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, I 2 = 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).
1. Kostapanos MS, Liberopoulos EN, Goudevenos JA, et al. Do statins have an antiarrhythmic activity? Cardiovasc Res 2007; 75:10–20.
2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation
: the Task Force for the Management of Atrial Fibrillation
of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369–2429.
3. Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect of statin
therapy and atrial fibrillation
a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2008; 51:828–835.
4▪▪. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation
: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: Primary prevention. Europace 2011; 13:308–328.
This review provides a contemporary evidence-based insight into the role of upstream therapies in primary (Part I) and secondary (Part II, published subsequently) prevention of atrial fibrillation.
5. White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. N Engl J Med 2000; 343:317–326.
6. Tveit A, Grundtvig M, Gundersen T, et al. Analysis of pravastatin to prevent recurrence of atrial fibrillation
after electrical cardioversion. Am J Cardiol 2004; 93:780–782.
7. Schwartz GG, Olsson AG, Chaitman B, et al. Effect of intensive statin
treatment on the occurrence of atrial fibrillation
after acute coronary syndrome: an analysis of the MIRACL trial. Circulation 2004; 110 (Suppl):S740.
8. Chello M, Patti G, Candura D, et al. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery. Crit Care Med 2006; 34:660–667.
9. Ozaydin M, Varol E, Aslan SM, et al. Effect of atorvastatin on the recurrence rates of atrial fibrillation
after electrical cardioversion. Am J Cardiol 2006; 97:1490–1493.
10. Patti G, Chello M, Candura D, et al. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation
in patients undergoing cardiac surgery. Results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) Study. Circulation 2006; 114:1455–1461.
11. Dernellis J, Panaretou M. Effect of C-reactive protein reduction on paroxysmal atrial fibrillation
. Am Heart J 2005; 150:1064.
12. Macfarlane PW, Norrie J. WOSCOPS Executive CommitteeThe value of the electrocardiogram in risk assessment in primary prevention: experience from the West of Scotland Coronary Prevention Study. J Electrocardiol 2007; 40:101–109.
13. Tsai CT, Lai LP, Hwang JJ, et al. Atorvastatin prevents atrial fibrillation
in patients with bradyarrhythmias and implantation of an atrial-based or dual-chamber pacemaker: a prospective randomized trial. Am Heart J 2008; 156:65–70.
14. 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.
15. 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; 156:373e9–e16.
16. Caorsi C, Pineda F, Munoz C. Pravastatin immunomodulates IL-6 and C-reactive protein, but not IL-1 and TNF-alpha, in cardio-pulmonary bypass. Eur Cytokine Netw 2008; 19:99–103.
17. Tamayo E, Alvarez FJ, Alonso O, et al. Effects of simvastatin on systemic inflammatory responses after cardiopulmonary bypass. J Cardiovasc Surg (Torino) 2009; 50:687–694.
18. Almroth H, Höglund N, Boman K, et al. Atorvastatin and persistent atrial fibrillation
following cardioversion: a randomized placebo-controlled multicentre study. Eur Heart J 2009; 30:827–833.
19. Maggioni AP, Fabbri G, Lucci D, et al. Effects of rosuvastatin on atrial fibrillation
occurrence: ancillary results of the GISSI-HF trial. Eur Heart J 2009; 30:2327–2336.
20. Haywood LJ, Ford CE, Crow RS, et al. 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.
21. 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.
22. Xia W, Yin Z, Li J, et al. Effects of rosuvastatin on asymmetric dimethylarginine levels and early atrial fibrillation
recurrence after electrical cardioversion. Pacing Clin Electrophysiol 2009; 32:1562–1566.
23. Negi S, Shukrullah I, Veledar E, et al. Statin
Therapy for the Prevention of Atrial Fibrillation
Trial (SToP AF trial). J Cardiovasc Electrophysiol 2011; 22:414–419.
24. Spadaccio C, Pollari F, Casacalenda A, et al. Atorvastatin increases the number of endothelial progenitor cells after cardiac surgery: a randomized control study. J Cardiovasc Pharmacol 2010; 55:30–38.
25. Baran C, 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 2011. [Epub ahead of print]
26. Demir K, Can I, Koc F, et al. Atorvastatin given prior to electrical cardioversion does not affect the recurrence of atrial fibrillation
in patients with persistent atrial fibrillation
who are on antiarrhythmic therapy. Med Princ Pract 2011; 20:464–469.
27. Macfarlane PW, Murray H, Sattar N, et al. The incidence and risk factors for new onset atrial fibrillation
in the PROSPER study. Europace 2011; 13:634–639.
28. Schwartz GG, Chaitman BR, Goldberger JJ, Messig M. High-dose atorvastatin and risk of atrial fibrillation
in patients with prior stroke or transient ischemic attack: analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Am Heart J 2011; 161:993–999.
29. 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.
30▪. Peña JM, MacFadyen J, Glynn RJ, Ridker PM. 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.
In the JUPITER trial, increasing levels of high-sensitivity C-reactive protein were associated with an increased risk of incident atrial fibrillation and random allocation to rosuvastatin significantly reduced that risk. This is the only trial with a significant benefit in primary prevention of atrial fibrillation with statin, contributing to the minor heterogeneity seen in this setting in our study.
31. Bang CN, Greve AM, Boman K, et al. Effect of lipid lowering on new-onset atrial fibrillation
in patients with asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Am Heart J 2012; 163:690–696.
32▪▪. Suleiman M, Koestler C, Lerman A, et al. Atorvastatin for prevention of atrial fibrillation
recurrence following pulmonary vein isolation: a double-blind, placebo-controlled, randomized trial. Heart Rhythm 2012; 9:172–178.
This is to date the only randomized trial with statin in patients with atrial fibrillation ablation. Atorvastatin following atrial fibrillation ablation did not decrease the risk of atrial fibrillation recurrence in the first 3 months. This suggests it should not be routinely administered to prevent periprocedural arrhythmias.
33. Schmermund A, Achenbach S, Budde T, et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation 2006; 113:427–437.
34. McLean DS, Ravid S, Blazing M, et al. Effect of statin
dose on incidence of atrial fibrillation
: data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) and Aggrastat to Zocor (A to Z) trials. Am Heart J 2008; 155:298–302.
35. Kourliouros A, Valencia O, Hosseini MT, et al. Preoperative high-dose atorvastatin for prevention of atrial fibrillation
after cardiac surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 2011; 141:244–248.
36. 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.
37. Fleiss JL. Statistical methods for rates and proportions. 2nd ed.New York:Wiley; 1981.
38. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22:719–748.
39. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177–188.
40. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557–560.
41. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation
after cardiac surgery. JAMA 2004; 291:1720–1729.
42▪. Rahimi K, Emberson J, McGale P, et al.
Effect of statins on atrial fibrillation
: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ 2011; 342:d1250. doi: 10.1136/bmj.d1250.
This is currently the largest pooled analysis on the effect of statins on atrial fibrillation, retrieving information from unpublished studies. How trials are pooled, based on short-term and long-term follow-up, is discussed in our article.
43. Fauchier L, de Groote P. Atrial fibrillation
and renin-angiotensin-aldosterone system: believe it or not. Europace 2011; 13:297–298.
44. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’ CollaboratorsEfficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–1278.
45. Strandberg TE, Vanhanen H, Tikkanen MJ. Effect of statins on C-reactive protein in patients with coronary artery disease. Lancet 1999; 353:118–119.
46. 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.
47. Dickersin K, Chan S, Chalmers TC, et al. Publication bias and clinical trials. Control Clin Trials 1987; 8:343–353.