Considering their potent anti-inflammatory and antioxidant properties, some clinical and experimental studies have suggested the use of statins to protect against atrial fibrillation . However, insufficient data are available at this time to allow recommending statins for the prevention of atrial fibrillation . In a previous meta-analysis, we found that the use of statins was significantly associated with a 61% decrease in the risk of incidence or recurrence of atrial fibrillation in patients with sinus rhythm . This benefit is still a subject of debate [4▪▪]. Considering the publication of several studies since 2007, we felt that an updating of this pooled analysis would be useful. Findings from meta-analyses may change when data from trials with a substantial number of patients are added, especially when odds ratios (ORs) border on the threshold of statistical significance. Since the anti-inflammatory effect of statins, one of the mechanisms for their potential antiarrhythmic capacity, has been surmised to be more pronounced in high-dose statin therapy, a secondary analysis based on the trials comparing a more intensive vs. a standard statin regimen was also performed.
We searched through Medline and Embase for all randomized controlled trials published from January 1980 through June 2012 that compared statins with a placebo or a control treatment. We conducted text searches with the terms ‘statin’ and ‘atrial fibrillation’. We looked for randomized controlled outcome trials that met all of the following specified criteria: direct comparison between a statin and control treatment or placebo or more vs. less intensive statin treatment, regardless of the background therapy in either group, publication before 30 June 2012 in peer-reviewed journals indexed in Medline, and incidence or recurrence of atrial fibrillation as a specified event during follow-up, although not necessarily a primary endpoint. We also manually searched references from selected clinical trials, recent meta-analyses, review articles, and abstracts from the major cardiology meetings. The final search identified 32 trials [5–29,30▪,31,32▪▪,33–35] that fulfilled the inclusion criteria. We reviewed the methodological quality of randomized controlled trials by using a scoring system developed by Jadad et al. . A flow diagram of the study selection process is illustrated in Fig. 1.
We calculated values for agreement using the methods described by Fleiss . We calculated ORs and 95% confidence intervals (CIs) for the incidence or recurrence of atrial fibrillation for each trial separately and for combinations of studies according to fixed-effect and random-effect models. We used a χ2-test to assess heterogeneity and I2 to quantify heterogeneity. In the presence of statistical homogeneity, defined as a χ2-test P value greater than 0.10 and I2 less than 50%, we analyzed the data using fixed-effects models. Pooled ORs and 95% CIs for fixed-effects models were calculated on the basis of the Mantel–Haenszel method. Otherwise, we used random-effects models [38–40]. The P value threshold for statistical significance was set at 0.05 for the effect sizes. We also generated a funnel plot to assess the presence of publication bias. Statistical calculations were performed using RevMan, version 4.2.6 (The Cochrane Collaboration, Oxford, UK).
Thirty-two published studies including 71 005 patients with sinus rhythm were included in the analysis. These studies investigated the use of statins in various populations (Table 1). Twenty-eight studies compared the use of statins vs. no statins in 61 773 patients and four studies compared more vs. less intensive statin regimens in 9232 patients. All included controlled trials were randomized and received Jadad scores of 2 (n = 6), 3 (n = 6), 4 (n = 5), or 5 (n = 15) points. The following statins were studied: atorvastatin (n = 19), pravastatin (n = 7), simvastatin (n = 3), and rosuvastatin (n = 4). Intervention doses for statins were variable. In the studies that compared the use of statins vs. no statins, comparisons were made with a placebo (n = 20) or a control regimen (n = 8). Other characteristics of the patients in each study, including concomitant medical treatment and biochemical characteristics, are given in Tables 2 and 3.
For the endpoint considered, the funnel plots with estimable ORs were rather symmetrical in each of the subgroups of studies (Fig. 2). Incidence or recurrence of atrial fibrillation occurred in 3112 patients. Overall, the use of statins was significantly associated with a decreased risk of atrial fibrillation compared with controls (OR 0.69, 95% CI 0.57–0.83, P < 0.0001) with heterogeneous results (Fig. 3). We then made an attempt to find relevant subgroups of trials with homogeneous results. Subgroup analyses were performed for populations with postoperative atrial fibrillation, primary and secondary prevention of atrial fibrillation, and more intensive vs. standard statin regimens. The use of statins was significantly and homogeneously associated with a major decrease in the risk of postoperative atrial fibrillation (OR 0.37, 95% CI 0.28–0.51, P < 0.00001). The benefit of statin therapy was different for the so-called primary prevention (i.e., prevention of new onset of atrial fibrillation) and for secondary prevention of atrial fibrillation. We found that statin therapy was not efficient for the primary prevention of atrial fibrillation (OR 1.00, 95% CI 0.86–1.15, P = 0.95) with results close to homogeneity (P = 0.03, I2 = 52%). In secondary prevention of atrial fibrillation, statin therapy was, in contrast, significantly associated with a decreased risk of atrial fibrillation recurrence, although results were heterogeneous (OR 0.57, 95% CI 0.36–0.91, P = 0.02) (Fig. 4). There was, finally, no evidence of a reduction in the risk of atrial fibrillation with more intensive vs. standard statin regimens, with homogeneous results in this subgroup of studies (OR 1.01, 95% CI 0.77–1.32, P = 0.96) (Fig. 4).
Our updated systematic analysis suggests that the use of statins was significantly associated with a decreased risk of incidence or recurrence of atrial fibrillation in a large number of patients with sinus rhythm in various clinical settings. However, this beneficial effect was not seen for all types of atrial fibrillation in all the patients. The use of statins was associated with a lack of benefit in primary prevention of atrial fibrillation, a significant but heterogeneous decreased risk of recurrence of atrial fibrillation in secondary prevention, and a very significant and homogeneous reduction in the risk of postoperative atrial fibrillation. More intensive vs. standard statin regimens were not associated with a reduction in the risk of atrial fibrillation.
The GISSI-HF investigators found a beneficial effect of rosuvastatin in reducing atrial fibrillation occurrence in patients with HF, but it was suggested that larger populations were needed to provide a definite answer to several unresolved issues . Our previous pooled analysis included only six randomized, rather small, short-term studies that compared statin with no-statin therapy. The present meta-analysis includes published data from 32 studies, which together involve about 20 times as many patients and 10 times as many atrial fibrillation events. The finding that the use of statins was associated with a decreased risk of incidence or recurrence of atrial fibrillation was borderline to significance in 2007, and it was not significant in the subgroups of patients with primary or secondary prevention of atrial fibrillation . We are now able to state that the benefit of statin therapy is very heterogeneous in the overall population against atrial fibrillation, without apparent benefit for the primary prevention of atrial fibrillation. By contrast, the benefit of statin therapy is significant in prevention of postoperative atrial fibrillation and in secondary prevention of atrial fibrillation, atrial fibrillation reduction ranging from 50 to 60% in these subgroups.
Although the definition of atrial fibrillation occurrence during follow-up was quite different in the studies, there is no reason to think that atrial fibrillation was less likely to be diagnosed in patients receiving a statin. Duration of follow-up in the studies was variable and may seem relatively short in some of them but was mostly appropriate according to the type of atrial fibrillation . A study evaluating new-onset atrial fibrillation, however, requires a long follow-up. It may be argued that the studies evaluating statins in primary prevention of atrial fibrillation had relatively short and inadequate follow-up duration. Too short a follow-up duration in these patients might have disadvantaged the active statin. However, the evaluation of the treatment effect (with OR 1.00) in around 60 000 patients strongly suggests there is a lack of benefit for the prevention of atrial fibrillation with statin in these patients.
In recent years, several meta-analyses have been published on the effect of statin on atrial fibrillation events and they, surprisingly, had a very different conclusion. A main reason for discrepancies in these meta-analyses is that they focused on different types of atrial fibrillation. Recently, a large analysis included published and unpublished data from 35 studies, which together involve about 110 000 patients [42▪]. The authors tested the hypothesis that statins may reduce the risk of atrial fibrillation in these trials, which have collected, but often not published, data on atrial fibrillation. Among these randomized trials, statin therapy did not reduce the risk of atrial fibrillation significantly vs. control in long-term trials. The large amount of unreported data has been a valuable addition to the medical literature. However, the manner in which disparate studies were pooled together and the possible extrapolation of these results is a matter of concern. On the basis of exclusion of short-term trials (which may seem appropriate to eliminate negative studies with insufficient effect of the active treatment), all the positive results and data on the possible benefit of statin on postoperative atrial fibrillation were excluded. The authors therefore performed a pooled analysis of negative studies rather than a systematic review on the subject. None of the studies in the analysis of long-term trials were performed in patients with a specific history of atrial fibrillation. It was consequently an evaluation of the effect of statin for primary prevention of atrial fibrillation, which indeed demonstrated a lack of benefit, as found in our analysis.
The magnitude of the antiarrhythmic effect of statin against atrial fibrillation is certainly lower than initially suggested. In secondary prevention of atrial fibrillation, the fact that statins sometimes fail to prevent atrial fibrillation may in part be explained by target and timing. This reasoning has also been proposed when some disappointing results were seen with angiotensin receptor blockers for preventing recurrences of atrial fibrillation . It is possible that statin therapy only plays an intermediate role in the risk of atrial fibrillation, when there is acute inflammation, which can be effectively decreased. Patients with low risk of atrial fibrillation or normal heart structure are unlikely to benefit from statin therapy for primary prevention of atrial fibrillation. At the other end of the atrial fibrillation continuum is statin therapy, which may only have a minor effect on patients highly prone to atrial fibrillation, with greater importance of mechanical or electrical remodelling. A self-perpetuating mechanism may operate for patients with older and definitely established substrate. Statin is unlikely to work very efficiently in this setting, especially if patients are treated for a short period. Of note, there is only one randomized trial currently published on the effect of statin for secondary prevention following atrial fibrillation ablation, with negative results on a relatively short-term follow-up.
We were not able to establish the correlation between the degree of low-density lipoprotein (LDL) reduction and the incidence or recurrence of atrial fibrillation at the individual level in the studies that compared the use of statins vs. no statins, as has been done with other cardiovascular events involving statin therapy . However, based on the pooled analysis of the four studies that compared more vs. less intensive statin regimens, it seems that no benefit was attributable to higher doses of statins or correlated with lower LDL levels. Our clinical analysis was not intended to address the issue of the mechanisms by which statins may prevent atrial fibrillation. These hypothetical mechanisms have been in part delineated elsewhere . The potential effect of statins as anti-inflammatory drugs might be unrelated to their effects on LDL particles [45,46]. The similar effect of more vs. less intensive statin therapy may indirectly support this hypothesis. It is possible that low doses of statin may be effective in reducing inflammation independently of its effect on LDL cholesterol reduction.
Because of the increase in life expectancy as well as a rise in the prevalence of heart failure in most countries, the overall global burden from atrial fibrillation is likely to increase substantially in the coming decades. Although not acutely life-threatening, the hemodynamic compromise and increased risk of stroke associated with atrial fibrillation cause significant morbidity and mortality. Atrial fibrillation is therefore responsible for impairment of the quality of life and causes a substantial burden on health services, but there is little reliable evidence on how to prevent it. Patients with coronary heart disease are currently treated with statins in most cases, and our finding may not have an impact on their treatment. In contrast, it remains to be determined whether statins may benefit atrial fibrillation patients without any type of established atherosclerotic disease or with a low risk of atherogenesis. As it remains uncertain whether the suppression of atrial fibrillation in these patients is beyond doubt beneficial, we feel that prescribing statins for this purpose alone should not be recommended at present.
The funnel plot of the trials was almost symmetrical, but we cannot exclude the possibility of a publication bias (i.e., the tendency for trials to be more likely to be published if their results are positive than if they are negative or null) . Publication bias can produce significant apparent effects when treatments are actually less effective, but this may apply to many fields in clinical medicine and there is no clear reason to think this risk was higher than usual in our analysis. Atrial fibrillation mechanisms may vary in different groups of patients. Significant heterogeneity found in OR calculations in this study reflects the heterogeneity of the different clinical settings included. The benefit of intervention therapies may be due to different protective effects against atrial fibrillation, and results cannot be directly extrapolated to other clinical settings.
The overall antiarrhythmic effect of statins on atrial fibrillation appears highly significant in a large number of different patients, and statins may reduce the risk of atrial fibrillation by as much as 30%. The highest benefit was seen for the prevention of postoperative atrial fibrillation and in secondary prevention of atrial fibrillation, with a heterogeneity deserving further explanation. Efficacy of statins for the primary prevention of atrial fibrillation seems limited, and this suggests that ‘upstream therapy’ of atrial fibrillation is probably not an appropriate term for statins compared with what is seen with some renin–angiotensin–aldosterone system blockers [2,4▪▪,43]. Large-scale, prospective, randomized clinical trials are probably still needed to establish whether statins produce a similar benefit and thus provide an appropriate therapeutic option in some subgroups of patients for the management of atrial fibrillation.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 80–81).
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