REVIEW ARTICLE
The Use of Statins to Prevent Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting: A Meta-analysis of 12 Studies Hui Zheng, MD, Song Xue, MD, PhD, Zhen-Lei Hu, MD, PhD, Jiang-Gui Shan, MD, and Wen-Gang Yang, MD
Abstract: There is no agreement on whether statins influence the incidence of atrial fibrillation after coronary artery bypass grafting. We performed a meta-analysis of 12 studies that compared statins with controls. Statin therapy significantly reduced the incidence of postoperative atrial fibrillation (POAF) (odds ratio, 0.50; 95% confidence interval, 0.35–0.73) and length of hospital stay (weighted mean difference, 20.72; 95% confidence interval, 20.99 to 20.45), an effect that survived detailed subgroup analysis. Meta-regression analysis revealed that patient characteristics did not influence the extent of improvement in the incidence of POAF attributable to statins. In conclusion, patients undergoing coronary artery bypass grafting benefit from perioperative treatment with statins, which significantly reduce the incidence of POAF and length of hospital stay. Key Words: atrial fibrillation, arrhythmia therapy, coronary artery bypass grafting, statins (J Cardiovasc Pharmacol Ô 2014;64:285–292)
INTRODUCTION
Postoperative atrial fibrillation (POAF) is a very common complication of coronary artery bypass grafting (CABG), reports of its incidence have a range of 30%– 45%.1 The occurrence of atrial fibrillation (AF) is associated with a reduction in cardiac output, hemodynamic instability, thromboembolic events, stroke, and renal insufficiency, all of which contribute to increased morbidity.1,2 Postoperative AF may be a particular problem after CABG, when it can induce a rapid ventricular rate that markedly increases myocardial oxygen consumption, aggravates myocardial ischemia, and causes cardiac dysfunction. Furthermore, several antiarrhythmic drugs used to treat AF have potentially harmful side effects and increase total mortality. Thus, it is essential for clinicians to find safer and more efficacious means of preventing AF after CABG. Received for publication February 12, 2014; accepted March 23, 2014. From the Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. The authors report no conflicts of interest. Reprints: Song Xue, MD, PhD, Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong New Area, Shanghai, China 200127 (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
The pathophysiologic causes of AF after CABG are not completely understood, but there is an increasing body of evidence to suggest that enhanced inflammatory responses may play a part.3,4 Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to attenuate postoperative inflammatory responses,5 in addition to their lipid-lowering properties and ability to stabilize atherosclerotic plaque. An increasing number of clinical and experimental studies have assessed the efficacy of preoperative administration of statins as a therapeutic intervention to reduce the incidence of AF after CABG, but their findings have been mixed. Many of these studies have enrolled relatively small cohorts, which might have been statistically underpowered to evaluate this endpoint. Consequently, it has not been established whether preoperative statin therapy can prevent the onset of AF after CABG. We undertook a meta-analysis of randomized trials and observational studies to examine the effectiveness of preoperative statins as a method for prevention of POAF, and to evaluate their influence on the length of hospital stay (LOS) in patients undergoing CABG.
MATERIALS AND METHODS Search Strategy All randomized controlled trials (RCTs) or observational studies that examined the influence of statins on AF after CABG were identified using a two-level search strategy. First, web-based searches of PubMed, Elsevier Database, Google Scholar, Web of Science, Ovid Database, and the Cochrane Library were undertaken to identify articles published in English between the date of their inception and December 31, 2012. Search terms included variants of the following keywords: “atrial fibrillation” and “coronary artery bypass graft or CABG or CAB or cardiopulmonary bypass or CPB” and “statin or HMG-CoA reductase inhibitor.” Second, a manual search was performed for secondary sources including the references of articles, reviews, and commentaries identified in the first search. All relevant studies were downloaded for combination, elimination of duplicates, and further analysis.
Inclusion Criteria Studies were included if they met the following criteria: recruitment of adult patients undergoing CABG; studies in which a group taking statins was compared with a control
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group; and the incidence of POAF was reported as an outcome measure. Studies that included patients undergoing hybrid surgery (for example, CABG with concomitant valve replacement surgery) were excluded, as were those in which details of the preoperative statin regimen and monitoring of POAF were not reported. Case reports, editorials, comments, letters, review articles, guidelines or secondary prevention trials, and studies only available in abstract form were not included in the meta-analysis.
Data Extraction Two independent investigators identified trials for inclusion and abstracted demographic, intervention, and outcome data in a standardized manner. Two reviewers independently assessed the methodological quality of every trial using the Jadad scale6 for RCTs, and the Downs and Black Checklist7 for both RCTs and observational trials. The Jadad score range was 0–5 points, according to the examination of randomization methods, blinding, and dropout (0–2: poor quality, 3–4: good quality, 5: excellent quality). The Downs and Black Checklist was scored on the basis of the presence of the following key sections: reporting (0–11 points); external validity (0–3 points); internal validity bias (0–7 points); internal validity confounding (0–6 points); and power (0–2 points). A score of 29 is considered the highest-quality study, and a score of zero indicates the poorest-quality study. Discrepancies between reviewers were resolved by discussion.
selected for meta-analysis to examine the effect of preoperative statin therapy on AF post-CABG, as outlined in Figure 1.
Characteristics of Included Studies The characteristics of included studies are summarized in Table 1. Of the 8458 patients, 5120 (60.53%) were taking preoperative statin therapy while 3338 (39.47%) were not. The age of the patients in each of the pooled groups, the prevalence of male sex, dyslipidemia, congestive heart failure (CHF), previous myocardial infarction (MI), hypertension, diabetes mellitus (DM), mean left ventricular ejection fraction (LVEF), and frequency of the preoperative use of betablockers, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and digoxin were compared (Table 2). The proportions of patients taking beta-blockers, or with diagnoses of DM or dyslipidemia, were higher in those taking statin therapy, whereas the proportions taking a CCB or digoxin were higher in the pooled control group. Of the 12 studies, 5 trials9–12,15 reported the impact of statins on LOS after CABG. The Jadad quality score was 4 (good), 4 (good), 1 (poor), and 1 (poor) for the 4 RCTs shown in Table 1, respectively. The mean score of the 12 studies on the Downs and
Statistical Analysis The incidence of POAF was treated as a dichotomous variable and LOS as a continuous variable. Odds ratio (OR) with 95% confidence interval (CI) was calculated for dichotomous variables, whereas the weighted mean difference with 95% CI was established for continuous variables. Pooled effect estimates were calculated using Review Manager Version 5.0 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). We used a fixed effects model in the meta-analyses when there was no significant heterogeneity among study results. A random-effects model was used when heterogeneity existed among enrolled studies. Heterogeneity between studies was assessed using the Q test and I2 statistic. An I2 value ,30%, 31%–50%, and .50% independently indicated mild, moderate, and notable heterogeneity.8 Subgroup and meta-regression analyses were performed to evaluate sources of heterogeneity. Publication bias was evaluated by the Begg test, the Egger weighted regression, and the Trim-andFill method using Stata version 10.0 (StataCorp, College Station, TX). SPSS version 13.0 (SPSS Inc, Chicago, IL) was used to compute P values comparing the baseline covariates of 2 groups by means of the 2-sample Student’s t test for continuous data and the chi-square test for categorical data. P , 0.01 was regarded as statistically significant.
RESULTS Studies Identified Four randomized trials9–12 and 8 observational trials13–20 that included 8458 patients who underwent CABG surgery were
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FIGURE 1. Identification of eligible trials for the meta-analysis. Ó 2014 Lippincott Williams & Wilkins
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TABLE 1. Baseline Characteristics of the Included Studies in the Meta-analysis Study
Location
Study Design
Control Group
Ji et al9 Karimi et al13 Kinoshita et al14 Mannacio et al10 Mariscalco et al15 Marín et al16 Miceli et al17 Ozaydin et al18 Sakamoto et al19 Song et al11 Sun et al12 Tamura et al20
China Iran Japan Italy Italy Spain UK Turkey Japan Korea China Japan
Randomized Retrospective Retrospective Randomized Retrospective Retrospective Retrospective Retrospective Retrospective Randomized Randomized Retrospective
Placebo Usual care Usual care Placebo Usual care Usual care Usual care Usual care Usual care Usual care Placebo Usual care
Definition of POAF Any episode of AF that was registered by the monitoring system on a rhythm strip or 12-lead ECG and lasting for $5 min with or without symptoms Episodes lasting for .5 min
An irregular cardiac rhythm without P-waves lasting .30 min on 12lead ECG NR
Episodes lasting for .15 min
NR
The documentation of AF of any duration at any time in the postoperative period on the basis of a rhythm strip or 12-lead ECG An irregular narrow complex rhythm (in the absence of bundle branch block) with the absence of discrete P-waves lasting $10 min Episodes lasting for $5 min Any documented AF of .5 min in duration or AF episodes requiring intervention for symptoms or hemodynamic compromise after CABG The occurrence of at least 1 episode of AF (with or without symptoms) lasting for .5 min
Surgery Type Elective off-pump CABG On-pump/off-pump CABG Elective off-pump CABG Elective on-pump/off-pump On-pump/off-pump CABG Elective on-pump/off-pump On-pump/off-pump CABG Elective on-pump/off-pump On-pump/off-pump CABG Elective off-pump CABG Elective on-pump CABG Elective on-pump/off-pump
No. Statins/All/Control
CABG CABG CABG
CABG
71/140/69 1532/1607/75 364/584/220 100/200/100 218/405/187 144/234/90 2152/4304/2152 267/362/95 77/203/126 62/124/62 49/100/51 84/195/111 Monitoring of POAF
Continuous ECG monitoring for at least 7 days after CABG, and subsequently, daily 12-lead ECG monitoring until hospital discharge Continuous telemonitor during the first 72 postoperative hours at the ICU Continuous ECG monitoring using a bedside monitor in the ICU and telemetry on the hospital ward for at least 7 days A 12-lead ECG monitoring before CABG, on admission to the ICU, 12 hours later, and every day thereafter until hospital discharge Daily until discharge with continuous ECG telemetry and standard 12lead ECG Continuously monitoring for the first 36–48 hours, and subsequently, daily 12-lead ECG on in case of any symptom performing until discharge A 12-lead ECG monitoring preoperatively, 2 hours postoperatively, and then daily thereafter until discharge Monitoring continuously during the operation and during the first 2 postoperative days in the ICU; monitoring with a 12-lead ECG during 1 week of hospitalization in the wards Daily with continuous ECG telemetry for a minimum of 11 days after CABG Daily with a 12-lead ECG
ECG monitoring at least 7 d
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TABLE 1. (Continued ) Baseline Characteristics of the Included Studies in the Meta-analysis Definition of POAF
Monitoring of POAF
An absent P-wave before QRS complex together with an irregular ventricular rhythm on the rhythm strips and AF episodes lasting $5 min
Monitoring continuously after CABG during stay in ICU; connecting to monitors for continuous ECG monitoring until the day of discharge
Drug Type
Statin Regimen
Age, yrs
Male
Previous MI
Atorvastatin Atorvastatin
20 mg/d for 7 d; before CABG 40 or 80 mg/d; at least 3 d before CABG Daily for at least 5 d; before CABG
65/66 60.9/60.6
48/49 1122/55
NR 531/32
69/68
293/166
108/54
20 mg/d for 7 d; before CABG Mean dose 22 mg/d; before and after CABG
61/59 66/66
75/70 182/148
21/25 140/98
An intermediate statin dose; a median of 31 d before CABG Dose NR; 24 h before CABG Mean dose 27 mg/d; mean 2.7 mo before CABG continued after CABG Dose not uniform; before CABG; omission on the day of CABG; mean 1.47 d after CABG 20 mg/d; 3 d before CABG; 30 d after CABG 20 mg/d; 7 d before CABG Mean 9.1 mg/d; mean 6.5 mo before CABG; reinitiation after CABG
NR
NR
NR
65/65 60/62
1774/1769 210/81
961/961 189/47
63/67
55/107
NR
62/64
39/42
8/5
64/65 66/67
32/35 67/89
NR 41/53
Atorvastatin, pitavastatin, fluvastatin, rosuvastatin, pravastatin, or simvastatin Rosuvastatin Atorvastatin, pravastatin, simvastatin, lovastatin, rosuvastatin, or fluvastatin One statin Statins Fluvastatin, atorvastatin, pravastatin, or simvastatin Atorvastatin, pravastatin, pitavastatin, rosuvastatin, simvastatin, or fluvastatin Atorvastatin Atorvastatin Atorvastatin or pravastatin Mean LVEF, % 56/55 47/45 59/58 NR 53.6/53.7 NR NR 53/53 66/63 NR 54/55 59.3/59.7
DM
Hypertension
Dyslipidemia
CHF
Beta-blockers
ACEI/ARB
CCB
Digoxin
Quality Score*
27/26 607/25 169/91 NR 69/53 NR 312/337 76/16 42/59 29/32 18/20 7/6
21/20 753/32 290/166 25/21 154/136 NR 1248/1266 132/43 54/81 35/37 16/15 66/78
14/13 745/35 NR NR 110/72 NR NR NR 77/38 15/15 10/9 NR
50/42 NR 69/44 NR NR NR NR 76/16 NR 15/14 35/32 NR
46/41 1242/61 210/122 73/68 144/137 NR NR 248/84 31/31 45/43 32/30 30/39
28/32 787/37 292/170 22/28 121/97 NR 962/1002 159/50 30/46 35/31 19/24 31/38
40/31 171/4 NR 30/27 56/52 NR NR NR 31/45 12/6 27/24 26/43
21/23 50/4 26/11 NR NR NR NR NR NR 8/7 13/18 0/2
4/26 -/22 -/21 4/25 -/22 -/17 -/23 -/18 -/20 1/23 1/20 -/20
Data are formatted as statins group/control group. *Quality assessment of included studies with the Jadad Score (only for RCT)/Downs and Black Checklist Score. ECG, electrocardiograph; ICU, intensive care unit; NR, not reported.
Black Checklist Scale was 21.4 6 2.6, and only 2 scored less than 20 points, suggesting that the overall quality of the studies included in the meta-analysis was good.
Effects of Statin Therapy on Postoperative Atrial Fibrillation The means of defining and monitoring the outcome of POAF are shown in Table 1. There was significant heterogeneity among the included studies (I2 = 84%; P , 0.00001).
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Using the random-effects model, our meta-analysis revealed that preoperative statin therapy was associated with a significant reduction in the incidence of POAF compared with the control group (OR, 0.50; 95% CI, 0.35–0.73; P = 0.003; Fig. 2).
Subgroup Analysis Controls To assess whether the heterogeneity lay within the pooled controls, studies were subdivided into those with Ó 2014 Lippincott Williams & Wilkins
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TABLE 2. Baseline Characteristics of Patients Variables
Sample Size
Prevalence (%)
Age, yr
Statin:4976 Control:3248 Statin:4976 Control:3248 Statin:2009 Control:570 Statin:813 Control:497 Statin:4779 Control:3002 Statin:4976 Control:3248 Statin:4876 Control:3148 Statin:2662 Control:934 Statin:2824 Control:1096 Statin:4976 Control:3248 Statin:2193 Control:781 Statin:2162 Control:588
Statin:63.8 Control:64.5 Statin:3897 (78.3) Control:2611 (80.4) Statin:971 (48.3) Control:182 (31.9) Statin:245 (30.1) Control:148 (29.8) Statin:1999 (41.8) Control:1275 (42.5) Statin:2794 (56.1) Control:1895 (58.3) Statin:1356 (27.8) Control:665 (21.1) Statin:0.560 Control:0.553 Statin:2101 (74.4) Control:656 (59.9) Statin:2486 (50.0) Control:1555 (47.9) Statin:393 (17.9) Control:232 (29.7) Statin:118 (5.5) Control:65 (11.1)
Male Dyslipidemia CHF Previous MI Hypertension DM Mean LVEF Beta-blockers ACEI or ARB CCB Digoxin
P 0.563 0.024 ,0.001 0.891 0.576 0.049 ,0.001 0.805 ,0.001 0.065 ,0.001 ,0.001
Comparison of preoperative variable between patients with CABG with statin pretreatment and those with usual care or placebo.
placebo controls and usual care controls. In the 3 studies with placebo-controlled groups,9,10,12 no heterogeneity was observed (I2 = 0%; P = 0.88), and the proportion of patients with POAF in the statin group was 16.8% compared with 35.9% in the placebo group (OR, 0.36; 95% CI, 0.23–0.57; P , 0.00001). In the 9 studies with usual care control groups (I2 = 86%; P , 0.00001),11,13–20 the proportion of patients diagnosed with AF after CABG was 16.5% in the statin group compared with 20.3% in the usual care group (OR, 0.56; 95% CI, 0.37–0.84; P = 0.005).
Influence of Study Design To identify whether the observed heterogeneity was a consequence of study design, studies were subdivided into randomized trials and observational trials. For 4 randomized trials,9–12 no heterogeneity was observed (I2 = 0%; P = 0.97), and overall the incidence of POAF was 16.0% in the statin group compared with 34.0% in the control group (OR, 0.37; 95% CI, 0.24–0.55; P , 0.00001). For the 8 observational trials,13–20 the pooled results showed significant heterogeneity for the POAF event (I2 = 87%; P , 0.00001). The random-effects model analysis indicated a higher risk of POAF in the nonstatin group (16.5% vs. 20.2%; OR, 0.57; 95% CI, 0.37–0.88; P = 0.01).
Surgery Type To assess the potential influence of surgery type, studies were subdivided into those in which patients underwent Ó 2014 Lippincott Williams & Wilkins
Statins Use in Prevention of AF Post-CABG
off-pump CABG only, either on-pump or off-pump CABG, and on-pump CABG only. In 3 trials that examined off-pump CABG surgery alone,9,11,14 the incidence of POAF was 13.7% in the statin group compared with 26.8% in the control group (I2 = 0%; OR, 0.44; 95% CI, 0.31–0.62; P , 0.00001). In 8 trials in which patients underwent on-pump and off-pump CABG,10,13,15–20 the pooled results showed that the overall OR for POAF was 0.56 (I2 = 86%; 95% CI, 0.36–0.88; P = 0.01), and the proportion of patients diagnosed with POAF was lower in the statin group than the control group (16.8% vs. 20.3%). Only 1 trial examined patients undergoing on-pump CABG surgery alone,12 in which the proportion of patients diagnosed with POAF was 18.4% in the statin group compared with 41.2% in the control group (OR, 0.32; 95% CI, 0.13–0.80; P = 0.01).
Timing of Statin Administration To examine the influence of the timing of statin administration, studies were subdivided into those with preoperative and perioperative regimens. In the preoperative regime, patients had been administered statins before CABG surgery only. In the perioperative regimen, patients had been administered statins before and after the CABG surgery. In the 7 studies in which a statin was administered preoperatively,9,10,12–14,16,17 the incidence of POAF was 16.2% in the statin group compared with 18.9% in pooled controls (I2 = 89%; OR, 0.50; 95% CI, 0.29–0.86; P = 0.01). The reported incidence of POAF in pooled patients administered perioperative statins in 5 studies11,15,18–20 was also significantly lower than that in pooled controls (18.4% vs. 32.9%, respectively; I2 = 0%; OR, 0.53; 95% CI, 0.41–0.70; P , 0.00001).
Meta-regression Analysis Meta-regression analysis was also undertaken to identify the relationship between mean change in the incidence of POAF effected by statin therapy and patient characteristics. Neither age, mean LVEF, male sex, previous MI, DM, hypertension, dyslipidemia, CHF, nor the use of routine postoperative prophylactic therapies were significantly associated with the treatment effect of statins on POAF after CABG, and no trends were evident (Table 3).
Effects of Statin Therapy on Length of Stay Five studies that included 969 patients9–12,15 reported the effect of statins on LOS. Pooled analysis using a fixed effects model indicated that statins significantly reduced LOS after CABG surgery compared with controls, and that there was no statistical heterogeneity (I2 = 0%, P = 0.66; weighted mean difference, 20.72; 95% CI, 20.99 to 20.45; P , 0.0001; Fig. 3).
Publication Bias Assessment of publication bias using the Begg’s tests showed that there was no potential publication bias among the included studies (P = 0.732); however, the Egger’s weighted regression statistic showed potential publication bias (P , 0.001). Consequently, we undertook further analysis with the Trim-and-Fill method and found that our pooled risk estimates were consistent (fixed pooling: Z = 22.872, P = 0.004; random pooling: Z = 23.577, P , 0.001), www.jcvp.org |
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FIGURE 2. Comparison of POAF incidence after CABG between statin group and control group.
suggesting that publication bias would not have affected our analysis in a meaningful way.
DISCUSSION In this meta-analysis, we pooled data of 8458 subjects investigated for POAF after CABG from 12 available published trials of statin therapy. The results reveal that statins significantly reduced the incidence of POAF and LOS. As a result of the significant heterogeneity between studies,
TABLE 3. Meta-regression Analyses of the Effects of Statins on AF After CABG Surgery Covariates Age Male Previous MI Mean LVEF DM Hypertension Dyslipidemia CHF Beta-blockers ACEI/ARB CCB Digoxin
No. Studies* 11 11 8 8 10 11 6 5 10 11 8 6
Regression Coefficient (95% CI) 0.04 4.95 0.77 0.83 22.35 0.79 0.60 20.48 20.38 20.18 20.05 21.25
(20.07 to 0.16) (0.25 to 9.66) (21.59 to 3.13) (24.17 to 5.82) (24.01 to 20.68) (20.91 to 2.49) (22.34 to 3.53) (22.92 to 1.97) (21.69 to 0.94) (22.38 to 2.02) (22.32 to 2.23) (24.64 to 2.14)
P 0.401 0.041 0.773 0.700 0.012 0.322 0.602 0.580 0.526 0.857 0.961 0.364
*Certain enrolled studies were not included because the value used for grouping was not reported in them.
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we performed subgroup and meta-regression analyses. In subgroup analyses of studies according to the type of controls, study design, surgery type, and timing of statin administration, we consistently found significant improvements in the incidence of AF after CABG surgery in patients taking statins. Furthermore, meta-regression analysis did not identify any relationship between the reduction in the incidence of POAF by statins and study characteristics. CABG is a highly effective means in addressing myocardial ischemia for patients with coronary heart disease (CHD), but POAF can significantly complicate CABG surgery. Dyslipidemia, an established risk factor for CHD, seems to increase the risk of AF.21 We found that the overall influence of statins on the incidence of POAF was independent of the proportion of patients with dyslipidemia in the pooled study population. We believe that statin therapy may not reduce the risk of POAF by reducing serum lipid concentrations. Indeed, recent studies have shown that inflammation, which promotes structural changes in the atria, plays an important role in the pathogenesis of AF,22 and C-reactive protein, a marker of systemic inflammation, is reported to be elevated in patients with AF.23 Furthermore, dyslipidemia seems to be associated with systemic inflammation and vascular damage in patients with CHD,24 and lipid-lowering drugs seems to reduce the concentrations of inflammatory markers such as C-reactive protein in patients with CHD.25,26 Our conclusion that statin therapy significantly reduces the incidence of POAF after CABG owing to its antiinflammatory effects is in line with current thinking.23,27 Hypertension is not only a risk factor for CAD but is also the most prevalent independent risk factor for developing AF.28 Hypertension is associated with left ventricular Ó 2014 Lippincott Williams & Wilkins
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FIGURE 3. Forest plot of pooled LOS in CABG patients.
hypertrophy, impaired ventricular filling, left atrial structural changes, and slowing of atrial conduction velocity.29 Antihypertensive therapy can decrease the risk of AF by reversing structural cardiac damage caused by hypertension or by blocking the renin–angiotensin system.30,31 The results of our meta-analysis suggest that a history of hypertension and the use of antihypertensive drugs, such as beta-blockers, ACEI/ARB, and CCB, did not influence the effect of statins on the incidence of AF after CABG. Patients who undergo on-pump CABG are considered to be at greater risk of POAF as a result of cardiopulmonary bypass (CPB) and cardioplegic arrest.32 Compared with offpump surgery, CPB can induce significant inflammatory reactions and oxidative stress, which result in postischemic tissue injury.33 Increasing evidence suggests that oxidative stress may also play a role in the pathogenesis of AF.34 A complementary DNA microarray analysis has revealed that the gene expression pattern of pro-oxidative stressor proteins is significantly altered in the atrial appendages of patients in AF.35 Reactive oxygen species are not only involved in inflammation but have also been implicated in cardiac structural and electrical remodeling, all of which can increase susceptibility to AF. It has been demonstrated that statins exert several beneficial pleiotropic effects in AF owing to their antiinflammatory and antioxidative properties.36 This may explain our finding that statins can significantly reduce the incidence of AF after on-pump or off-pump CABG. Risk factors such as advanced age, male sex, CHF, previous MI, DM, and various pharmacological prophylactic interventions are also associated with incident AF.37 We found that a history of dyslipidemia or DM, and the routine use of prophylactic therapies such as CCB, beta-blocker, or digoxin showed differences between the 2 groups, but age, sex, mean LVEF, a history of cardiovascular diseases such as CHF, previous MI, or hypertension, and the use of an ACEI or ARB did not. Nonetheless, meta-regression analysis revealed that patients undergoing CABG showed favorable responses to statins, evidenced by a significant reduction in the incidence of POAF. Our findings raise the possibility that addressing these risk factors would further improve the response to statin therapy. They also indicate Ó 2014 Lippincott Williams & Wilkins
that statin therapy should be administered throughout the perioperative period. Numerous observational and randomized trials38,39 have demonstrated that administering statins before CABG decreases the risk of perioperative mortality and stroke40 and ameliorates the systemic inflammatory response. The use of atorvastatin has been reported to increase the number of circulating early endothelial progenitor cells both preoperatively and postoperatively.41 Moreover, after CABG, statin therapy may limit progression of atherosclerosis in native coronary arteries, improve saphenous vein graft patency, and reduce the incidence of postoperative cardiovascular events and allcause mortality, although there have been few reports of adverse events.42 We also found that treatment with statins can significantly reduce hospital LOS after CABG. Previous studies have reported that AF is a major predictor of longer hospitalization and was associated with an extension in LOS of 3–4 days.2,43 It seems likely that the influence of statins on LOS after CABG can be attributed to the reduction of risk for AF and/or cardiovascular adverse events. Because only 6 trials reported LOS data and the sample size was relatively small, additional trials are warranted. Our study has some limitations. We used pooled data reported from several published relevant trials and found significant heterogeneity among the studies; however, we were unable to make a comprehensive evaluation of the sources of heterogeneity because the studies’ original datasets were not available. Furthermore, meta-analysis may be influenced by publication and language biases, inflated estimates because of flaws in the methodology of the included studies, and the tendency for negative results not to be published. Our results should be confirmed by adequately powered, multicenter large-scale double-blind placebo-controlled randomized trials.
CONCLUSIONS Our meta-analysis revealed that patients undergoing CABG benefit from statin therapy, which reduces the incidence of POAF and hospital LOS. Our findings provide www.jcvp.org |
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further evidence that risk factors such as hypertension and dyslipidemia should be strictly controlled in patients undergoing CABG, and that statins should be used perioperatively to achieve their maximal benefit for patients. REFERENCES 1. Mathew JP, Fontes ML, Tudor IC, et al; Investigators of the Ischemia Research and Education Foundation; Multicenter Study of Perioperative Ischemia Research Group. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA. 2004;291:1720–1729. 2. Creswell LL, Schuessler RB, Rosenbloom M, et al. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg. 1993;56:539–549. 3. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation. 2003;108:3006–3010. 4. Anselmi A, Possati G, Gaudino M. Postoperative inflammatory reaction and atrial fibrillation: simple correlation or causation? Ann Thorac Surg. 2009;88:326–333. 5. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of AF: a systematic review of the published data. J Am Coll Cardiol. 2007;50:2021–2028. 6. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. 7. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and nonrandomised studies of health care interventions. J Epidemiol Community Health. 1998;52:377–384. 8. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558. 9. Ji Q, Mei Y, Wang X, et al. Effect of preoperative atorvastatin therapy on atrial fibrillation following off-pump coronary artery bypass grafting. Circ J. 2009;73:2244–2249. 10. Mannacio VA, Iorio D, De Amicis V, et al. Effect of rosuvastatin pretreatment on myocardial damage after coronary surgery: a randomized trial. J Thorac Cardiovasc Surg. 2008;136:1541–1548. 11. Song YB, On YK, Kim JH, et al. The effects of atorvastatin on the occurrence of postoperative atrial fibrillation after off-pump coronary artery bypass grafting surgery. Am Heart J. 2008;156:373.e9–373.e16. 12. Sun Y, Ji Q, Mei Y, et al. Role of preoperative atorvastatin administration in protection against postoperative atrial fibrillation following conventional coronary artery bypass grafting. Int Heart J. 2011;52:7–11. 13. Karimi A, Bidhendi LM, Rezvanfard M, et al. The effect of a high dose of atorvastatin on the occurrence of atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg. 2012;94:8–14. 14. Kinoshita T, Asai T, Nishimura O, et al. Statin for prevention of atrial fibrillation after off-pump coronary artery bypass grafting in Japanese patients. Circ J. 2010;74:1846–1851. 15. Mariscalco G, Lorusso R, Klersy C, et al. Observational study on the beneficial effect of preoperative statins in reducing atrial fibrillation after coronary surgery. Ann Thorac Surg. 2007;84:1158–1164. 16. Marín F, Pascual DA, Roldán V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol. 2006;97:55–60. 17. Miceli A, Fino C, Fiorani B, et al. Effects of preoperative statin treatment on the incidence of postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting. Ann Thorac Surg. 2009;87:1853–1858. 18. Ozaydin M, Dogan A, Varol E, et al. Statin use before by-pass surgery decreases the incidence and shortens the duration of postoperative atrial fibrillation. Cardiology. 2007;107:117–121. 19. Sakamoto H, Watanabe Y, Satou M. Do preoperative statins reduce atrial fibrillation after coronary artery bypass grafting? Ann Thorac Cardiovasc Surg. 2011;17:376–382. 20. Tamura K, Arai H, Ito F, et al. Pravastatin treatment before coronary artery bypass grafting for reduction of postoperative atrial fibrillation. Gen Thorac Cardiovasc Surg. 2010;58:120–125. 21. Haywood LJ, Ford CE, Crow RS, et al, ALLHAT Collaborative Research Group. Atrial fibrillation at baseline and during follow-up in ALLHAT (antihypertensive and lipid-lowering treatment to prevent heart attack trial). J Am Coll Cardiol. 2009;54:2023–2031.
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22. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997;96: 1180–1184. 23. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001;104:2886–2891. 24. März W, Scharnagl H, Winkler K, et al. Low-density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study. Circulation. 2004;110:3068–3074. 25. König D, Deibert P, Winkler K, et al. Association between LDLcholesterol, statin therapy, physical activity and inflammatory markers in patients with stable coronary heart disease. Exerc Immunol Rev. 2005; 11:97–107. 26. Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction. Circulation. 2002;106:1447–1452. 27. Peña JM, MacFadyen J, Glynn RJ, et al. High-sensitivity C-reactive protein, statin therapy, and risks of atrial fibrillation: an exploratory analysis of the JUPITER trial. Eur Heart J. 2012;33:531–537. 28. Conen D, Tedrow UB, Koplan BA, et al. Influence of systolic and diastolic blood pressure on the risk of incident atrial fibrillation in women. Circulation. 2009;119:2146–2152. 29. Lau YF, Yiu KH, Siu CW, et al. Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications. J Hum Hypertens. 2012;26:563–569. 30. Okin PM, Wachtell K, Devereux RB, et al. Regression of electrocardiographic left ventricular hypertrophy and decreased incidence of newonset atrial fibrillation in patients with hypertension. JAMA. 2006;296: 1242–1248. 31. Du H, Fan J, Ling Z, et al. Effect of nifedipine versus telmisartan on prevention of atrial fibrillation recurrence in hypertensive patients. Hypertension. 2013;61:786–792. 32. Ascione R, Caputo M, Calori G, et al. Predictors of atrial fibrillation after conventional and beating heart coronary surgery: a prospective, randomized study. Circulation. 2000;102:1530–1535. 33. Matata BM, Sosnowski AW, Galinanes M. Off-pump bypass graft operation significantly reduces oxidative stress and inflammation. Ann Thorac Surg. 2000;69:785–791. 34. Youn JY, Zhang J, Zhang Y, et al. Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase. J Mol Cell Cardiol. 2013; 62:72–79. 35. Kim YH, Lim DS, Lee JH, et al. Gene expression profiling of oxidative stress on atrial fibrillation in humans. Exp Mol Med. 2003;35:336–349. 36. Reilly SN, Jayaram R, Nahar K, et al. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation. 2011;124: 1107–1117. 37. Arsenault KA, Yusuf AM, Crystal E, et al. Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery. Cochrane Database Syst Rev. 2013;1:CD003611. 38. Kulik A, Ruel M. Lipid-lowering therapy and coronary artery bypass graft surgery: what are the benefits? Curr Opin Cardiol. 2011;26:508– 517. 39. Kulik A, Voisine P, Mathieu P, et al. Statin therapy and saphenous vein graft disease after coronary bypass surgery: analysis from the CASCADE randomized trial. Ann Thorac Surg. 2011;92:1284–1290. 40. Kuhn EW, Liakopoulos OJ, Stange S, et al. Meta-analysis of patients taking statins before revascularization and aortic valve surgery. Ann Thorac Surg. 2013;96:1508–1516. 41. Baran Ç, Durdu S, Dalva K, et al. Effects of preoperative short term use of atorvastatin on endothelial progenitor cells after coronary surgery: a randomized, controlled trial. Stem Cell Rev. 2012;8:963–971. 42. Mills EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol. 2008;52: 1769–1781. 43. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation. 1996;94:390–397.
Ó 2014 Lippincott Williams & Wilkins
The Use of Statins to Prevent Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting: A Meta-analysis of 12 Studies Hui Zheng, MD, Song Xue, MD, PhD, Zhen-Lei Hu, MD, PhD, Jiang-Gui Shan, MD, and Wen-Gang Yang, MD
Abstract: There is no agreement on whether statins influence the incidence of atrial fibrillation after coronary artery bypass grafting. We performed a meta-analysis of 12 studies that compared statins with controls. Statin therapy significantly reduced the incidence of postoperative atrial fibrillation (POAF) (odds ratio, 0.50; 95% confidence interval, 0.35–0.73) and length of hospital stay (weighted mean difference, 20.72; 95% confidence interval, 20.99 to 20.45), an effect that survived detailed subgroup analysis. Meta-regression analysis revealed that patient characteristics did not influence the extent of improvement in the incidence of POAF attributable to statins. In conclusion, patients undergoing coronary artery bypass grafting benefit from perioperative treatment with statins, which significantly reduce the incidence of POAF and length of hospital stay. Key Words: atrial fibrillation, arrhythmia therapy, coronary artery bypass grafting, statins (J Cardiovasc Pharmacol Ô 2014;64:285–292)
INTRODUCTION
Postoperative atrial fibrillation (POAF) is a very common complication of coronary artery bypass grafting (CABG), reports of its incidence have a range of 30%– 45%.1 The occurrence of atrial fibrillation (AF) is associated with a reduction in cardiac output, hemodynamic instability, thromboembolic events, stroke, and renal insufficiency, all of which contribute to increased morbidity.1,2 Postoperative AF may be a particular problem after CABG, when it can induce a rapid ventricular rate that markedly increases myocardial oxygen consumption, aggravates myocardial ischemia, and causes cardiac dysfunction. Furthermore, several antiarrhythmic drugs used to treat AF have potentially harmful side effects and increase total mortality. Thus, it is essential for clinicians to find safer and more efficacious means of preventing AF after CABG. Received for publication February 12, 2014; accepted March 23, 2014. From the Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. The authors report no conflicts of interest. Reprints: Song Xue, MD, PhD, Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Pudong New Area, Shanghai, China 200127 (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
The pathophysiologic causes of AF after CABG are not completely understood, but there is an increasing body of evidence to suggest that enhanced inflammatory responses may play a part.3,4 Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to attenuate postoperative inflammatory responses,5 in addition to their lipid-lowering properties and ability to stabilize atherosclerotic plaque. An increasing number of clinical and experimental studies have assessed the efficacy of preoperative administration of statins as a therapeutic intervention to reduce the incidence of AF after CABG, but their findings have been mixed. Many of these studies have enrolled relatively small cohorts, which might have been statistically underpowered to evaluate this endpoint. Consequently, it has not been established whether preoperative statin therapy can prevent the onset of AF after CABG. We undertook a meta-analysis of randomized trials and observational studies to examine the effectiveness of preoperative statins as a method for prevention of POAF, and to evaluate their influence on the length of hospital stay (LOS) in patients undergoing CABG.
MATERIALS AND METHODS Search Strategy All randomized controlled trials (RCTs) or observational studies that examined the influence of statins on AF after CABG were identified using a two-level search strategy. First, web-based searches of PubMed, Elsevier Database, Google Scholar, Web of Science, Ovid Database, and the Cochrane Library were undertaken to identify articles published in English between the date of their inception and December 31, 2012. Search terms included variants of the following keywords: “atrial fibrillation” and “coronary artery bypass graft or CABG or CAB or cardiopulmonary bypass or CPB” and “statin or HMG-CoA reductase inhibitor.” Second, a manual search was performed for secondary sources including the references of articles, reviews, and commentaries identified in the first search. All relevant studies were downloaded for combination, elimination of duplicates, and further analysis.
Inclusion Criteria Studies were included if they met the following criteria: recruitment of adult patients undergoing CABG; studies in which a group taking statins was compared with a control
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group; and the incidence of POAF was reported as an outcome measure. Studies that included patients undergoing hybrid surgery (for example, CABG with concomitant valve replacement surgery) were excluded, as were those in which details of the preoperative statin regimen and monitoring of POAF were not reported. Case reports, editorials, comments, letters, review articles, guidelines or secondary prevention trials, and studies only available in abstract form were not included in the meta-analysis.
Data Extraction Two independent investigators identified trials for inclusion and abstracted demographic, intervention, and outcome data in a standardized manner. Two reviewers independently assessed the methodological quality of every trial using the Jadad scale6 for RCTs, and the Downs and Black Checklist7 for both RCTs and observational trials. The Jadad score range was 0–5 points, according to the examination of randomization methods, blinding, and dropout (0–2: poor quality, 3–4: good quality, 5: excellent quality). The Downs and Black Checklist was scored on the basis of the presence of the following key sections: reporting (0–11 points); external validity (0–3 points); internal validity bias (0–7 points); internal validity confounding (0–6 points); and power (0–2 points). A score of 29 is considered the highest-quality study, and a score of zero indicates the poorest-quality study. Discrepancies between reviewers were resolved by discussion.
selected for meta-analysis to examine the effect of preoperative statin therapy on AF post-CABG, as outlined in Figure 1.
Characteristics of Included Studies The characteristics of included studies are summarized in Table 1. Of the 8458 patients, 5120 (60.53%) were taking preoperative statin therapy while 3338 (39.47%) were not. The age of the patients in each of the pooled groups, the prevalence of male sex, dyslipidemia, congestive heart failure (CHF), previous myocardial infarction (MI), hypertension, diabetes mellitus (DM), mean left ventricular ejection fraction (LVEF), and frequency of the preoperative use of betablockers, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and digoxin were compared (Table 2). The proportions of patients taking beta-blockers, or with diagnoses of DM or dyslipidemia, were higher in those taking statin therapy, whereas the proportions taking a CCB or digoxin were higher in the pooled control group. Of the 12 studies, 5 trials9–12,15 reported the impact of statins on LOS after CABG. The Jadad quality score was 4 (good), 4 (good), 1 (poor), and 1 (poor) for the 4 RCTs shown in Table 1, respectively. The mean score of the 12 studies on the Downs and
Statistical Analysis The incidence of POAF was treated as a dichotomous variable and LOS as a continuous variable. Odds ratio (OR) with 95% confidence interval (CI) was calculated for dichotomous variables, whereas the weighted mean difference with 95% CI was established for continuous variables. Pooled effect estimates were calculated using Review Manager Version 5.0 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). We used a fixed effects model in the meta-analyses when there was no significant heterogeneity among study results. A random-effects model was used when heterogeneity existed among enrolled studies. Heterogeneity between studies was assessed using the Q test and I2 statistic. An I2 value ,30%, 31%–50%, and .50% independently indicated mild, moderate, and notable heterogeneity.8 Subgroup and meta-regression analyses were performed to evaluate sources of heterogeneity. Publication bias was evaluated by the Begg test, the Egger weighted regression, and the Trim-andFill method using Stata version 10.0 (StataCorp, College Station, TX). SPSS version 13.0 (SPSS Inc, Chicago, IL) was used to compute P values comparing the baseline covariates of 2 groups by means of the 2-sample Student’s t test for continuous data and the chi-square test for categorical data. P , 0.01 was regarded as statistically significant.
RESULTS Studies Identified Four randomized trials9–12 and 8 observational trials13–20 that included 8458 patients who underwent CABG surgery were
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FIGURE 1. Identification of eligible trials for the meta-analysis. Ó 2014 Lippincott Williams & Wilkins
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Statins Use in Prevention of AF Post-CABG
TABLE 1. Baseline Characteristics of the Included Studies in the Meta-analysis Study
Location
Study Design
Control Group
Ji et al9 Karimi et al13 Kinoshita et al14 Mannacio et al10 Mariscalco et al15 Marín et al16 Miceli et al17 Ozaydin et al18 Sakamoto et al19 Song et al11 Sun et al12 Tamura et al20
China Iran Japan Italy Italy Spain UK Turkey Japan Korea China Japan
Randomized Retrospective Retrospective Randomized Retrospective Retrospective Retrospective Retrospective Retrospective Randomized Randomized Retrospective
Placebo Usual care Usual care Placebo Usual care Usual care Usual care Usual care Usual care Usual care Placebo Usual care
Definition of POAF Any episode of AF that was registered by the monitoring system on a rhythm strip or 12-lead ECG and lasting for $5 min with or without symptoms Episodes lasting for .5 min
An irregular cardiac rhythm without P-waves lasting .30 min on 12lead ECG NR
Episodes lasting for .15 min
NR
The documentation of AF of any duration at any time in the postoperative period on the basis of a rhythm strip or 12-lead ECG An irregular narrow complex rhythm (in the absence of bundle branch block) with the absence of discrete P-waves lasting $10 min Episodes lasting for $5 min Any documented AF of .5 min in duration or AF episodes requiring intervention for symptoms or hemodynamic compromise after CABG The occurrence of at least 1 episode of AF (with or without symptoms) lasting for .5 min
Surgery Type Elective off-pump CABG On-pump/off-pump CABG Elective off-pump CABG Elective on-pump/off-pump On-pump/off-pump CABG Elective on-pump/off-pump On-pump/off-pump CABG Elective on-pump/off-pump On-pump/off-pump CABG Elective off-pump CABG Elective on-pump CABG Elective on-pump/off-pump
No. Statins/All/Control
CABG CABG CABG
CABG
71/140/69 1532/1607/75 364/584/220 100/200/100 218/405/187 144/234/90 2152/4304/2152 267/362/95 77/203/126 62/124/62 49/100/51 84/195/111 Monitoring of POAF
Continuous ECG monitoring for at least 7 days after CABG, and subsequently, daily 12-lead ECG monitoring until hospital discharge Continuous telemonitor during the first 72 postoperative hours at the ICU Continuous ECG monitoring using a bedside monitor in the ICU and telemetry on the hospital ward for at least 7 days A 12-lead ECG monitoring before CABG, on admission to the ICU, 12 hours later, and every day thereafter until hospital discharge Daily until discharge with continuous ECG telemetry and standard 12lead ECG Continuously monitoring for the first 36–48 hours, and subsequently, daily 12-lead ECG on in case of any symptom performing until discharge A 12-lead ECG monitoring preoperatively, 2 hours postoperatively, and then daily thereafter until discharge Monitoring continuously during the operation and during the first 2 postoperative days in the ICU; monitoring with a 12-lead ECG during 1 week of hospitalization in the wards Daily with continuous ECG telemetry for a minimum of 11 days after CABG Daily with a 12-lead ECG
ECG monitoring at least 7 d
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TABLE 1. (Continued ) Baseline Characteristics of the Included Studies in the Meta-analysis Definition of POAF
Monitoring of POAF
An absent P-wave before QRS complex together with an irregular ventricular rhythm on the rhythm strips and AF episodes lasting $5 min
Monitoring continuously after CABG during stay in ICU; connecting to monitors for continuous ECG monitoring until the day of discharge
Drug Type
Statin Regimen
Age, yrs
Male
Previous MI
Atorvastatin Atorvastatin
20 mg/d for 7 d; before CABG 40 or 80 mg/d; at least 3 d before CABG Daily for at least 5 d; before CABG
65/66 60.9/60.6
48/49 1122/55
NR 531/32
69/68
293/166
108/54
20 mg/d for 7 d; before CABG Mean dose 22 mg/d; before and after CABG
61/59 66/66
75/70 182/148
21/25 140/98
An intermediate statin dose; a median of 31 d before CABG Dose NR; 24 h before CABG Mean dose 27 mg/d; mean 2.7 mo before CABG continued after CABG Dose not uniform; before CABG; omission on the day of CABG; mean 1.47 d after CABG 20 mg/d; 3 d before CABG; 30 d after CABG 20 mg/d; 7 d before CABG Mean 9.1 mg/d; mean 6.5 mo before CABG; reinitiation after CABG
NR
NR
NR
65/65 60/62
1774/1769 210/81
961/961 189/47
63/67
55/107
NR
62/64
39/42
8/5
64/65 66/67
32/35 67/89
NR 41/53
Atorvastatin, pitavastatin, fluvastatin, rosuvastatin, pravastatin, or simvastatin Rosuvastatin Atorvastatin, pravastatin, simvastatin, lovastatin, rosuvastatin, or fluvastatin One statin Statins Fluvastatin, atorvastatin, pravastatin, or simvastatin Atorvastatin, pravastatin, pitavastatin, rosuvastatin, simvastatin, or fluvastatin Atorvastatin Atorvastatin Atorvastatin or pravastatin Mean LVEF, % 56/55 47/45 59/58 NR 53.6/53.7 NR NR 53/53 66/63 NR 54/55 59.3/59.7
DM
Hypertension
Dyslipidemia
CHF
Beta-blockers
ACEI/ARB
CCB
Digoxin
Quality Score*
27/26 607/25 169/91 NR 69/53 NR 312/337 76/16 42/59 29/32 18/20 7/6
21/20 753/32 290/166 25/21 154/136 NR 1248/1266 132/43 54/81 35/37 16/15 66/78
14/13 745/35 NR NR 110/72 NR NR NR 77/38 15/15 10/9 NR
50/42 NR 69/44 NR NR NR NR 76/16 NR 15/14 35/32 NR
46/41 1242/61 210/122 73/68 144/137 NR NR 248/84 31/31 45/43 32/30 30/39
28/32 787/37 292/170 22/28 121/97 NR 962/1002 159/50 30/46 35/31 19/24 31/38
40/31 171/4 NR 30/27 56/52 NR NR NR 31/45 12/6 27/24 26/43
21/23 50/4 26/11 NR NR NR NR NR NR 8/7 13/18 0/2
4/26 -/22 -/21 4/25 -/22 -/17 -/23 -/18 -/20 1/23 1/20 -/20
Data are formatted as statins group/control group. *Quality assessment of included studies with the Jadad Score (only for RCT)/Downs and Black Checklist Score. ECG, electrocardiograph; ICU, intensive care unit; NR, not reported.
Black Checklist Scale was 21.4 6 2.6, and only 2 scored less than 20 points, suggesting that the overall quality of the studies included in the meta-analysis was good.
Effects of Statin Therapy on Postoperative Atrial Fibrillation The means of defining and monitoring the outcome of POAF are shown in Table 1. There was significant heterogeneity among the included studies (I2 = 84%; P , 0.00001).
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Using the random-effects model, our meta-analysis revealed that preoperative statin therapy was associated with a significant reduction in the incidence of POAF compared with the control group (OR, 0.50; 95% CI, 0.35–0.73; P = 0.003; Fig. 2).
Subgroup Analysis Controls To assess whether the heterogeneity lay within the pooled controls, studies were subdivided into those with Ó 2014 Lippincott Williams & Wilkins
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TABLE 2. Baseline Characteristics of Patients Variables
Sample Size
Prevalence (%)
Age, yr
Statin:4976 Control:3248 Statin:4976 Control:3248 Statin:2009 Control:570 Statin:813 Control:497 Statin:4779 Control:3002 Statin:4976 Control:3248 Statin:4876 Control:3148 Statin:2662 Control:934 Statin:2824 Control:1096 Statin:4976 Control:3248 Statin:2193 Control:781 Statin:2162 Control:588
Statin:63.8 Control:64.5 Statin:3897 (78.3) Control:2611 (80.4) Statin:971 (48.3) Control:182 (31.9) Statin:245 (30.1) Control:148 (29.8) Statin:1999 (41.8) Control:1275 (42.5) Statin:2794 (56.1) Control:1895 (58.3) Statin:1356 (27.8) Control:665 (21.1) Statin:0.560 Control:0.553 Statin:2101 (74.4) Control:656 (59.9) Statin:2486 (50.0) Control:1555 (47.9) Statin:393 (17.9) Control:232 (29.7) Statin:118 (5.5) Control:65 (11.1)
Male Dyslipidemia CHF Previous MI Hypertension DM Mean LVEF Beta-blockers ACEI or ARB CCB Digoxin
P 0.563 0.024 ,0.001 0.891 0.576 0.049 ,0.001 0.805 ,0.001 0.065 ,0.001 ,0.001
Comparison of preoperative variable between patients with CABG with statin pretreatment and those with usual care or placebo.
placebo controls and usual care controls. In the 3 studies with placebo-controlled groups,9,10,12 no heterogeneity was observed (I2 = 0%; P = 0.88), and the proportion of patients with POAF in the statin group was 16.8% compared with 35.9% in the placebo group (OR, 0.36; 95% CI, 0.23–0.57; P , 0.00001). In the 9 studies with usual care control groups (I2 = 86%; P , 0.00001),11,13–20 the proportion of patients diagnosed with AF after CABG was 16.5% in the statin group compared with 20.3% in the usual care group (OR, 0.56; 95% CI, 0.37–0.84; P = 0.005).
Influence of Study Design To identify whether the observed heterogeneity was a consequence of study design, studies were subdivided into randomized trials and observational trials. For 4 randomized trials,9–12 no heterogeneity was observed (I2 = 0%; P = 0.97), and overall the incidence of POAF was 16.0% in the statin group compared with 34.0% in the control group (OR, 0.37; 95% CI, 0.24–0.55; P , 0.00001). For the 8 observational trials,13–20 the pooled results showed significant heterogeneity for the POAF event (I2 = 87%; P , 0.00001). The random-effects model analysis indicated a higher risk of POAF in the nonstatin group (16.5% vs. 20.2%; OR, 0.57; 95% CI, 0.37–0.88; P = 0.01).
Surgery Type To assess the potential influence of surgery type, studies were subdivided into those in which patients underwent Ó 2014 Lippincott Williams & Wilkins
Statins Use in Prevention of AF Post-CABG
off-pump CABG only, either on-pump or off-pump CABG, and on-pump CABG only. In 3 trials that examined off-pump CABG surgery alone,9,11,14 the incidence of POAF was 13.7% in the statin group compared with 26.8% in the control group (I2 = 0%; OR, 0.44; 95% CI, 0.31–0.62; P , 0.00001). In 8 trials in which patients underwent on-pump and off-pump CABG,10,13,15–20 the pooled results showed that the overall OR for POAF was 0.56 (I2 = 86%; 95% CI, 0.36–0.88; P = 0.01), and the proportion of patients diagnosed with POAF was lower in the statin group than the control group (16.8% vs. 20.3%). Only 1 trial examined patients undergoing on-pump CABG surgery alone,12 in which the proportion of patients diagnosed with POAF was 18.4% in the statin group compared with 41.2% in the control group (OR, 0.32; 95% CI, 0.13–0.80; P = 0.01).
Timing of Statin Administration To examine the influence of the timing of statin administration, studies were subdivided into those with preoperative and perioperative regimens. In the preoperative regime, patients had been administered statins before CABG surgery only. In the perioperative regimen, patients had been administered statins before and after the CABG surgery. In the 7 studies in which a statin was administered preoperatively,9,10,12–14,16,17 the incidence of POAF was 16.2% in the statin group compared with 18.9% in pooled controls (I2 = 89%; OR, 0.50; 95% CI, 0.29–0.86; P = 0.01). The reported incidence of POAF in pooled patients administered perioperative statins in 5 studies11,15,18–20 was also significantly lower than that in pooled controls (18.4% vs. 32.9%, respectively; I2 = 0%; OR, 0.53; 95% CI, 0.41–0.70; P , 0.00001).
Meta-regression Analysis Meta-regression analysis was also undertaken to identify the relationship between mean change in the incidence of POAF effected by statin therapy and patient characteristics. Neither age, mean LVEF, male sex, previous MI, DM, hypertension, dyslipidemia, CHF, nor the use of routine postoperative prophylactic therapies were significantly associated with the treatment effect of statins on POAF after CABG, and no trends were evident (Table 3).
Effects of Statin Therapy on Length of Stay Five studies that included 969 patients9–12,15 reported the effect of statins on LOS. Pooled analysis using a fixed effects model indicated that statins significantly reduced LOS after CABG surgery compared with controls, and that there was no statistical heterogeneity (I2 = 0%, P = 0.66; weighted mean difference, 20.72; 95% CI, 20.99 to 20.45; P , 0.0001; Fig. 3).
Publication Bias Assessment of publication bias using the Begg’s tests showed that there was no potential publication bias among the included studies (P = 0.732); however, the Egger’s weighted regression statistic showed potential publication bias (P , 0.001). Consequently, we undertook further analysis with the Trim-and-Fill method and found that our pooled risk estimates were consistent (fixed pooling: Z = 22.872, P = 0.004; random pooling: Z = 23.577, P , 0.001), www.jcvp.org |
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FIGURE 2. Comparison of POAF incidence after CABG between statin group and control group.
suggesting that publication bias would not have affected our analysis in a meaningful way.
DISCUSSION In this meta-analysis, we pooled data of 8458 subjects investigated for POAF after CABG from 12 available published trials of statin therapy. The results reveal that statins significantly reduced the incidence of POAF and LOS. As a result of the significant heterogeneity between studies,
TABLE 3. Meta-regression Analyses of the Effects of Statins on AF After CABG Surgery Covariates Age Male Previous MI Mean LVEF DM Hypertension Dyslipidemia CHF Beta-blockers ACEI/ARB CCB Digoxin
No. Studies* 11 11 8 8 10 11 6 5 10 11 8 6
Regression Coefficient (95% CI) 0.04 4.95 0.77 0.83 22.35 0.79 0.60 20.48 20.38 20.18 20.05 21.25
(20.07 to 0.16) (0.25 to 9.66) (21.59 to 3.13) (24.17 to 5.82) (24.01 to 20.68) (20.91 to 2.49) (22.34 to 3.53) (22.92 to 1.97) (21.69 to 0.94) (22.38 to 2.02) (22.32 to 2.23) (24.64 to 2.14)
P 0.401 0.041 0.773 0.700 0.012 0.322 0.602 0.580 0.526 0.857 0.961 0.364
*Certain enrolled studies were not included because the value used for grouping was not reported in them.
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we performed subgroup and meta-regression analyses. In subgroup analyses of studies according to the type of controls, study design, surgery type, and timing of statin administration, we consistently found significant improvements in the incidence of AF after CABG surgery in patients taking statins. Furthermore, meta-regression analysis did not identify any relationship between the reduction in the incidence of POAF by statins and study characteristics. CABG is a highly effective means in addressing myocardial ischemia for patients with coronary heart disease (CHD), but POAF can significantly complicate CABG surgery. Dyslipidemia, an established risk factor for CHD, seems to increase the risk of AF.21 We found that the overall influence of statins on the incidence of POAF was independent of the proportion of patients with dyslipidemia in the pooled study population. We believe that statin therapy may not reduce the risk of POAF by reducing serum lipid concentrations. Indeed, recent studies have shown that inflammation, which promotes structural changes in the atria, plays an important role in the pathogenesis of AF,22 and C-reactive protein, a marker of systemic inflammation, is reported to be elevated in patients with AF.23 Furthermore, dyslipidemia seems to be associated with systemic inflammation and vascular damage in patients with CHD,24 and lipid-lowering drugs seems to reduce the concentrations of inflammatory markers such as C-reactive protein in patients with CHD.25,26 Our conclusion that statin therapy significantly reduces the incidence of POAF after CABG owing to its antiinflammatory effects is in line with current thinking.23,27 Hypertension is not only a risk factor for CAD but is also the most prevalent independent risk factor for developing AF.28 Hypertension is associated with left ventricular Ó 2014 Lippincott Williams & Wilkins
J Cardiovasc Pharmacol ä Volume 64, Number 3, September 2014
Statins Use in Prevention of AF Post-CABG
FIGURE 3. Forest plot of pooled LOS in CABG patients.
hypertrophy, impaired ventricular filling, left atrial structural changes, and slowing of atrial conduction velocity.29 Antihypertensive therapy can decrease the risk of AF by reversing structural cardiac damage caused by hypertension or by blocking the renin–angiotensin system.30,31 The results of our meta-analysis suggest that a history of hypertension and the use of antihypertensive drugs, such as beta-blockers, ACEI/ARB, and CCB, did not influence the effect of statins on the incidence of AF after CABG. Patients who undergo on-pump CABG are considered to be at greater risk of POAF as a result of cardiopulmonary bypass (CPB) and cardioplegic arrest.32 Compared with offpump surgery, CPB can induce significant inflammatory reactions and oxidative stress, which result in postischemic tissue injury.33 Increasing evidence suggests that oxidative stress may also play a role in the pathogenesis of AF.34 A complementary DNA microarray analysis has revealed that the gene expression pattern of pro-oxidative stressor proteins is significantly altered in the atrial appendages of patients in AF.35 Reactive oxygen species are not only involved in inflammation but have also been implicated in cardiac structural and electrical remodeling, all of which can increase susceptibility to AF. It has been demonstrated that statins exert several beneficial pleiotropic effects in AF owing to their antiinflammatory and antioxidative properties.36 This may explain our finding that statins can significantly reduce the incidence of AF after on-pump or off-pump CABG. Risk factors such as advanced age, male sex, CHF, previous MI, DM, and various pharmacological prophylactic interventions are also associated with incident AF.37 We found that a history of dyslipidemia or DM, and the routine use of prophylactic therapies such as CCB, beta-blocker, or digoxin showed differences between the 2 groups, but age, sex, mean LVEF, a history of cardiovascular diseases such as CHF, previous MI, or hypertension, and the use of an ACEI or ARB did not. Nonetheless, meta-regression analysis revealed that patients undergoing CABG showed favorable responses to statins, evidenced by a significant reduction in the incidence of POAF. Our findings raise the possibility that addressing these risk factors would further improve the response to statin therapy. They also indicate Ó 2014 Lippincott Williams & Wilkins
that statin therapy should be administered throughout the perioperative period. Numerous observational and randomized trials38,39 have demonstrated that administering statins before CABG decreases the risk of perioperative mortality and stroke40 and ameliorates the systemic inflammatory response. The use of atorvastatin has been reported to increase the number of circulating early endothelial progenitor cells both preoperatively and postoperatively.41 Moreover, after CABG, statin therapy may limit progression of atherosclerosis in native coronary arteries, improve saphenous vein graft patency, and reduce the incidence of postoperative cardiovascular events and allcause mortality, although there have been few reports of adverse events.42 We also found that treatment with statins can significantly reduce hospital LOS after CABG. Previous studies have reported that AF is a major predictor of longer hospitalization and was associated with an extension in LOS of 3–4 days.2,43 It seems likely that the influence of statins on LOS after CABG can be attributed to the reduction of risk for AF and/or cardiovascular adverse events. Because only 6 trials reported LOS data and the sample size was relatively small, additional trials are warranted. Our study has some limitations. We used pooled data reported from several published relevant trials and found significant heterogeneity among the studies; however, we were unable to make a comprehensive evaluation of the sources of heterogeneity because the studies’ original datasets were not available. Furthermore, meta-analysis may be influenced by publication and language biases, inflated estimates because of flaws in the methodology of the included studies, and the tendency for negative results not to be published. Our results should be confirmed by adequately powered, multicenter large-scale double-blind placebo-controlled randomized trials.
CONCLUSIONS Our meta-analysis revealed that patients undergoing CABG benefit from statin therapy, which reduces the incidence of POAF and hospital LOS. Our findings provide www.jcvp.org |
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