Impact of perioperative high-intensity statin treatment on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis

Yeiwon Lee; Somin Im; Yoonjin Kang; Suk Ho Sohn; Myoung-Jin Jang; Ho Young Hwang

doi:10.4266/acc.2024.00633

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Original Article Meta-analysis Impact of perioperative high-intensity statin treatment on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis: Yeiwon Lee¹, Somin Im², Yoonjin Kang², Suk Ho Sohn², Myoung-Jin Jang³, Ho Young Hwang²; Acute and Critical Care 2024;39(4):507-516.
DOI: https://doi.org/10.4266/acc.2024.00633
Published online: November 25, 2024

¹Department of Critical Care, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

²Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

³Medical Research Collaborating Center, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Corresponding Author: Ho Young Hwang Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-3020, Fax: +82-2-765-7117, E-mail: scalpel@snu.ac.kr

• Received: April 15, 2024 • Revised: May 30, 2024 • Accepted: October 6, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
KEY MESSAGES
NOTES
REFERENCES

Abstract

Background
This meta-analysis was conducted to evaluate the impact of high-intensity statin treatment on new-onset postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG).
Methods
Four databases were searched for studies that enrolled patients who underwent CABG and investigated the impact of perioperative use of high-intensity statins on the occurrence rate of POAF. The primary outcome was the incidence of POAF. Secondary outcomes were operative mortality and perioperative myocardial infarction (PMI). Publication bias was assessed using a funnel plot and Egger’s test.
Results
Nine articles (eight randomized controlled trials and one non-randomized study: n=3,072) were selected. Rosuvastatin (20 mg) was used in four studies, while atorvastatin (40–80 mg) was used in the other five studies. Reported incidences of POAF in the included studies ranged from 11% to 48.8%. Pooled analyses showed that the incidence of POAF was significantly lower in patients treated with high-intensity statins than in patients in the control group patients (odds ratio, 0.43; 95% CI, 0.27–0.68; P<0.001). Subgroup analyses showed that the impact of high-intensity statins was significant in studies using atorvastatin but not in studies using rosuvastatin. There was no significant subgroup difference in the primary endpoint between studies using a placebo and those using low-dose statins. Secondary outcomes, including operative mortality and the incidence of PMI, were not affected by high-intensity statin treatment.
Conclusions
Perioperative use of high-intensity statins is associated with a 57% reduction in the occurrence of POAF among patients undergoing CABG.
Keywords: atrial fibrillation; coronary artery bypass grafting; meta-analysis; HMG-CoA statins

INTRODUCTION

Postoperative atrial fibrillation (POAF) is one of the most common complications after cardiac surgery, including coronary artery bypass grafting (CABG). Previous studies have reported new-onset POAF in up to 50% of patients who underwent CABG [1]. POAF after CABG affects not only early outcomes but also long-term survival, and increases the risk of stroke [2,3]. Mechanisms of POAF are multifactorial, with the inflammatory response after surgery an important contributor [4-6]. Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have pleiotropic effects, including anti-inflammatory effects, in addition to their cholesterol-lowering effects [7]. Based on this, previous studies have analyzed the impact of statin treatment on the incidence of POAF after CABG. However, differences in study design and the types and doses of statins used have resulted in discrepant findings between studies [8,9]. Moreover, several prior systematic review studies [10-12] have been conducted to investigate the potential role of statins in preventing POAF. However, these studies included heterogeneous types of surgery (e.g., CABG, valve surgery, or combined). In our study, by contrast, we focused solely on isolated CABG, for which statin therapy is strongly recommended [13]. In addition, data regarding the impact of high-intensity statins on POAF after CABG are very limited. Therefore, we performed a meta-analysis to determine the impact of perioperative use of high-intensity statins on the occurrence of POAF after CABG.

MATERIALS AND METHODS

Data Source and Literature Search

This study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [14]. Full-text articles evaluating the impact of high-intensity statins on POAF after CABG were searched for in Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus databases on August 30, 2023, without any restriction on language or publication year. The following keywords and medical subject heading terms were used to search Medline: (("Atrial fibrillation"[MeSH Terms]) OR ("atrial fibrillation"[Title/Abstract])) AND (("Hydroxymethylglutaryl-CoA Reductase Inhibitors"[MeSH Terms]) OR ("statin"[Title/Abstract]) OR ("lovastatin"[Title/Abstract]) OR ("rosuvastatin"[Title/Abstract]) OR ("ceravastatin"[Title/Abstract]) OR ("Simvastatin"[Title/Abstract]) OR ("atorvastatin"[Title/Abstract]) OR ("pravastatin"[Title/Abstract]) OR ("fluvastatin"[Title/Abstract])) AND (("Coronary artery bypass"[MeSH Terms]) OR ("Coronary artery bypass"[Title/Abstract]) OR ("Coronary artery surgery"[Title/Abstract]) OR ("CABG"[Title/Abstract]) OR ("Surgical revascularization"[Title/Abstract]) OR ("Coronary revascularization"[Title/Abstract]) OR ("Myocardial revascularization"[Title/Abstract])). Search strategies for other databases were modified from this strategy based on the format of the databases.

Study Selection

Study selection was independently performed by two reviewers (YL and HYH) based on the selection criteria. Any disagreements between the reviewers were resolved through discussion among the three authors (with MJJ). Study selection was conducted after two levels of screening: titles and abstracts of the searched studies were screened at the first level and full texts were reviewed at the second level. Studies that compared the occurrence rate of POAF after CABG based on the use of high-intensity statins were included.

Data Extraction

Study characteristics and patients' baseline data were extracted independently by two reviewers (YL and SI). Data regarding study outcomes were also independently extracted by two reviewers (MJJ and HYH). Any disagreements between the two reviewers were resolved through discussion among these four authors.

Assessment of Quality

Overall study quality was assessed independently by two reviewers (MJJ and HYH) using the Revised Cochrane Risk-of-Bias tool (RoB2) for randomized controlled trials (RCTs) and the Risk Of Bias In Non-randomized Studies of Interventions ([ROB]INS-I) for non-randomized studies (NRSs) [15,16]. In the RoB2, each of five domains was assessed with judgments (few concerns, some concerns, many concerns) and overall ROB was determined by the worst risk of bias in the five domains. In ROBINS-I, seven domains were rated with judgments (low, moderate, serious, or critical) and overall ROB was determined as the highest ROB level in the seven domains. Any disagreements between reviewers were resolved through discussion by three authors (MJJ, HYH, SI).

Statistical Analysis

The primary outcome was the occurrence of POAF after surgery. Secondary outcomes included operative mortality and postoperative complications such as perioperative myocardial infarction (PMI), acute kidney injury (AKI), and stroke. Statistical heterogeneity among studies was assessed with the chi-square test and the I² statistic. I² values of 25%, 50% and 75% were considered indicators of low, moderate, and high heterogeneity, respectively [17]. Random-effects models with the DerSimonian and Laird method were used when substantial heterogeneity was observed (I²>50%); otherwise, fixed-effects models were applied using inverse variance methods.

Binary outcomes were compared as odds ratios (ORs) with 95% CIs. For studies reporting numbers of events without ORs, ORs and 95% CIs were calculated based on the numbers of events according to the formula by adding 0.5 to all cells for studies with zero cell counts [18]. For the NRS, which reported the number of patients and ORs of POAF of the control group versus the high-intensity statin group with different doses, the overall OR of the control group versus the high-intensity statin group was estimated according to the method of Hamling et al. [19]. Pooled estimates from the RCTs and NRS were obtained. Subgroup differences were assessed using Cochran’s Q test for heterogeneity. A funnel plot and Egger’s test for asymmetry were applied to assess the possibility of publication bias for the primary outcome and for the secondary outcomes when at least five studies were pooled. To assess the impact of publication bias on pooled estimates, sensitivity analysis was performed using the Copas selection model [20]. Pooled analyses for secondary outcomes were also performed for outcomes drawn from at least five studies. All analyses were performed using R version 4.2.1 (R packages meta and metasens). Two-sided P-values<0.050 were considered to indicate statistical significance.

RESULTS

Identification of Studies

The database searches initially yielded 1,787 articles. After reviewing the titles and abstracts, 79 manuscripts remained for full-text screening. Ultimately, a total of nine studies were analyzed in this review (Figure 1) [21-29].

Study Characteristics and Patient Populations

The nine included studies involved 3,072 patients. Eight of the studies [21-28] were RCTs, while the other study was an NRS reporting the adjusted results of multivariable analyses [29]. Rosuvastatin (20 mg) was used in four studies [21,23,24,27], while atorvastatin (40–80 mg) was used in the other five studies (Table 1). On average, the included patients were in their 60s, and more than 70% were male. Hypertension (21%–90%) and diabetes mellitus (23%–65%) were common comorbidities (Table 2). The duration of administration of high-intensity statins ranges from 3 to 14 days prior to surgery, contingent upon the protocols established within the included studies.

Quality of the Included Studies

Six [22,24-28] of the eight included RCTs were considered to have low overall ROB with low risk for all five domains. Two RCTs [21,23] were classified as having some concerns; in one RCT [21], 15% of the randomized patients were excluded from the analysis, while the other RCT [23] did not report the randomization process, concealment of the allocation sequence, or patient characteristics. One RCT had unclear ROB for the domain of bias arising from the randomization processes, but overall ROB was also graded as low. The NRS [29] was graded as having an overall moderate ROB (Table 3).

Impact of High-Intensity Statin Treatment on POAF

Reported incidences of POAF in the included studies ranged from 11% to 48.8%. Pooled analysis was performed using a random-effects model due to high heterogeneity (I²=80.6%, P<0.001). Pooled estimates from all included studies with 3,072 patients demonstrated a significant reduction of POAF in the high-intensity statin group (OR, 0.43; 95% CI, 0.27–0.68) (Figure 2). Pooled estimate from RCTs did not demonstrate statistically significant differences from the OR obtained from the NRS (P=0.708).

Subgroup Analyses of the Impact of High-Intensity Statin Treatment on POAF

Subgroup analyses for the primary endpoint were performed based on the type of statin (atorvastatin vs rosuvastatin) used in the treatment group and the medication used in the control group patients (placebo vs low dose of statin). Pooled analysis showed that the impact of high-intensity statins was significant in studies using atorvastatin but not in studies using rosuvastatin. There was no significant subgroup difference in the primary endpoint between studies using a placebo and those using low-dose statins (Figure 3).

Impact of High-Intensity Statin Treatment on Secondary Outcomes

Operative mortality, PMI, AKI, and stroke were reported in five [22,24-26,28], six [22,24-28], three [24,26,27], and three studies [24-26], respectively. Pooled analyses evaluating operative mortality and PMI demonstrated that high-intensity statins were not significantly associated with either operative mortality or PMI (Figure 4).

Publication Bias

Egger's test for asymmetry suggested a publication bias for the primary outcome (P=0.022). The funnel plot showed that there was a potential lack of small studies showing a non-significant effect of high-intensity statins on the primary outcome (Figure 5). There was no significant publication bias for secondary outcomes, such as operative mortality and PMI.

DISCUSSION

This meta-analysis demonstrated that perioperative use of high-intensity statins is associated with a 57% reduction in the occurrence of POAF in patients undergoing CABG. Statins have been used as key treatments for the primary and secondary prevention of coronary artery disease because of their cholesterol-lowering effect through inhibition of hepatic cholesterol biosynthesis [13]. In addition, statins exhibit pleiotropic effects, including antioxidant, antithrombotic, and anti-inflammatory activities [30]. The anti-inflammatory activity of statins is expected to be beneficial for preventing POAF because the perioperative inflammatory response has been suggested to be one of the mechanisms underlying the occurrence of POAF after cardiac surgery, including CABG [4-6]. However, results of previous studies have been contradictory [31-34]. This may be partly due to the different types and intensities of statins used in the studies. In the present meta-analysis, only studies that used high-intensity statins were included. Given this inclusion criterion, we did not limit the search strategy to RCTs, because a limited number of studies was expected to fulfill this criterion. However, all but one study was an RCT and both pooled analyses based on the RCTs and based on all studies showed a significant benefit of high-intensity statins preventing POAF. In addition, subgroup analyses were completed based on the medication used in control group patients, because all patients with coronary artery disease, including those who undergo CABG, might be treated with statins in the current era. Pooled analyses showed that the impact of high-intensity statins on POAF was significant even in studies where the control group patients received low- or intermediate-intensity statin treatment.

Subgroup analysis according to the type of statin revealed that the impact of high-intensity statins on POAF was statistically significant, without any heterogeneity, in studies that used atorvastatin. However, the effect was not statistically significant and was highly heterogeneous in studies using rosuvastatin. One large RCT [24] reported a neutral effect of high-intensity rosuvastatin on POAF. In that study, the authors randomized patients into rosuvastatin 20 mg or placebo groups. The prevalence of POAF among CABG patients in that study was 19.5% (157/806 patients) and 19.4% (157/808) in the experimental and control groups, respectively.

Although the reasons underlying the different effects of atorvastatin and rosuvastatin have not yet been fully elucidated, one possible explanation is a difference in the solubility of these two statins; atorvastatin is a lipophilic statin, whereas rosuvastatin is a hydrophilic one. A recent review article [35] commented that the liver-specific, carrier-mediated mechanisms required for hydrophilic statin uptake could possibly reduce the efficacy of the statin at extrahepatic sites.

The selected secondary outcomes are well-documented postoperative complications following cardiac surgery. These complications are often managed with statin therapy, as they have been linked to the perioperative inflammatory response and oxidative stress, against which statins have demonstrated efficacy. The pooled analysis revealed no significant correlation between high-intensity statin use and PMI. This outcome may be attributed to the varying definitions of MI in the included studies. Although each study clearly defined PMI for their data, the lack of a uniform definition likely influenced the overall result.

Studies have indicated no significant difference in operative mortality between the high-intensity statin group and the control group. The precise mechanisms underlying the association between preoperative statin therapy and cardiac mortality remain unclear. However, Heeschen et al. [36] concluded that statin therapy is less effective in reducing the risk of death when initiated after the onset of an acute coronary syndrome and initiating statin therapy during hospitalization did not reduce early cardiac events. These results may account for our findings. Despite a neutral effect being reported in the largest included study, our pooled analyses showed a significant effect of high-intensity statins on POAF.

In conclusion, the perioperative use of high-intensity statins was related to a reduced risk of POAF in patients who underwent CABG. Subgroup analyses revealed that the impact of high-intensity statins was significant in studies using atorvastatin, whereas no significant effect was observed in studies using rosuvastatin. There are several limitations that should be noted. First, the included total number of studies was relatively small; however, eight of the nine included studies were RCTs. Second, the funnel plot and Egger's test revealed publication bias due to the absence of small studies showing negative results of high-intensity statins on POAF.

KEY MESSAGES

▪ Preoperative administration of high-intensity statins may significantly reduce the occurrence of atrial fibrillation after coronary artery bypass.

▪ Subgroup analyses showed that the impact of high-intensity statins was significant in studies using atorvastatin but not in studies using rosuvastatin.

NOTES

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

None.

ACKNOWLEDGMENTS

The authors thank Pf. Mohammad Bagher Khosravi for confirming some of the data used in this paper via mail.

AUTHOR CONTRIBUTIONS

Conceptualization: SHS, HYH. Data curation: MJJ, HYH. Formal analysis: YL, SI, YK, MJJ, HYH. Methodology: MJJ, HYH. Project administration: SHS, MJJ, HYH. Visualization: MJJ, HYH. Writing – original draft: YL, MJJ, HYH. Writing – review & editing: YL, MJJ, HYH. All authors read and agreed to the published version of the manuscript.

Figure 1.

Flow diagram based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Figure 2.

Pooled analysis for the risk of the primary endpoint, i.e., postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) among patients who received perioperative high-intensity statin treatment (HIS group) compared to those who did not receive it (control group). Pooled estimates from both randomized controlled trials (RCTs) and a non-randomized study (NRS) showed that the use of perioperative high-intensity statin treatment was associated with a significant reduction in the incidence of POAF. OR: odds ratio. a) Number and proportion were from all study patients who underwent either CABG or valve surgery whereas the OR and 95% CI were from those who underwent CABG.

Figure 3.

Subgroup analyses for the risk of the primary endpoint, i.e., postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) in patients who received perioperative high-intensity statin treatment (HIS group) compared to those did not receive it (control group). The impact of the HIS on POAF was statistically significant in studies using atorvastatin but not in those using rosuvastatin (A). The impact was significant for both studies using a placebo and those using low-dose statins for control group patients (B). OR: odds ratio. a) Number and proportion were from all study patients who underwent either CABG or valve surgery whereas the OR and 95% CI were from those who underwent CABG.

Figure 4.

Pooled analyses for the risks of the secondary endpoints, including (A) early mortality and (B) perioperative myocardial infarction (PMI) in patients who received perioperative high-intensity statin treatment (HIS group) compared to those who did not receive it (control group). Pooled estimates showed that the risk of the secondary outcomes was not significantly different between the two groups OR: odds ratio; RCT: randomized controlled trials.

Figure 5.

Funnel plots and Egger’s tests for asymmetry for (A) the primary endpoint, postoperative atrial fibrillation (POAF), and secondary outcomes such as (B) early mortality and (C) perioperative myocardial infarction (PMI). The funnel plot indicated a potential lack of small studies reporting a non-significant effect of high-intensity statins on the primary endpoint. OR: odds ratio.

Table 1.

Study characteristics of the study group patients who had perioperative high-intensity statin treatment and those of the control group patients

Study	Operative era	Study type	Country	Number of patients			Type of statin		Statin dose (mg)
Study	Operative era	Study type	Country	Total	Study	Control	Study	Control	Study	Control
Mirbolouk et al. [21]	2017–2018	RCT	Iran	160	84	76	RSV	RSV	20	5
Bastani et al. [22]	-	RCT	Iran	100	50	50	ATV	ATV	80	20
Osmanovic et al. [23]	-	RCT	Bosnia and Herzegovina	160	80	80	RSV	No	20	0
Zheng et al. [24]	2011–2013	RCT	China	1,614	806	808	RSV	No	20	0
Aydin et al. [25]	2012	RCT	Turkey	60	30	30	ATV	No	40	0
Baran et al. [26]	2010	RCT	Turkey	60	30	30	ATV	No	40	0
Mannacio et al. [27]	2005–2007	RCT	Italy	200	100	100	RSV	No	20	0
Patti et al. [28]	2003–2005	RCT	Italy	200	101	99	ATV	No	40	0
Karimi et al. [29]	2010–2011	NRS	Iran	560	485	75	ATV	No	80	0

RCT: randomized controlled study; RSV: rosuvastatin; ATV: atorvastatin; NRS: non-randomized study.

Table 2.

Patients characteristics of the study group patients who had perioperative high-intensity statin treatment and those of the control group patients

Study	Age (yr)		Female		Smoking		HTN		DM		Dyslipidemia		Use of BB		OPCAB		LVEF (%)
Study	S	C	S	C	S	C	S	C	S	C	S	C	S	C	S	C	S	C
Mirbolouk et al. [21]	60±9	58±7	32.1	38.2	35.7	27.6	68.3	65.8	35.7	64.5	32.1	39.5	88.1	77.6	-	-	-	-
Bastani et al. [22]	-	-	-	-	-	-	-	-	-	-	-	-	-	-	0	0	-	-
Osmanovic et al. [23]	-	-	-	-	-	-	-	-	-	-	-	-	100	100	21.3		-	-
Zheng et al. [24]^a)	59±9	60±10	20.2	21.3	23.9	25.5	64.7	63.8	32.3	30.2	-	-	84.7	83.6	51.1	50.4	60.5±0.3	61.0±0.3
Aydin et al. [25]	63±11	62±12	20	23.3	-	-	53.3	60	43	36.7	36.7	36.7	63.3	56.7	0	0	-	-
Baran et al. [26]	61±9	62±8	36.7	40	33.3	26.7	66.7	56.7	22.7	33.3	-	-	47.2	52.8	0	0	49.4±7.2	48.7±7.8
Mannacio et al. [27]	61±9	59±8	25	30	-	-	25	21	-	-	-	-	73	68	0	0	-	-
Patti et al. [28]^a)	66±9	67±8	20.8	32.3	24.8	24.2	90.1	82.8	32	42	19	20	72	60	0	0	52±9	52±10
Karimi et al. [29]	61±10	61±10	27.2	26.7	17.1	21.3	47.4	42.7	40	33	46	47	77	81	1	3	46.7±9.1	45.2±9.2

Values are presented as mean±standard deviation.

S: study group; C: control group; HTN: hypertension; DM: diabetes mellitus; BB: beta-blocker; OPCAB: off-pump coronary artery bypass grafting; LVEF: left ventricular ejection fraction.

^a)Data from the entire study patients who underwent either coronary artery bypass grafting or valve surgery.

Table 3.

Quality assessment of included studies

Quality assessment by revised Cochrane risk-of-bias tool for randomized trials
Study	Bias arising from the randomization process	Bias due to deviations from intended interventions	Bias due to missing outcome data	Bias in measurement of the outcome	Bias in selection of the reported result	Overall
Mirbolouk et al. [21]	Low	Low	Some concerns	Low	Low	Some concerns
Bastani et al. [22]	Low	Low	Low	Low	Low	Low
Osmanovic et al. [23]	Some concerns	Low	Low	Low	Low	Some concerns
Zheng et al. [24]	Low	Low	Low	Low	Low	Low
Aydin et al. [25]	Low	Low	Low	Low	Low	Low
Baran et al. [26]	Low	Low	Low	Low	Low	Low
Mannacio et al. [27]	Low	Low	Low	Low	Low	Low
Patti et al. [28]	Low	Low	Low	Low	Low	Low

Quality assessment by risk of bias in non-randomized studies of interventions for non-randomized studies
Study	Bias due to confounding	Bias in selection of participants into the study	Bias in measurement of interventions	Bias due to departures from intended interventions	Bias due to missing data	Bias in measurement of outcomes
Karimi et al. [29]	Moderate	Low	Low	Low	Low	Low

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Impact of perioperative high-intensity statin treatment on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis

Acute Crit Care. 2024;39(4):507-516. Published online November 25, 2024

DOI: https://doi.org/10.4266/acc.2024.00633

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Impact of perioperative high-intensity statin treatment on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis

Figure 1. Flow diagram based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Figure 2. Pooled analysis for the risk of the primary endpoint, i.e., postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) among patients who received perioperative high-intensity statin treatment (HIS group) compared to those who did not receive it (control group). Pooled estimates from both randomized controlled trials (RCTs) and a non-randomized study (NRS) showed that the use of perioperative high-intensity statin treatment was associated with a significant reduction in the incidence of POAF. OR: odds ratio. a) Number and proportion were from all study patients who underwent either CABG or valve surgery whereas the OR and 95% CI were from those who underwent CABG.

Figure 3. Subgroup analyses for the risk of the primary endpoint, i.e., postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) in patients who received perioperative high-intensity statin treatment (HIS group) compared to those did not receive it (control group). The impact of the HIS on POAF was statistically significant in studies using atorvastatin but not in those using rosuvastatin (A). The impact was significant for both studies using a placebo and those using low-dose statins for control group patients (B). OR: odds ratio. a) Number and proportion were from all study patients who underwent either CABG or valve surgery whereas the OR and 95% CI were from those who underwent CABG.

Figure 4. Pooled analyses for the risks of the secondary endpoints, including (A) early mortality and (B) perioperative myocardial infarction (PMI) in patients who received perioperative high-intensity statin treatment (HIS group) compared to those who did not receive it (control group). Pooled estimates showed that the risk of the secondary outcomes was not significantly different between the two groups OR: odds ratio; RCT: randomized controlled trials.

Figure 5. Funnel plots and Egger’s tests for asymmetry for (A) the primary endpoint, postoperative atrial fibrillation (POAF), and secondary outcomes such as (B) early mortality and (C) perioperative myocardial infarction (PMI). The funnel plot indicated a potential lack of small studies reporting a non-significant effect of high-intensity statins on the primary endpoint. OR: odds ratio.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Impact of perioperative high-intensity statin treatment on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis

Study	Operative era	Study type	Country	Number of patients			Type of statin		Statin dose (mg)
Study	Operative era	Study type	Country	Total	Study	Control	Study	Control	Study	Control
Mirbolouk et al. [21]	2017–2018	RCT	Iran	160	84	76	RSV	RSV	20	5
Bastani et al. [22]	-	RCT	Iran	100	50	50	ATV	ATV	80	20
Osmanovic et al. [23]	-	RCT	Bosnia and Herzegovina	160	80	80	RSV	No	20	0
Zheng et al. [24]	2011–2013	RCT	China	1,614	806	808	RSV	No	20	0
Aydin et al. [25]	2012	RCT	Turkey	60	30	30	ATV	No	40	0
Baran et al. [26]	2010	RCT	Turkey	60	30	30	ATV	No	40	0
Mannacio et al. [27]	2005–2007	RCT	Italy	200	100	100	RSV	No	20	0
Patti et al. [28]	2003–2005	RCT	Italy	200	101	99	ATV	No	40	0
Karimi et al. [29]	2010–2011	NRS	Iran	560	485	75	ATV	No	80	0

Study	Age (yr)		Female		Smoking		HTN		DM		Dyslipidemia		Use of BB		OPCAB		LVEF (%)
Study	S	C	S	C	S	C	S	C	S	C	S	C	S	C	S	C	S	C
Mirbolouk et al. [21]	60±9	58±7	32.1	38.2	35.7	27.6	68.3	65.8	35.7	64.5	32.1	39.5	88.1	77.6	-	-	-	-
Bastani et al. [22]	-	-	-	-	-	-	-	-	-	-	-	-	-	-	0	0	-	-
Osmanovic et al. [23]	-	-	-	-	-	-	-	-	-	-	-	-	100	100	21.3		-	-
Zheng et al. [24]^a)	59±9	60±10	20.2	21.3	23.9	25.5	64.7	63.8	32.3	30.2	-	-	84.7	83.6	51.1	50.4	60.5±0.3	61.0±0.3
Aydin et al. [25]	63±11	62±12	20	23.3	-	-	53.3	60	43	36.7	36.7	36.7	63.3	56.7	0	0	-	-
Baran et al. [26]	61±9	62±8	36.7	40	33.3	26.7	66.7	56.7	22.7	33.3	-	-	47.2	52.8	0	0	49.4±7.2	48.7±7.8
Mannacio et al. [27]	61±9	59±8	25	30	-	-	25	21	-	-	-	-	73	68	0	0	-	-
Patti et al. [28]^a)	66±9	67±8	20.8	32.3	24.8	24.2	90.1	82.8	32	42	19	20	72	60	0	0	52±9	52±10
Karimi et al. [29]	61±10	61±10	27.2	26.7	17.1	21.3	47.4	42.7	40	33	46	47	77	81	1	3	46.7±9.1	45.2±9.2

Quality assessment by revised Cochrane risk-of-bias tool for randomized trials
Study	Bias arising from the randomization process	Bias due to deviations from intended interventions	Bias due to missing outcome data	Bias in measurement of the outcome	Bias in selection of the reported result	Overall
Mirbolouk et al. [21]	Low	Low	Some concerns	Low	Low	Some concerns
Bastani et al. [22]	Low	Low	Low	Low	Low	Low
Osmanovic et al. [23]	Some concerns	Low	Low	Low	Low	Some concerns
Zheng et al. [24]	Low	Low	Low	Low	Low	Low
Aydin et al. [25]	Low	Low	Low	Low	Low	Low
Baran et al. [26]	Low	Low	Low	Low	Low	Low
Mannacio et al. [27]	Low	Low	Low	Low	Low	Low
Patti et al. [28]	Low	Low	Low	Low	Low	Low

Table 1. Study characteristics of the study group patients who had perioperative high-intensity statin treatment and those of the control group patients

RCT: randomized controlled study; RSV: rosuvastatin; ATV: atorvastatin; NRS: non-randomized study.

Table 2. Patients characteristics of the study group patients who had perioperative high-intensity statin treatment and those of the control group patients

Values are presented as mean±standard deviation.

S: study group; C: control group; HTN: hypertension; DM: diabetes mellitus; BB: beta-blocker; OPCAB: off-pump coronary artery bypass grafting; LVEF: left ventricular ejection fraction.

Data from the entire study patients who underwent either coronary artery bypass grafting or valve surgery.

Table 3. Quality assessment of included studies