Pillinger M, Katz S, Sedlis SP, et al. Effect of colchicine on platelet-platelet and platelet-leukocyte interactions: a pilot study in healthy sub- jects. Inflammation. 2016;39(1):182-9.
12. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381 (26):2497-505.
13. Shah B, Pillinger M, Zhong H, Cronstein B, Xia Y, Lorin JD, et al. Effects of acute col- chicine administration prior to percutaneous coronary intervention: COLCHICINE- PCI randomized trial. Circ Cardiovasc Interv. 2020;13(4):e008717.
14. Akodad M, Lattuca B, Nagot N, Georgescu V, Buisson M, Cristol JP, et al. COLIN trial: value of colchicine in the treatment of patients with acute myocardial infarction and inflammatory response. Arch Cardiovasc Dis. 2017;110(6-7):395-402.
15. Moher D, Liberati A, Tetzlaff J, Altman DG, P. Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006-12.
16. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.
17. Kjaergard LL, Villumsen J, Gluud C. Reported Methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001; 135(11):982-9.
18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-58.
19. Zarpelon CS, Netto MC, Jorge JC, Fabris CC, Desengrini D, Jardim Mda S, et al. Colchi- cine to reduce atrial fibrillation in the postoperative period of myocardial revascular- ization. Arq Bras Cardiol. 2016;107(1):4-9.
20. O’Keefe Jr JH, McCallister BD, Bateman TM, Kuhnlein DL, Ligon RW, Hartzler GO. In- effectiveness of colchicine for the prevention of restenosis after coronary angio- plasty. J Am Coll Cardiol. 1992;19(7):1597-600.
21. Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, et al. Novel ap- proaches for preventing or limiting events (Naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol. 2009;54(23):2157-63.
22. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: re- sults from the ARMYDA (atorvastatin for reduction of MYocardial damage during angioplasty) study. Circulation. 2004;110(6):674-8.
23. Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes under- going early percutaneous coronary intervention: results of the ARMYDA-ACS ran- domized trial. J Am Coll Cardiol. 2007;49(12):1272-8.
24. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-31.
25. Borden WB, Redberg RF, Mushlin AI, Dai D, Kaltenbach LA, Spertus JA. Patterns and intensity of medical therapy in patients undergoing percutaneous coronary inter- vention. Jama. 2011;305(18):1882-9.
26. Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clin Ther. 2006;28(1):26-35.
27. Nidorf M, Thompson PL. Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease. Am J Cardiol. 2007;99(6):805-7.