Colchicine in prevention of atrial fibrillation following cardiac surgery: systematic review and meta-analysis.

OBJECTIVES: Inflammation is one of the predictors of atrial fibrillation (AF) following surgical or interventional cardiac procedures. Recent evidence suggests that colchicine may represent a new strategy to prevent AF following cardiac procedures. This study aims to assess the antiinflammatory efficacy of colchicine in prevention of early AF event (EAFE).
MATERIALS AND METHODS: We reviewed all available studies that assessed the effectiveness of colchicine therapy on the occurrence of AF in patients undergoing cardiac procedures. Meta-analysis was performed by random effect inverse variance-weighted method by entering AF events and the total population from each study.
RESULTS: After thorough review of the databases, we found three studies comparing colchicine and placebo which had EAFE as the outcome. Of 584 patients, 286 patients were on colchicine and 298 on placebo. All the three studies were randomized. After pooled analysis, colchicine was associated with significant reduction in AF events compared to placebo (odds ratio = 0.44 [0.29, 0.66], P < 0.001). There was no statistical heterogeneity between included studies (χ(2) = 0.45, P = 0.80, I(2) = 0%).
CONCLUSION: Colchicine may prove beneficial in the prevention of AF following cardiac surgery. Further research is warranted.

Introduction

Atrial fibrillation (AF) is the most frequent supraventricular arrhythmia and has been associated with increased risk of death, stroke, and hospitalization.[12345] Radiofrequency catheter ablation has proven to be an effective treatment strategy for AF.[6] Even though ablation is most effective treatment for AF, it causes the inflammatory changes which are associated with the early AF events (EAFEs).[7] Other cardiac surgeries are also associated with early postoperative AF (POAF) which occur in up to 30% of patients undergoing coronary artery bypass surgery and 50% after valvular surgery.[8] This type of cardiac surgery also causes AF by inflammatory changes.[910] Cardiac surgery is becoming more common due to advances in technology and research, safe and easy to use technique and increase in a number of the older population. American and European task force have suggested that prevention of AF is one of the important goals following cardiac surgery.[111213] Despite ongoing improvements in the procedure, EAFE often occurs.[14] The cause of EAFE remains unknown but may involve an inflammatory response due of thermal injury, pericarditis, or both.[7] Because EAFE is responsible for a higher risk of late recurrence, it is of particular interest.[1516] Corticosteroids has proven to be beneficial in reducing the inflammation and POAF incidence in few published studies,[17] but benefits of corticosteroids are largely outweigh by the harm it cause, specifically in patients with hypertension and structural heart disease. That is why it is important to find the anti-inflammatory agent which is safe and efficacious. Colchicine is used as antigout drug since a long time; it has antiinflammatory efficacy and reduces the inflammation by inhibiting the microtubule polymerization. In the colchicine for the prevention of the Postpericardiotomy Syndrome (COPPS) trial,[18] colchicine proved to be safe and efficacious in the prevention of postpericardiotomy syndrome following cardiac surgery by reducing the inflammation. Because of antiinflammatory effect, it might be beneficial in reducing the EAFE occurred mainly due to inflammation following cardiac procedures. Due to the above mentioned reason, together with the limited antiinflammatory strategies available to prevent EAFE following cardiac surgery, the clinical relevance of evaluating the possible antiinflammatory effect of colchicine specifically in cardiac surgery patient is even more important.

Materials and Methods

Search Strategy Study Selection

We evaluated all the relevant studies published before April 2014, and an inclusion criterion was the randomized clinical trial on pharmacological prevention of AF following cardiac surgery and patients receiving colchicine therapy compared with placebo. The studies were searched by two independent reviewers to remove irrelevant reports and to identify multiple reports from the same study. Disagreements were resolved by a discussion to make final decisions or by agreements of a third investigator, if necessary. Studies were searched from the Cochrane Collaboration Database of Randomized Trials, ClinicalTrials.gov, CINAHL, Google Scholar, PubMed, and Scopus. In addition, all the abstracts from annual scientific session from American Heart Association, American College of Cardiology, Heart Rhythm Society and the European Society of Cardiology were electronically or manually searched. Studies were excluded if they were not randomized controlled trial or if they were animal trial. From all the included studies baseline data, type of cardiac procedure, incidence of AF following the colchicine dose versus placebo, preoperative AF incidence and inflammatory cytokines blood level information were collected. Furthermore, information on side effect of the colchicine was collected.

Selected Published Clinical Studies

Of 48 citations retrieved, 17 studies assessing the effect of colchicine therapy on the incidence of AF were identified. Thirteen studies were excluded because they were editorial, review or early result of the included study. One study was excluded, because it was studying the late recurrence [Figure 1]. Finally, three randomized studies were included for the analysis:[192021] One published study by Deftereos et al.[19] on effect of colchicine postpulmonary vein antrum isolation (PVAI), one published study by Imazio et al. on effect of colchicine postcardiotomy,[20] and one abstract[21] by Egami et al. presented at the American Heart Association's annual scientific session studying the effect of colchicine on AF post-PVAI.

Figure 1

Selection process of studies included in the systematic review (AF = Atrial fibrillation; PVAI = Pulmonary vein antrum isolation). Search Criteria: (“colchicine”[MeSH Terms] OR “colchicine”[All Fields]) AND (“atrial fibrillation”[MeSH Terms] OR (“atrial”[All Fields] AND “fibrillation”[All Fields]) OR “atrial fibrillation”[All Fields])

Imazio et al.[20] assessed the association between colchicine and postcardiac surgery associated AF in multi-center, double-blind, randomized study of the 336 patients (average 65 years of age and 69% male). There was no difference in baseline characteristics between the groups. Most of the patients were undergoing coronary artery bypass graft (CABG) (49.7%) and valvular surgery (27.3%). Only 19 (5.6%) patients had a previous history of AF. Colchicine was administered at 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month. The primary endpoint of the study was the incidence of POAF between day 3 and day 30 after the surgery. In 1 month, patients on colchicine had less incidence of AF compared to control group (20 [12%] vs. 35 [21%], P = 0.02 odds ratio [OR] =0.51 [0.28, 0.92]). Gastrointestinal (GI) side effects were similar between groups (16.5% vs. 4.2%, P = 0.08). Patients on colchicine had shorter overall hospital stay (24.2 ± 8.9, vs. 21.4 ± 7.9, P = 0.03). Most patients without POAF were on colchicine and beta-blocker preoperatively, had small LA diameter (<45 mm), undergoing CABG surgery and did not develop pericardial effusion. In multivariable analysis after adjusting for the LA diameter >45 mm and preoperative beta-blocker, colchicine showed 48% reduction in POAF (heart rate = 0.52, [0.28, 0.96], P = 0.036).

Egami et al.[21] prospectively assessed the association between short duration of colchicine on reduction of EAFE after PVAI by randomizing 87 patients in colchicine (n = 36) and placebo (n = 51) group. The population had an average age of 64 years where 57 (65.5%) patients were males. In colchicine group, patients were treated with 0.5 mg/day colchicine for 2 weeks from the next day after catheter ablation. Patients were followed-up at 48 h, 2nd, 4th, and 12 weeks after the procedures and early recurrence was observed in 11 (30.6%) patients in colchicine group and 27 (52.9%) patients in control. In univariate logistic regression, patients on colchicine had 61% less chance of developing AF (OR = 0.33 [0.12, 0.95]). No side effects were reported in both the groups. Patients were also subdivided by high vs. low left atrial epicardial adipose tissue (LA-EAT) volume and level of C-reactive protein (CRP) was analyzed to study the effect of colchicine in both groups. In low LA-EAT volume group, colchicine showed a significant reduction in CRP 2 days after the ablation but there was no significant difference in CRP level for high LA-EAT group.

Deftereos et al.[19] studied the effect of colchicine on prevention of early AF recurrence after PVAI by randomizing 161 patients with Paroxysmal AF undergoing PVAI with 0.5 mg of twice daily colchicine versus placebo. Colchicine was administered from day 1 (the day of the ablation procedure) at a dose of 0.5 mg twice daily. Patients were followed-up for 3 months after PVAI to detect the AF recurrence. Baseline characteristics were similar between the groups, and the average age was 62 years, and 115 (71%) of patients were male. AF recurrence was observed in 27 (33.5%) patients in control and 13 (16%) patients in colchicine group (OR = 0.39 [0.16, 0.96], P = 0.001) (log-rank P = 0.01). Furthermore, the authors studied the effect of colchicine on the inflammatory marker interleukin-6 (IL-6) and CRP, where both markers were similar between groups at day 1 after the procedure but showed significant reduction at day 4 in the patients who were on colchicine. Moreover, inflammatory markers’ blood level was high in patients with recurrence. Deftereos et al.[19] also studied the safety of the colchicine in comparison to placebo where GI side effects were more common in patients who were on colchicine (13.6% vs. 5%). In multivariate analysis, colchicine significantly predicted the EAFE prevention mainly by significant reduction in IL-6 and CRP level. Taken together, these clinical studies suggest a possible beneficial effect of colchicine therapy in preventing either incidence or early recurrence of AF in patients undergoing a cardiac procedure.

Statistical Analysis

To provide an overall estimate of the effect of colchicine therapy in preventing EAFE in patients undergoing cardiac surgery we performed a meta-analysis by including the publications selected above. The presence of heterogeneity among studies was evaluated with Cochrane Q χ2 test, and inconsistency was assessed with I2 test that describes the percentage of the variability in effect estimates that is due to heterogeneity: Values of 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity (I2). Publication bias was assessed using the Egger's test and displayed as a funnel plot of precision. Statistical level of significance for the summary treatment effect estimate was two-tailed P < 0.05 and analyzed by Der Simonian and Laird random effect method.[22] Heterogeneity and publication bias were considered statistically significant at a two-tailed P < 0.1. The meta-analysis was performed by the Review Manager 5.2 (The Cochrane Collaboration, 2011).

Results

Efficacy Outcome

Overall, 584 patients undergoing cardiac surgery were included, out of which 286 (48.97%) received colchicine and 298 (51.03%) received placebo. Tables 1 and 2 summarize the study and population characteristics, respectively. After pooled analysis, colchicine was significantly associated with reduction in AF events compared to placebo (OR = 0.44 [0.29, 0.66], P < 0.001) [Figure 2]. Although there was no significant publication bias, the numbers of included studies were limited [Figure 3]. In addition, pooled analysis was performed only for the study on the patients who underwent PVAI and colchicine was associated with 62% less chance of AF events compared to placebo after PVAI (OR = 0.38 [0.21, 0.68], P = 0.001) [Figure 4].

Table 1

Characteristics of the studies included in the meta-analysis

Table 2

Baseline characteristics of study patients

Figure 2

Forest plot showing the odds ratio of early atrial fibrillation associated with colchicine use in each study and the overall OR. Square boxes denote OR; horizontal lines represent 95% confidence interval

Figure 3

Funnel plot of the standard error of logarithm odds ratio against OR, displayed as OR. There is no presence of publication bias on visual estimation

Figure 4

Forest plot showing the odds ratio of atrial fibrillation associated with colchicine use in pulmonary vein antrum isolation study and the overall OR. Square boxes denote OR; horizontal lines represent 95% confidence interval

Safety Outcome

Colchicine is associated with gastro intestinal side effect. Out of three studies, Imazio et al.[20] reported GI side effects in 16 colchicine and 7 control patients and all the patient stopped the drug due to side effect. In Deftereos et al.[19] study 7 colchicine patients and 1 control patient reported GI side effect. No side effects were reported by Egami et al. study.[21] Metanalysis was not performed for side effect as side effects were very few in included studies.

Discussion

This is the first meta-analysis focusing on the efficacy of colchicine in preventing AF postcardiac procedure. Our result shows that colchicine reduces the early AF nearly by 56% compared to placebo. Because EAFE can lead to late recurrence, it is of particular interest. Colchicine effectively reduces the inflammation, which is evidenced by reduction in blood level of inflammatory cytokines in two of the included study.[1921] In a study by Deftereos et al.,[19] there was a significant reduction in the blood level of CRP and IL-6 after colchicine treatment, and this reduction was associated with less recurrence. Study by Egami et al.[21] showed reduction in CRP level after introduction of colchicine treatment. More importantly, it is evident that inflammatory cytokines are related with AF.[2324] Thus, from this meta-analysis, it is clear that the anti-inflammatory property of colchicine is benefiting in reduction of postcardiac surgery related AF event. Colchicine safety is still concern, because in the study by Imazio et al.,[20] patients on colchicine had significantly more GI side effects than placebo which leads to withdrawal of the patients from the study. In Egami et al. study,[21] there was no side effect and in Deftereos et al.[19] study, there were more side effects in the colchicine group but it was tolerable. Major reason of lesser side effects in other two studies may be due to lower the dose of colchicine (0.5 mg vs. 1.0). A recent multicenter trial by Deftereos et al.[19] studying long-term effect and quality of life effect of colchicine in prevention of AF post-PVAI showed that colchicine associated with significant reduction in AF recurrence rate within 15 months after a single procedure, along with improvements in physical and psychological health-related quality of life scores. Thus, side effects were tolerable and from the improvement in quality-of-life score, it is clear the benefit of elimination of AF outweigh the adverse effect it causes. Hence, side effect should be of little concern compared to elimination of AF.

Major limitation of our study was the number of included studies were very few, and 2 of the study had PVAI only as the cardiac procedure, which is the treatment of AF. Although PVAI eliminates all the triggers causing AF in paroxysmal patient, it is not 100% successful and success can be variable depending on co-morbidity and inflammation caused by PVAI which contribute to early recurrence and procedure failure. Hence, chances of developing AF are low in patients after PVAI compared to other cardiac surgeries which is also evidenced by the OR of Imazio et al.[20] study vs. other two studies. Another limitation is that Egami et al.[21] had presented the result at the conference, so we could not be able to determine other details like co-morbidity in that study which might influence the final results. In addition, best dose and duration of colchicine are unknown, Deftereos et al.[19] proved good criteria that colchicine should be given for 3 months based on significant elevation of CRP for 3 months after AF ablation,[8] but more studies are needed to decide appropriate dose and timing of colchicine administration. Although EAFE predicts the late recurrence of AF, it is likely that EAFE could be due to failed ablation procedure rather than inflammation. In a study by Deftereos et al.,[19] no antiarrhythmic was given postablation, while in Imazio et al.[20] study, patients were on the beta blocker. Hence, result in the study by Imazio et al.[20] was confounded by beta blocker but it was not analyzed as confounder in studying the relationship between colchicine and AF. While there was no information about antiarrhythmic in the study by Egami et al.,[21] Imazio et al. study might have missed the recurrences reported on first 2 days as colchicine was started at day 3, so results could have been underestimated. Despite several limitations colchicines’ role in preventing AF after cardiac surgery, cannot be disregarded. Furthermore, colchicine is cheap, effective, and one of the very few antiinflammatory agents with minor side effect compared to other drugs like corticosteroids. Furthermore, it reduces the hospital stay and life-threatening complications of cardiac surgery which reduces the overall cost and improves the quality-of-life.

Implications for Further Studies

The results of our meta-analysis have to be interpreted as only hypothesis-generating, rather than conclusion-drawing. Indeed, although the pooled treatment effect is quite impressive, with a reduction of more than 50% of the risk of developing AF, the small number of studies, with different clinical indications (two for PVAI and one for various cardiac surgery), different colchicine dosage and duration in each study and different intervals and length of follow-up make our results not definite, but worthy of further investigation. Furthermore, in COPPS substudy, most of the AF happened after non-CABG surgery so separate study is warranted for different cardiac procedures. Thus, our results suggest that an appropriately designed randomized double-blind clinical trial testing the effectiveness of colchicine therapy in preventing AF recurrence in a patients undergoing cardiac surgery would be warranted to determine the exact dosage and duration of colchicine treatment in preventing the AF recurrence.

Conclusion

Colchicine may represent a novel strategy in preventing early AF recurrence postcardiac procedures, by antiinflammatory action. The results of our meta-analysis suggest a striking reduction of AF occurrence associated with colchicine use. This might have clinical and cost benefit in the prevention of AF following cardiac surgery. Further research study is warranted to determine the exact dose and duration of colchicine.