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.
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.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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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