review article colchicine for prevention of postoperative ... · “heart surgery”,...

Int J Clin Exp Med 2019;12(2):1344-1354www.ijcem.com /ISSN:1940-5901/IJCEM0069275

Review ArticleColchicine for prevention of postoperative atrial fibrillation following cardiac surgery: a meta-analysis of randomized controlled trials

Zhi Li*, Hongguang Han*, Yu Liu*, Yuji Zhang, Liming Yu, Yan Zhu, Xiaodong Xue, Yuanchen He, Huishan Wang

Department of Cardiovascular Surgery, General Hospital of Shenyang Military Command, Shenyang, China. *Equal contributors.

Received November 16, 2017; Accepted May 3, 2018; Epub February 15, 2019; Published February 28, 2019

Abstract: The most common complication following cardiac surgery, postoperative atrial fibrillation (POAF) increases hospital costs and morbidity. Inflammation may be an important pathogenic factor for POAF. Colchicine, an ancient and natural anti-inflammatory drug, has potential antiarrhythmic properties which have aroused interest regarding its use for POAF prevention. To evaluate effects of colchicine on POAF prevention following cardiac surgery, published randomized controlled trials (RCTs), reporting the effects of colchicine on POAF prevention, were searched up to the end of January 2017 in Cochrane library, PubMed, and EMBASE databases. Four RCTs, involving 1272 patients (636 in colchicine group, 636 in controls group), were included in the meta-analysis. Data are expressed as odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI). Colchicine significantly reduced incidence of POAF following cardiac surgery (OR = 0.6, 95% CI = 0.45 - 0.79; P<0.001), especially Coronary Artery Bypass Grafting (CABG) (OR = 0.5, 95% CI = 0.31 - 0.80; P<0.01), and shortened length of hospitalization (MD = -1.35, 95% CI = -1.76 - -0.94; P<0.001), compared with controls. Although colchicine therapy has been associated with increased incidence of gastrointestinal side effects (OR = 3.44, 95% CI = 2.27 - 5.22; P<0.001), it did not increase treatment discontinuation (OR = 1.45; 95% CI = 0.95 - 2.24; P = 0.09). Collectively, colchicine may prove beneficial in POAF prevention following cardiac surgery, especially CABG. However, because of the small number of studies in CABG, further research with larger RCTs is warranted to confirm the effects of colchicine for POAF prevention.

Keywords: Colchicine, atrial fibrillation, meta-analysis

Introduction

The most common complication following car-diac surgery, postoperative atrial fibrillation (POAF) increases hospital costs and morbidity [1-3]. Therefore, POAF prevention is of great importance for clinical management.

It has been postulated that inflammation is implicated in the development of POAF [4]. Therefore, use of an agent with anti-inflamma-tory properties may be effective in preventing POAF [5]. Colchicine, an ancient and natural anti-inflammatory drug, in patients with gout, has unique antiarrhythmic properties, arousing interest regarding its use in POAF prevention [6].

Recently, several studies regarding effects of colchicine in POAF prevention have been pub-lished [7-10]. However, the role of colchicine in

POAF prevention following cardiac surgery, especially CABG, remains unknown. This study, therefore, undertook a meta-analysis of pub-lished studies, evaluating the effects of colchi-cine in POAF prevention following cardiac sur-gery, to ascertain the significance of colchicine-related adverse events.

Materials and methods

Search strategy

Published randomized controlled trials (RCTs), reporting the effects of colchicine in POAF pre-vention, were searched up to the end of Feb- ruary 2017 in Cochrane library, EMBASE, and PubMed databases. The following keywords were used in the search: “Coronary Artery By- pass”, “Coronary Artery Bypass Surgery”, “Aor- tocoronary Bypass”, “Coronary Artery Bypass Grafting”, “CABG”, “coronary artery bypass gra-

Colchicine for prevention of atrial fibrillation

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ft”, “cardiac surgery”, “cardiothoracic surgery”, “heart surgery”, “cardiopulmonary bypass”, “colchicine”, “atrial fibrillation”, “Auricular Fib- rillation”, “Arrhythmia”, “Randomized controlled trial”, “Randomized”, and “placebo”.

Eligibility criteria and exclusion criteria

Studies were selected for meta-analysis if they fulfilled the following entry criteria [11]: (1) Par- ticipants: patients after heart surgery; (2) In- tervention: colchicine (no matter what regimen applied); (3) Control: control (placebo or no col-chicine); (4) Outcome: incidence of POAF; and (5) Study design: randomized design. No lan-guage restrictions were applied.

Data extraction and outcome measures

All data were independently abstracted, in dup- licate, by two investigators (Z.L and Z.Y.J). Dis- crepancies were resolved by consensus. When necessary, original authors were contacted for supplementary information. The following data were extracted from each study: first author’s last name, number of patients, country, design, colchicine dose, type of surgery, definition of AF

to meet endpoint, method of AF detection, fol-low up, cohort mean age, mean ejection frac-tion, gender, diabetes, hypertension, chronic obstructive pulmonary disease (COPD), current smoker, previous history of AF, prior congestive heart failure (CHF), previous cardiac surgery, CABG surgery, valvular surgery, and aortic sur-gery. Extracted data were entered into a stan-dardized Excel file.

Risk of bias assessment

Risk of bias was evaluated on the basis of Cochrane Risk of Bias Methods [12], by two authors (Y.C.H. and L.M.Y.), and assigned a value of ‘high’, ‘low’, or ‘unclear’ based on the following: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assess-ment, incomplete outcome data, and selective reporting.

Grading quality of evidence

The GRADE system was used to assess quality of evidence. Evidence from cohort studies be- gan with a grade of “Low”. The quality of evi-

Figure 1. Process of literature search and study selection.


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Table 1. Characteristics of included studies

First author (year) N Country Design Colchicine dose Type of

Surgery

Definition of AF to Meet Endpoint

Method of AF detection

Follow-Up

Tabbalat, 2016 360 Jordan MC, OL 2 mg 12-24 hours before surgery, 1 mg day of surgery, and 0.5 mg bid from 1 day postoperative until discharge and 0.25 mg bid if <70 kg or intolerant to highest dose

Cardiac surgery

AF lasting more than 5 min

ECGs monitor

2 months

Imazio, 2014 360 Italy MC, DB Colchicine: 0.5 mg bid for 1 month if ≥70 kg and 0.25 mg twice day if <70 kg or intolerant to highest dose

Cardiac surgery

AF lasting more than 30 s

cECG monitor

3 months

Sarzaeem, 2014 216 Iran DB 1 mg night before and on day of surgery, 0.5 mg bid for 5 days postoperative

CABG only

AF lasting at least 10 min

ECG 6 months

Imazio, 2011 336 Italy MC, DB 1.0 mg bid on first day, then maintenance dose of 0.5 mg bid for 1 month if ≥70 kg and 0.25 mg bid if <70 kg or intolerant to highest dose

Cardiac surgery

AF lasting more than 5 min

cECG monitor

12 months

MC = multicenter; OL = open-label; AF = atrial fibrillation; ECG = electrocardiography; bid. = Eis in die; DB = double-blind; cECG = continuous electrocardiography; CABG = coronary artery bypass grafting.

Table 2. Baseline clinical characteristics of selected studiesColchicine (n = 636) Placebo (n = 636) p-Value

Age, yrs 64.4±12.1 (n = 457) 65.7±10.6 (n = 455) 0.10LVEF 53.3±10.6 (n = 636) 53.3±10.2 (n = 636) 0.88Female 167/636 (26.26%) 187/636 (29.40%) 0.21Diabetes mellitus 207/636 (32.55%) 209/636 (32.86%) 0.90Hypertension 412/636 (64.78%) 409/636 (64.31%) 0.86COPD 28/636 (4.40%) 32/636 (5.03%) 0.60Current smoker 120/467 (25.70%) 125/469 (26.65%) 0.74Previous history of AF 26/528 (4.92%) 26/528 (4.92%) 1.00Prior CHF 27/348 (7.76%) 37/348 (10.63%) 0.19Previous cardiac surgery 18/349 (5.16%) 20/347 (5.76%) 0.72CABG surgery 392/636 (61.64%) 363/636 (57.08%) 0.10Valvular surgery 128/528 (24.24%) 147/528 (27.84%) 0.18Aortic surgery 17/528 (3.22%) 20/528 (3.79%) 0.62LVEF, left ventricular ejection fraction; COPD, chronic obstructive pulmonary disease; AF, atrial fibrillation; CHF, congestive heart failure; CABG, Coronary artery bypass grafting.

dence was upgraded for large magnitude of effect, plausible residual confounding that would not reduce the effect size, and a dose response gradient. It was downgraded for inconsistency, indirectness, imprecision, and publication bias. Finally, quality of evidence was categorized as high, moderate, low, and very low [13].

Statistical analysis

All statistical analyses were conducted with Review Manager Version 5.3, Stata Version 12 and GRADE system. A two-tailed P-value <0.05 was considered statistically significant. Results are expressed as odds ratios (OR) or mean dif-ference (MD) with 95% confidence intervals (CI) (using a fixed-effect approach unless there was

ity (I2>50%) [14]. Potential publication bias was assessed using Begg’s funnel plot test [15].

Results

Study identification and selection

The initial search yielded 31 relevant publica-tions, of which 24 were excluded for various reasons (11 duplications, or 13 reviews) based on titles and abstracts. The remaining seven were then retrieved for full text review. Three of them were also excluded because they were irrelevant to the current analysis. Thus, four studies were included in the final analysis [7-10]. A flow chart of studies included in the meta-analysis is shown in Figure 1.

significant heterogeneity, in which case a random-effects statistical model was used). Heterogeneity across studies was tested by using I2 statistic. I2 sta-tistic of 25% to 50%, 50% to 75%, and 75% to 100% were, respectively, consid-ered to have low heteroge-neity, moderate heteroge-neity, and high degree of heterogeneity. An I2 value greater than 50% indicates significant heteroge-neity. A fixed-effects model was used (I2<50%) and random-effects model was used in the case of significant heterogene-


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Study characteristics

Characteristics of included studies are shown in Table 1 and baseline clinical characteristics of selected studies are presented in Table 2. Of the 4 included trials, two were done in Italy [9, 10], one in Jordan [7], and one in Iran [8]. These studies were published between 2011 and 2016. Sample sizes of these studies rang- ed from 216 to 360 (total 1272). One study in this meta-analysis enrolled patients undergoing CABG only [8]. The remaining three stud-ies included patients undergoing CABG and/or other cardiac surgery [7, 9, 10]. Different regi-mens of colchicine were administered orally. Timing of initiation for colchicine was 1/2-3 days pre-operation or 3 day post-operation and continued for 5 days or 1 month, or until dis-charge [7-10] (Table 1). Three studies adminis-tered colchicine during the perioperative period

information to determine blinding of outcome assessment [9], leading to unclear risk of bias for these items. Tabbalat et al. [7] described methods of randomized but performed an open-label study, leading to high risk of bias for items such as allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. They also had no suffi-cient information to determine selective report-ing, leading to unclear risk of bias for the two items.

Effect of colchicine on incidence of POAF

Overall, four studies, including 1272 patients, were included in this analysis (636 in the col-chicine group and 636 in the control group). Meta-analysis of the two studies, using a fixed effects model, suggested that colchicine sig-nificantly reduced incidence of POAF in patients undergoing cardiac surgery (OR = 0.6, 95% CI =

Figure 2. Risk-of-bias analysis. A. Risk-of-bias summary: author judgments regarding each risk-of-bias item for each included study. B. Risk-of-bias graph: author judgments regarding each risk-of-bias item presented as per-centages across all included studies.

[7-9], while one study admin-istered colchicine after sur-gery [10]. There were no sta-tistically significant differenc-es in baseline clinical charac-teristics of selected studies (Table 2).

Methodological bias of in-cluded studies

Details concerning risks of bias of the included studies, ac- cording to the Cochrane assessment tool, are listed in Figure 2. Both of the included comparisons were RCTs, three in a double-blind design [8-10] and one in an open-label design [7]. Overall quali-ty was good, although only one trial [10] was at low risk of bias for all quality criteria. Sarzaeem et al. described methods of randomized and double blind but had no sufficient information to deter-mine blinding of outcome assessment and selective reporting [8], leading to unclear risk of bias for the two items. Imazio et al. described meth-ods of randomized and dou-ble blind but had no sufficient


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0.45 - 0.79; P<0.001; Figure 3A), especially Coronary Artery Bypass Grafting (OR = 0.5, 95% CI = 0.31 - 0.80; P<0.01; Figure 3C), com-pared with controls. There were no heterogene-ities among the studies (I2 = 0% and 0%, het-erogeneity p = 0.48 and 0.33; Figure 3A and 3C). Although one of the experimental studies was an open-label study [7], when we removed the study, heterogeneity was not reduced but increased (I2 = 15%, Figure 3B). Thus, the open-label study did not have any effect on the accu-racy of results indicating that colchicine signifi-cantly reduced incidence of POAF in patients undergoing cardiac surgery.

Effect of colchicine on length of hospitalization (LOH)

Four trials [7-10] reported the effect of colchi-cine on POAF but only 2 trials [8, 10] provided available data in LOH (expressed as mean ± standard deviation), with a total of 288 patients. Pooled analysis, using a fixed effects model, showed that colchicine significantly reduc-

ed LOH after surgery (MD = -1.35, 95% CI = -1.76 - -0.94; P<0.001; Figure 4), with no statistical heterogeneity between the trials (I2 = 34%, heterogeneity P = 0.22).

Gastrointestinal side effects and treatment discontinuation

Pooled analysis revealed that colchicine use was associated with increased incidence of gastrointestinal side effects (anorexia, diar-rhea, nausea, vomiting, and abdominal pain), compared to placebo (OR = 3.44, 95% CI = 2.27 - 5.22; P<0.001, I2 = 42%) (Figure 5). However, the rate of treatment discontinuation was not significantly different between colchi-cine group and placebo (OR = 2.44; 95% CI = 0.76 - 7.8; P = 0.13, I2 = 77%) (Figure 6A). Due to significant heterogeneity of the studies (I2 = 77%), sensitivity analyses were performed to ascertain the reliability and stability of results. In sensitivity analyses, 1 study [7], whose research design was open-label, was removed and results were dramatically changed (OR =

Figure 3. Forest plots from meta-analyses for the effects of colchicine on incidence of POAF undergoing cardiac surgery (A), the effects of colchicine on incidence of POAF undergoing cardiac surgery after removing 1 study in open-label study (B) and CABG (C). The effect size of each study is proportional to the statistical weight. A diamond indicates the overall summary estimate for the analysis; the width of the diamond represents the 95% CI. POAF, postoperative atrial fibrillation CI, confidence interval.


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1.45; 95% CI = 0.95 - 2.24; P = 0.09, I2 = 0%) (Figure 6B).

Publication bias

Begg’s funnel plot of the included studies did not suggest any significant publication bias regarding the effects of ranolazine on incidence of AF (Begg’s test p = 0.145, Figure 7).

Quality of evidence

Following the GRADE system, evidence quality was assessed by reviewing whether the studies had limitations or flaws. The results of the four studies were not completely consistent, down-grading the quality of evidence for this out-come. Two studies reported that colchicine had no significant protective effects on POAF [7, 9]

Figure 4. Forest plots from meta-analyses for the effects of colchicine on length of hospitalization. The effect size of each study is proportional to the statistical weight. A diamond indicates the overall summary estimate for the analysis; the width of the diamond represents the 95% CI. CI, confidence interval.

Figure 5. Forest plots from meta-analyses for the effects of colchicine on gastrointestinal side effects. The effect size of each study is proportional to the statistical weight. A diamond indicates the overall summary estimate for the analysis; the width of the diamond represents the 95% CI. CI, confidence interval.

Figure 6. Forest plots from meta-analyses for the effects of colchicine on treatment discontinuation (A) and the effects of colchicine on treatment discontinuation after removing 1 study in open-label study (B). The effect size of each study is proportional to the statistical weight. A diamond indicates the overall summary estimate for the analysis; the width of the diamond represents the 95% CI. CI, confidence interval.


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but the other two reported that colchicine did have a preventive effect on POAF [8, 10]. It was a moderate type of evidence that colchicine had a preventive effect on POAF (Table 3).

Discussion

This study, by pooling results of available ran-domized controlled trials, found that colchicine could significantly reduce incidence of POAF following cardiac surgery, especially CABG, and shorten LOH, compared with controls. Although colchicine therapy has been associated with increased incidence of gastrointestinal side effects, it was not increased to the point of treatment discontinuation. Therefore, colchicine may prove beneficial for POAF prevention fol-lowing cardiac surgery.

It has been postulated that inflammatory pro-cesses triggered by cardiac surgery have been implicated in the development of POAF [4]. Therefore, use of an agent with anti-inflamma-tory properties may be effective in preventing POAF [5]. Colchicine is an ancient and natural anti-inflammatory drug [6]. Recently, several studies, regarding effects of colchicine in POAF prevention, have been published [7-10]. Some studies have shown that colchicine can prevent POAF. In 2011, Imazio et al. found that a signifi-cant reduction in incidence of POAF was noted

ed the effects of colchicine therapy for POAF prevention in 360 patients. POAF occurred in 14.5% of patients on colchicine (p = 0.14), com-pared with 20.5% of patients with no colchicine [7]. Colchicine failed to significantly reduce incidence of POAF. Therefore, the role of colchicine in POAF prevention, following cardiac surgery, especially CABG, remains unknown.

This study, therefore, performed meta-analysis of published studies to assess the efficacy of colchicine in POAF prevention for patients after heart surgery. The results of this meta-analysis suggest that colchicine administration is effective and safe for POAF prevention, follow-ing cardiac surgery, especially CABG. Interest- ingly, Wang’s [16] findings were not consistent with our findings, as they found that colchicine therapy was not associated with a significant protective effects on POAF. It is believed that the reasons for this are multifaceted and are mainly attributable to the selection of studies: First, the studies they included were missing Sarzaeem’s [8] findings in 2014. Second, the two included articles [17, 18] were not direct studies about the effects of colchicine on pre-vention of AF, thus, there was no inaccurate record of occurrence of AF. Third, the heteroge-neity of their research was high (I2 = 47.3%), whereas this present study does not show het-erogeneity (I2 = 0%). It is worth mentioning that

Figure 7. Funnel plots (with pseudo 95% CIs) of all the individual studies in the meta-analyses for the effects of colchicine on POAF incidence. POAF, postoperative atrial fibrillation; OR, odds ratio, SE, standard error; CI, confi-dence interval.

in patients treated with 1 mg colchicine, twice daily (12.0% vs. 22.0%, p<0.05), in 336 patients [10]. In 2014, Sarza- eem et al. reported their find-ings regarding 216 patients treated with colchicine vs. pla-cebo; POAF was significantly reduced in the colchicine group (14.8% vs. 30.6%, p<0.01) [8]. One other study has shown that colchicine cannot effectively prevent POAF. In 2014, Imazio et al. evaluated the efficacy of colchicine in preventing AF, after cardiac surgery, in 360 patients [9]. Their results, however, indi-cated that colchicine has no significant protective effect on POAF, inconsistent with previous results. In 2016, Ta- bbalat et al. further assess-


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Table 3. Summary of findings table using GRADE methodology for colchicine on prevention of POAFColchicine for Prevention of Postoperative Atrial Fibrillation after Heart Surgery: A Meta-Analysis of Randomized Controlled TrialsPatient or population: Patients after Heart SurgeryIntervention: Colchicine

Outcomes

Illustrative comparative risks* (95% CI)Relative effect

(95% CI)No of Participants

(studies)Quality of the

evidence (GRADE) CommentsAssumed risk Corresponding risk

Control Incidence of postoperative atrial fibrillation

Effects of colchicine in preventing postoperative atrial fibrillation Study population OR 0.52 (0.38 to 0.71) 1248 (4 studies) ⊕⊕⊕⊝ moderate1

204 per 1000 118 per 1000 (89 to 154)

Moderate

207 per 1000 120 per 1000 (90 to 156)*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio; GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1The results are inconsistent.


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the findings of this current study were also con-firmed by Lee [5], Kreidieh [19], and Trivedi [20]. However, this present research is slightly different from the three studies mentioned above. Not only does this study find colchicine playing a preventive role in POAF, following car-diac surgery, but also in POAF following CABG. Similarly, due to an increase in the number of selected studies, none of the above studies showed heterogeneity. Although Trivedi’s find-ings also showed no statistically significant het-erogeneity [20], only one of the included three studies regarded cardiac surgery [10] and the remaining two concerned radiofrequency abla-tion [21, 22]. This was not enough to show that colchicine has a preventive effect on POAF fol-lowing cardiac surgery.

Although POAF may be transient, it can increase hospital stays, thus, increasing health-care costs [23]. This study’s results found that patients receiving colchicine had shorter overall hospital stays. Therefore, colchicine can not only prevent POAF but also reduce patient health-care costs.

A statistically higher incidence of gastrointesti-nal side effects (anorexia, diarrhea, nausea, vomiting, and abdominal pain) in the colchicine group has attracted a high degree of attention. Fortunately, rates of treatment discontinuation have shown no significant statistical differenc-es in the colchicine group. These findings are similar to another meta-analysis performed on colchicine for POAF [5]. Colchicine is currently in Class IIb recommendations for reduction of POAF [24, 25]. One strategy to reduce in gastro-intestinal side effects may be to optimize dos-age and timing of colchicine therapy, avoiding pre-operative administration. Another strategy is to choose the right patients, especially those at higher risk of POAF, such as those with heart failure, advanced age, and COPD [26] instead of routine administration to all patients under-going cardiac surgery. Further studies may be required in determining the optimal treatment protocol to reduce incidence of gastrointestinal intolerance, so that patients may benefit from adjunctive prophylaxis with colchicine.

Several potential limitations of this meta-analy-sis merit consideration. First, overestimation of the treatment effect is more likely in smaller studies compared with larger samples. Seco- nd, these studies lacked homogeneity regard-

ing the dose of colchicine. This may lead to potential underestimation and/or overestima-tion of the true incidence of POAF. Third, it was possible that missing and unpublished data may have led to bias in effect size.

In conclusion, despite various limitations, this present study is clinically valuable because it reveals that colchicine leads to lower incidence of POAF, following cardiac surgery, especially CABG. Additional large-scale, multicenter, ran-domized controlled parallel trials are necessary to confirm these positive results.

Acknowledgements

This work was supported in part by a Grant- in-Aid from National Natural Science Found- ation of China (Grant No. 81600311), Postdoc- toral Science Foundation of China (Grant No. 2016M593030), Doctoral Scientific Research Foundation of Liaoning Province in China (Gr- ant No. 201601402), and Liaoning Province, Science and Technology public relations Pro- ject of China (Grant No. 201602805).

Disclosure of conflict of interest

None.

Address correspondence to: Huishan Wang, Depart- ment of Cardiovascular Surgery, General Hospital of Shenyang Military Command, 83 Wenhua Road, Shenhe District, Shenyang 110016, China. Tel: +86-24-28897382; Fax: +86-24-23912376; E-mail: hui- [email protected]

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