Abstract
Background. Postoperative atrial fibrillation (AF) remains the most common arrhythmic complication following cardiac surgery. We performed a meta-analysis based on all currently available randomized controlled trials (RCTs) to confirm the hypothesis that statins pretreatment may lower the risk of postoperative AF in patients undergoing cardiac surgery. Methods and results. The published literature was scanned by formal searches of electronic databases up through August 2010. RCTs were eligible for inclusion if they compared preoperative statins treatment versus control in patients scheduled for cardiac surgery and had the data of postoperative AF reported. Pre-specified criteria were met by eight RCTs involving 841 patients. During the follow-up period, 80 of 422 patients (19.0%) in the statins pretreatment group developed postoperative AF, significantly less than 149 of 419 (35.6%) patients assigned to the control group (P < 0.001). Postoperative hospital stay was significantly shortened in patients pretreated with statins compared with the control (P < 0.01). Conclusions. This meta-analysis supports the effectiveness of statins pretreatment on reducing the incidence of postoperative AF in patients undergoing cardiac surgery.
Key words::
| Abbreviations | ||
| AF | = | atrial fibrillation |
| CI | = | confidence interval |
| MI | = | myocardial infarction |
| OR | = | odds ratio |
| RCT | = | randomized controlled trial |
Key messages
Postoperative atrial fibrillation (AF) remains the most common arrhythmic complication following cardiac surgery.
The present meta-analysis supports the effectiveness of statins pretreatment on reducing the incidence of postoperative AF in patients undergoing cardiac surgery.
Atrial fibrillation (AF) is the most common arrhythmic complication occurring after cardiac surgery, with an incidence in contemporary series ranging from 10% to 65% (Citation1). Previous studies have suggested that postoperative AF is associated with increased risk of stroke, prolonged hospital stay, higher cost, and greater risk of long-term mortality (Citation2,Citation3). Although the pathophysiology of this complication is multifactorial, a significant role of perioperative systemic inflammatory response elicited by cardiac surgery has been postulated experimentally and clinically (Citation4–6).
While inflammation may be a pathogenetic component of postoperative AF, the clinical role for anti-inflammatory drugs still remains unclear. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been proven to be potent anti-inflammatory agents. Recently, the results of several randomized controlled trials (RCTs) evaluating the beneficial effects of statins given before cardiac surgery on preventing postoperative AF have been reported (Citation7–14). However, most of these studies were of relatively small size and perhaps underpowered to evaluate adequately the end-point. Thus, we performed a meta-analysis to confirm the hypothesis that statins pretreatment may lower the risk of postoperative AF.
Methods
We conducted a systematic literature search of Cochrane CENTRAL, clinicaltrials.gov, and PubMed (1980 through August 2010) for RCTs comparing preoperative statins therapy with the control for the prevention of AF following cardiac surgery without any language restrictions. The following medical subject headings and key words were used: ‘atrial fibrillation’, ‘cardiac surgery’, in combination with ‘statin’, ‘hydroxymethylglutaryl-CoA reductase inhibitor’, and the generic names of all available statins.
Two investigators (LD and FZ) then independently scanned all abstracts and obtained full-text reports of works that indicated or suggested eligibility. After obtaining full reports, the two reviewers independently assessed eligibility from the full-text articles with divergences resolved after consensus.
The primary end-point or outcome was postoperative AF. Other clinical outcomes of interest were postoperative hospital stay, mortality, myocardial infarction (MI), stroke, and the composite of death, MI, or stroke during follow-up.
All statistical analyses were performed based on the intention-to-treat principle. Odds ratios (OR) with 95% confidence intervals (CI) were computed as summary statistics. The pooled OR was calculated with the Mantel–Haenszel method for fixed effects and the DerSimonian and Laird method for random effects (Citation15,Citation16). To assess heterogeneity across trials, we used Cochran's test and means of I2 statistic (Citation17). A funnel plot as well as the adjusted rank correlation test, according to the method of Begg and Mazumdar (Citation18), was used to assess publication bias with respect to the primary outcome of interest, postoperative AF. A sensitivity analysis was performed by comparing the treatment effects obtained with each trial removed consecutively from the analysis with the overall treatment effects. Results were considered statistically significant at two-sided P < 0.05. Statistical analyses were performed with the Stata version 9 statistical package (Stata Corp., College Station, Texas, USA).
Results
A total of eight RCTs were finally included in this meta-analysis, involving 841 patients (422 in statins pretreatment group and 419 in control group) (Citation7–14). The main characteristics of these trials and the base-line characteristics of enrolled patients in individual trials are shown in and . The study drug was respectively rosuvastatin 20 mg/d for 1 week (Citation11), simvastatin 20 mg/d for 3 weeks (Citation13), pravastatin 40 mg/d for 2 days (Citation10), or atorvastatin 40 mg/d for 7 days (Citation7), or 20 mg/d for 3 days (Citation9), 7 days (Citation12), or 3 weeks (Citation8,Citation14) before the planned operation.
Table I. Main characteristics of the randomized trials included in the meta-analysis.
Table II. Base-line clinical and angiographic characteristics of the study population.
During the follow-up period, 80 of 422 patients (19.0%) in the statins pretreatment group developed postoperative AF, significantly less than 149 of 419 (35.6%) patients assigned to the control group (OR 0.40; 95% CI 0.29–0.55; P < 0.001) by the fixed-effect model (). There was no significant heterogeneity between trials (I2 = 0%; P = 1.0). No evidence of publication bias with respect to postoperative AF was found using the Begg funnel plot and rank correlation test (P = 0.90). Omission of individual trials from the analysis did not have any relevant influence on the overall results.
Figure 1. Odds ratios of postoperative atrial fibrillation associated with statins versus control from individual studies and overall population. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.
Postoperative hospital stay was significantly shortened in patients pretreated with statins compared with those in the control group (SMD –0.39; 95% CI –0.53 to –0.24; P < 0.01; P = 0.11 for heterogeneity) by the fixed-effect model. With respect to other outcomes of interest, the statins arm did not differ significantly from the control arm (OR 0.98, 95% CI 0.14–7.10, P = 0.98 for death; OR 0.85, 95% CI 0.30–2.47, P = 0.77 for MI; OR 0.70, 95% CI 0.14–3.63, P = 0.67 for stroke; respectively). The composite of death, MI, or stroke was similar between the statins group and the control group (3.2% versus 3.6%; OR 0.89; 95% CI 0.36–2.18; P = 0.79; P = 0.52 for heterogeneity) by the fixed-effect model.
Discussion
The present meta-analysis demonstrates the antiarrhythmic effects of statins pretreatment in patients undergoing cardiac surgery. Patients who received statins therapy prior to cardiac operation had a significant reduction in the odds of postoperative AF compared with the controls.
Although the underlying mechanisms for the development of postoperative AF after cardiac surgery are not precisely known, there is increasing evidence that inflammation plays an important role. Such inflammation may be induced by extracorporeal circulation or cardiopulmonary bypass (Citation19,Citation20). Moreover, the degree of postoperative inflammation can negatively affect atrial conduction and duration of atrial fibrillation (Citation21,Citation22). Thus, there has been a recent interest in using anti-inflammatory drugs for preventing postoperative AF after cardiac surgery.
Initial cohort studies in this area suggested that statins treatment was associated with a 40%–50% reduction in the incidence of postoperative AF in patients undergoing cardiac surgery (Citation23–26), but these positive findings were recently refuted by two large-scale cohort studies of >4,000 consecutive patients undergoing bypass or valve surgery (Citation27,Citation28). In both studies, the investigators found that statins treatment did not reduce the incidence of postoperative AF. However, the conclusions of all these investigations were weakened by the limitations of non-randomized study designs. A previous meta-analysis provided evidence that preoperative statins therapy exerted substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients (Citation29). The meta-analysis, however, included only three randomized trials, and a number of randomized trials have been published since then. In contrast, the present meta-analysis includes all available RCTs and has the potential to increase the power and improve the precision of treatment effects and safety. It demonstrated that pretreatment with statins decreases the incidence of postoperative AF after cardiac surgery compared with the controls. Moreover, hospital stay was significantly shortened in patients with statins intake prior to planned operation.
Although the exact mechanisms underlying the observed association of preoperative statins therapy and postoperative AF are unclear, accumulating evidence suggests that statins exert multiple effects independent of their effect on cholesterol. Besides the anti-inflammatory properties, statins can improve endothelial NO production, reduce oxidative stress, and inhibit neurohormonal activation (Citation30). For these reasons, statins may be able to prevent, decelerate, or even reverse electrical and structural remodeling in AF.
A limitation of this meta-analysis is that the individual trials varied considerably in study design, with different duration, dose, and type of statins used. However, the purpose of our study was to assess whether statins pretreatment is useful in preventing postoperative AF, but not to test a predefined dosage of a specific statins. Additionally, the present meta-analysis is not based on individual patient data, and the time-to-event analyses could not be performed. Moreover, this meta-analysis is only based on eight small-size trials, and the total number of patients is also not large, therefore the findings should be interpreted with some caution.
In conclusion, this meta-analysis of RCTs supports the effectiveness of statins pretreatment on reducing the incidence of postoperative AF in patients undergoing cardiac surgery. Further studies are needed to identify the optimal statins type, dose, and time of onset before planned operation. The effects of statins on non-coronary cardiac surgery also need to be further clarified in future dedicated studies, as most trials included in the present meta-analysis only enrolled patients undergoing coronary bypass surgery.
Declaration of interest: This work was supported by the National Natural Science Foundation of China (No. 81000614) and Young Scientific ‘Phosphor’ Foundation from the Shanghai Science and Technology Development (No. 08QA14019). The authors declare no other conflicts of interest.
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