Remote ischemic preconditioning and its role in the prevention of new onset atrial fibrillation post‐cardiac surgery. A meta‐analysis of randomized control trials

Abstract Background The denouement of remote ischemic preconditioning on new onset atrial fibrillation (NOAF) post‐cardiac surgery is not well‐established. An updated meta‐analysis of randomized control trials was performed by comparing remote ischemic preconditioning with controls and the outcome of interest was NOAF. Methods The systemic review was performed in accordance with the PRISMA (Preferred reporting items for systemic review) and AHA (American Heart Association) guidelines. PubMed database was searched to include relevant randomized control trials from inception to July 2019. We used Mantel‐Haenzsel method with random error model to calculate risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed using the I 2 test> 50% or χ 2 P < .05. Publication bias was visually assessed using a funnel plot. Results Twelve randomized control trials were included in the final analysis. Remote ischemic preconditioning did not alter the risk of NOAF post‐cardiac surgery [RR: 0.95, CI: 0.83‐1.09, P = .48, I 2 = 37%, χ 2 P = .09]. Conclusion In conclusion, the present meta‐analysis failed to provide any evidence for the beneficial effect of remote ischemic preconditioning in the prevention of NOAF.

fibrillation (NOAF) post-cardiac surgery. Therefore, we performed an updated meta-analysis of randomized control trials by comparing remote ischemic preconditioning with controls and the outcome of interest was NOAF, for pooled estimation in meta-analysis.

| ME THODS
The systemic review was performed in accordance with the PRISMA (Preferred reporting items for systemic review) and AHA (American heart association) guidelines. 4,5 We performed a systematic search through PubMed database to identify relevant randomized control trials from inception to July 2019. The following terms were used for systematic search in the PubMed database-"remote ischemic pre-condition*, "remote ischemic precondition*", "cardiac surgery", "bypass-surgery", "bypass", "surgical aortic valve replacement", SAVR. The search strategy is further elaborated in the supplementary file. The inclusion criteria for studies were: randomized control trials studying the effect of remote ischemic preconditioning juxtaposed to controls in subjects undergoing cardiac surgery and reporting the incidence of NOAF. Articles were not excluded based on sample size. Only manuscripts published in English were considered for final analysis. The database search was augmented with manual search of bibliographies of included articles, to include relevant articles not identified by database search. The PRISMA flow chart for inclusion of studies is depicted in Figure 1.
Two authors AK and MS independently screened the abstracts to include relevant articles and performed data extraction. Any disparity was resolved by mutual consensus. Data extraction was performed in accordance with a standardized predefined data extraction form. The following data were extracted from each study: author's name, year of study, study design, number randomized, mean age, percentage male, primary outcomes of interest, number of individuals with NOAF in the intervention and control group.
We used Mantel-Haenzsel method with random error model to calculate risk ratio (RR) with 95% confidence interval (CI).
Publication bias was visually assessed using funnel plot. The analysis was carried out using RevMan Version 5.3. (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

| RE SULTS
The systematic search unveiled a total of 171 eligible articles.
Twelve randomized control trials were included in the final analysis. 3,[6][7][8][9][10][11][12][13][14][15][16] This sums up to a total of 2652 procedures in the remote ischemic preconditioning group and 2667 procedure in the control group. There were three prominent studies of the 12 included studies, 10 (Figure 2). There was no heterogeneity associated with the pooled estimate as evident from the I 2 and χ 2 P-value. Visual inspection of the funnel plot did not depict publication bias ( Figure S1).

| D ISCUSS I ON
An updated meta-analysis comparing remote ischemic preconditioning with controls using the data from 12 randomized control trials with 2652 procedures in the intervention arm and 2667 procedures in the control arm was performed. The main result of this meta-analysis concluded that remote ischemic preconditioning prior to cardiac surgery did not curtail the risk of NOAF. To our knowledge, this was the first meta-analysis researching the effect of remote ischemic preconditioning on NOAF, prior to cardiac surgery.
A study by Krogstad et al had similar conclusion as our metaanalysis which found no difference in the incidence of NOAF among the remote ischemic precondition group as compared to the control group undergoing cardiac surgery. 15 Besides, the three large trials, studying the effect of remote ischemic preconditioning on clinical outcomes in patients undergoing cardiac surgery, namely the RIPHeart trail, the ERICCA trial, and the study by Hong et al, found no beneficial effect of remote ischemic preconditioning on the incidence of NOAF post-surgery. 10,14,16 The results of this meta-analysis are however incongruous with the results of a randomized control trial which concluded that remote ischemic preconditioning reduced the inducibility and sustainability of nonvalvular atrial fibrillation. Additionally, the study also concluded that these changes were possibly mediated by alteration in the electrophysiological properties of the atria. 17  MicroRNA (miR) expression of the atrial myocardium among subjects undergoing coronary artery bypass surgery. 9 The study adumbrated regarding the prevention of miR upregulation by remote ischemic preconditioning prior to cardiac surgery. Increased miR expression has been associated with greater extent of myocardial injury following ischemia reperfusion injury. 18   Finally, the method used for inducing remote ischemic preconditioning varied slightly in each trial and has not been attributed in the present analysis.
In conclusion, the present meta-analysis of randomized control trials did not delineate any beneficial effect of remote ischemic preconditioning on the risk of NOAF.

CO N FLI C T O F I NTE R E S T
Authors declare no conflict of interests for this article.