Influence of Dexmedetomidine on Post-operative Atrial Fibrillation After Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials

Background: Previous clinical studies and meta-analysis evaluating the influence of dexmedetomidine on postoperative atrial fibrillation showed inconsistent results. We performed an updated meta-analysis to evaluate the influence of dexmedetomidine on incidence of postoperative atrial fibrillation after cardiac surgery. Methods: Randomized controlled trials that evaluated the potential influence of dexmedetomidine on the incidence of atrial fibrillation after cardiac surgery were obtained by search of PubMed, Embase, and Cochrane's Library databases from inception to April 12, 2021. A random-effects model incorporating the potential publication bias was used to pool the results. Influences of patient or study characteristics on the efficacy of dexmedetomidine on atrial fibrillation after cardiac surgery were evaluated by meta-regression and subgroup analyses. Results: Fifteen studies with 2,733 patients were included. Pooled results showed that dexmedetomidine significantly reduced the incidence of atrial fibrillation compared to control (OR: 0.72, 95% CI: 0.55–0.94, p = 0.02) with mild heterogeneity (I2 = 26%). Subgroup analysis showed that dexmedetomidine significantly reduced the incidence of atrial fibrillation in studies from Asian countries (OR: 0.41, 95% CI: 0.26–0.66, p < 0.001), but not in those from non-Asian countries (OR: 0.89, 95% CI: 0.71–1.10, p = 0.27; p for subgroup difference = 0.004). Meta-regression analysis showed that the mean age and proportion of male patients may modify the influence of dexmedetomidine on POAF (coefficient = 0.028 and 0.021, respectively, both p < 0.05). Subgroup analysis further showed that Dex was associated with reduced risk of atrial fibrillation after cardiac surgery in studies with younger patients (mean age ≤ 61 years, OR = 0.44, 95% CI: 0.28–0.69, p = 0.004) and smaller proportion of males (≤74%, OR = 0.55, 95% CI: 0.36–0.83, p = 0.005), but not in studies with older patients or larger proportion of males (p for subgroup difference = 0.02 and 0.04). Conclusions: Current evidence supports that perioperative administration of dexmedetomidine may reduce the risk of incidental atrial fibrillation after cardiac surgery, particularly in Asians.


INTRODUCTION
Post-operative atrial fibrillation (POAF) is a common complication, which affects up to 35% of patients after cardiac surgery (1,2). Clinically, POAF has been related with a higher incidence of neurocognitive dysfunction, prolonged hospital stay, and increased risk of all-cause mortality in these patients (3). Current risk factors for POAF after cardiac surgery include aging, diabetes mellitus, and impaired cardiac function etc. (4). However, no definite strategy has been confirmed as an effective preventative method for POAF (5,6). Dexmedetomidine (Dex) is well-applied perioperative medication for patients that received cardiac surgery (7). Pharmacologically, Dex is a highly selective α2-adrenoreceptor agonist which exerts various clinical efficacies during perioperative periods, such as sedation, analgesia, antianxiety, and diuresis (8,9). Besides, use of Dex is suggested to reduce POAF after cardiac surgeries in some previous randomized controlled trials (RCTs) (10)(11)(12), although other RCTs generally did not support a preventative efficacy of Dex for POAF (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A few meta-analyses have been performed to evaluate the influence of Dex on POAF after cardiac surgery. Early meta-analyses including RCTs before 2017 consistently showed that Dex was not associated with reduced incidence of POAF after cardiac surgeries (25)(26)(27)(28)(29), while a recent metaanalysis including RCTs up to 2018 showed that Dex was effective in preventing POAF after cardiac surgeries (30). However, results of this meta-analysis are confounded by including two RCTs with overlapped patients (10,31), which both showed a significant preventative efficacy of Dex on POAF. Besides, three RCTs have been published since the last meta-analysis (12,23,24), including a large-scale RCT which suggested a lack of preventative efficacy of Dex on POAF (24). Accordingly, we performed an updated meta-analysis to systematically evaluate the possible influence of Dex on POAF after cardiac surgery. Multiple predefined subgroup analyses were also performed to explore the potential influences of patient or study characteristics on the outcome.

METHODS
We followed the instructions of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (32) and the Cochrane Handbook guidelines (33) during the designing, performing, and reporting of the meta-analysis.

Search Strategy
PubMed, Embase, and the Cochrane's Library (Cochrane Center Register of Controlled Trials) databases were searched for relevant studies with a combined strategy of: (1) "dexmedetomidine"; (2) "heart" OR "cardiac surgery" OR "coronary artery bypass graft" OR CABG OR "atrial fibrillation" OR arrhythmia OR "cardiac"; and (3) "random" OR "randomized" OR "randomised" OR "randomly." Only clinical studies were considered. The references of related reviews and original articles were also searched as complementation. The latest database search was performed on April 12, 2021.

Study Selection
Inclusion criteria were: (1) peer-reviewed articles in English; (2) designed as parallel-group RCTs; (3) included adult patients scheduled for open heart surgery who were randomly allocated to a perioperative administration of Dex or a non-Dex control group; and (4) reported the incidence of POAF during the index hospitalization. For studies with overlapped patients, the one with the largest sample size was included (33). Reviews, studies including children or neonates, preclinical studies, observational studies, and repeated reports were excluded.

Data Extraction and Quality Assessment
Study search, data extraction, and quality evaluation were conducted by two independent authors. If disagreement occurred, it was resolved by consensus between the two authors. We extracted data regarding study information (first author, publication year, and study country), study design (blind or open-label), patient information [number of participants, mean age, gender, body weight or body mass index (BMI), and surgery type], details of Dex administration (regimen, timing and duration), and components of controls. Quality evaluation was achieved using the Cochrane's Risk of Bias Tool (33) according to the following aspects: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessors; (5) incomplete outcome data; (6) selective outcome reporting; and (7) other potential bias.

Statistical Analysis
Incidence of POAF in each arm was evaluated via odds ratio (OR) and its 95% confidence intervals (CIs). We used the Cochrane's Q test to detect the heterogeneity, and significant heterogeneity was suggested if P < 0.10 (34). The I 2 statistic was also calculated, and an I 2 > 50% reflected significant heterogeneity. Pooled analyses were calculated using a randomeffect model because this method could incorporate the influence of potential heterogeneity and retrieves a more generalized result (33). Sensitivity analysis by excluding one study at a time was used to determine the robustness of the finding. Subgroup analyses were performed to determine the potential influences of study characteristics on the results of meta-analysis, including country of the study, type of surgery, mean age of the patients, proportions of the males, with or without loading dose of Dex, timing of Dex administration, regimen of controls, or score of study quality. Meta-regression analyses were also performed to evaluate the potential influences of mean age of the patients and proportions of the males on the effect of Dex on POAF. Medians of continuous variables were used as cut-off values for defining of subgroups. Publication bias was evaluated by visual inspection of funnel plots, and the Egger's regression asymmetry test (35). P-values < 0.05 were considered statistically significant. The RevMan (Version 5.1; Cochrane, Oxford, UK) and Stata software (Version 12.0; Stata, College Station, TX) were applied for statistical analyses.

Search Results
In summary, 1,478 articles were obtained through the database search. After exclusion of duplicate studies, 1,331 articles were screened. Among them, 1,281 articles were subsequently excluded based on titles and abstracts primarily because these studies were irrelevant. Among the 50 potentially relevant articles, 35 were further excluded via full-text review based on reasons listed in Figure 1. Finally, 15 RCTs (10-24) were included into the meta-analysis. Table 1 shows the characteristics of the included studies. Overall, 15 RCTs (10-24) with 2,733 patients who received cardiac surgery -1,388 patients in the Dex group and 1,345 patients in the control group -were included. These studies were published between 1997 and 2020. All of the studies included patients that underwent open-heart cardiac surgery. Among them, ten RCTs included patients who underwent elective coronary artery bypass grafting (CABG) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), while the other five included patients who underwent mixed type of open-heart surgeries, including CABG, valvular surgeries, and aortic surgeries (10,16,(22)(23)(24).

Meta-Analysis Results
Mild heterogeneity was detected among the included RCTs (p for Cochrane's Q test = 0.16, I 2 = 26%). Pooled results with a random-effect model showed that Dex significantly reduced the incidence of POAF after cardiac surgery compared to control (OR: 0.72, 95% CI: 0.55-0.94, p = 0.02; Figure 2A). Sensitivity analysis by excluding one study at a time did not significantly affect the results (OR: 0.72-0.80, p all < 0.05). Subgroup analysis according to the origin of the study showed that Dex significantly reduced the incidence of atrial fibrillation in studies from Asian countries (OR: 0.41, 95% CI: 0.26-0.66, p < 0.001), but not in those from non-Asian countries (OR: 0.89, 95% CI: 0.71-1.10, p = 0.27; p for subgroup difference = 0.004; Figure 2B), which fully resolved the heterogeneity (I 2 = 0% for both subgroups). Results of meta-regression analysis showed that the mean age and proportion of male patients may modify the influence of dexmedetomidine on POAF (coefficient = 0.028 and 0.021, respectively, both p < 0.05;

Publication Bias
The funnel plots were symmetrical, suggesting low-risk of publication bias (Figure 3). Egger's regression tests showed similar results (p = 0.301).

DISCUSSION
In this updated meta-analysis of RCTs, we found that perioperative use of Dex is associated with 28% reduction of POAF after cardiac surgeries. The results seem to be stable since sensitivity analysis by excluding one study a time showed consistent results. Besides, subgroup analysis showed that Dex was associated with reduced POAF in Asian studies, but not in non-Asian studies. Moreover, both meta-regression and subgroup analyses showed that Dex was associated with reduced POAF in studies with younger patients and smaller proportion of males, but not in studies with older patients or larger proportion of males. These findings indicated that perioperative administration of Dex may reduce the risk of POAF after cardiac surgery, particularly in Asians. Moreover, age and sex of the patients may affect the potential preventative efficacy of Dex on POAF. Compared with previous meta-analyses of the same fields, our study has multiple strengths. Firstly, 15 up-to-date RCTs were included, which represents the most recent understanding of the influence of Dex on POAF after cardiac surgeries. In addition, strict inclusion criteria were applied, which avoided the confounding effects of including studies with overlapped patients. Finally, multiple sensitivity and subgroup analyses were performed to shown the stability of the results. Results of metaanalysis are consistent with the previous observed potential antiarrhythmic efficacy of Dex. An early study showed that the potential anti-arrhythmic efficacy of Dex could be related to its inhibition on sympatholytic properties and activation of the vagus nerve (36). A subsequent retrospective case series supported that Dex may have novel antiarrhythmic properties for the acute termination of reentrant supraventricular tachycardia (37). A recent experimental study in rat model of ischemic cardiomyopathy (ICM) showed that Dex conferred anti-arrhythmic effects in the context of ICM via upregulation of connexin 43 and suppression of inflammation and fibrosis (38). Future studies are needed to determine the exact pharmacological mechanisms that underlying the possible anti-arrhythmic efficacy of Dex.
Results of subgroup analyses showed that Dex reduced POAF after cardiac surgery in Asian studies, but not in non-Asian studies. Previous studies showed that Caucasians are associated with higher risk of POAF after cardiac surgery than patients of other ethnicity, including the Asians (39,40). In our meta-analysis, the incidence of POAF in patients of control group from non-Asian countries was also higher than that from Asian countries (24.1 vs. 17.9%). These findings may suggest that  Dex is more effective in reducing POAF after cardiac surgery in low-risk populations. Subgroup analyses also showed that Dex was associated with reduced POAF in studies with younger patients and smaller proportion of males, but not in studies with older patients or larger proportion of males, suggesting the potential preventative role of Dex on POAF may be more effective in young patient and in the females. The possible reasons for the findings are also to be determined. It has been shown that advanced age is a risk factor for POAF after cardiac surgery (41). Besides, men have been suggested to have higher incidence of POAF than women after CABG (42). Taken together, results of subgroup analysis may suggest that Dex was more effective for the prevention of POAF in low-risk patients. Since high-risk patients such as aged men are likely to have multiple comorbidities for POAF, and a single intervention of Dex may not be effective. These findings should be validated in large-scale RCTs. Currently, Dexmedetomidine was recommended to be applied with a loading dose (0.4-1 µg/kg) and continuous infusion (0.2-0.8 µg/kg/h). Results of subgroup analysis showed no difference in reducing POAF after cardiac surgery between studies with and without a loading dose of Dex. Considering the possible adverse effect related with loading dose of Dex (such as hemodynamic instability and possible induction of severe arrhythmia) (43), continuous Dex infusion may be adequate for these patients. In addition, influence of Dex infusion timing on POAF is also clinically important. Although the subgroup difference was not significant, results of subgroup analysis indicated that Dex infusion in ICU after the surgery may be adequate for prevention of POAF (Table 4, 9 studies, OR = 0.64). Future large-scale RCTs are needed to determine whether postoperative use of Dex confers similar efficacy in preventing of POAF as compared to pre-operative use of Dex.
Our study has some limitations. First, the meta-analysis was based on data from study level rather than individual patient data. Accordingly, influences of a few key characteristics on the possible preventative role of Dex for POAF could not be analyzed in our meta-analysis, such as left atrial volume (44), renal function (45), and concurrent cardiovascular medications including perioperative use of beta-blockers, amiodarone, and electrolyte replacement protocol for K and Mg etc. (46), which have all been suggested to affect the risk of POAF after cardiac surgery. Moreover, the sample sizes of the included RCTs varied significantly, most of which were of small scale. Therefore, large-scale RCTs are still needed to validate the findings of the meta-analysis. In addition, weight is one of critical risks leading POAF after cardiac surgery (47). However, only five of the included studies reported body weight, while another five reported BMI. The limited available datasets and differences in body weight and BMI reported in the studies prevented further analyses in subgroup analyses. Besides, quality of some included studies is not good, which may affect the reliability of the findings. However, subgroup analysis did not support that difference in quality score may significantly affect the results. Finally, the optimal regimens of Dex administration for prevention POAF remains to be determined, such as dose, initiating time, and duration. Future studies are warranted in this regard.
In conclusion, results of this updated meta-analysis suggested that perioperative administration of Dex may reduce the risk of POAF after cardiac surgery, particularly in Asians. More studies are warranted to determine whether the age and sex of the patients may affect the potential preventative efficacy of Dex on POAF.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
SP, GC, and PL contributed to the conception and design of the study. SP and HY performed literature search, study identification, quality evaluation, and data extraction. SP, JW, and HY performed the statistical analysis. SP, HY, GC, and PL wrote the first draft of the manuscript. All authors contributed to manuscript revision, and read and approved the submitted version.

FUNDING
This study was supported by the Pudong New Area Commission of Science Technology of Shanghai (PKJ2018-Y17).