Comparison of Atorvastatin and Simvastatin in Prevention of Atrial Fibrillation After Successful Cardioversion

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1 Comparison of Atorvastatin and Simvastatin in Prevention of Atrial Fibrillation After Successful Cardioversion Summary Franjo Naji, 1 MD, David Suran, 1 MD, Vojko Kanic, 1 MD, Damijan Vokac, 1 MD, and Miso Sabovic, 2 MD Recent data have shown that statins can help prevent atrial fibrillation (AF). We hypothesized that statins vary in their ability to prevent AF after successful electrical cardioversion (EC). Sixty-five patients (29 receiving atorvastatin and 36 receiving simvastatin) who had undergone successful EC for persistent AF were included in the study. They received statins at least one month before EC, and continued the treatment through 2 years of followup. The statins they received were selected independently by their attending physicians. In the follow-up period, AF reoccurred in 11 (38.0%) patients of the atorvastatin group and in 24 (66.7%) patients of the simvastatin group. Using a logistic regression model, the unadjusted odds ratio (OR) of having an AF recurrence for patients on atorvastatin versus those on simvastatin was 0.31 (95% CI , P = 0.02). After adjustment for other potentially confounding variables (age, sex, hypertension, diabetes, ischemic heart disease, echocardiographic characteristics, and therapy), treatment with atorvastatin retained its significance for maintaining sinus rhythm in a multivariate model (OR 0.20, CI 0.04 to 0.98, P < 0.05). Our study suggests that atorvastatin and simvastatin exert different effects on the AF recurrence rate after successful EC. Larger prospective randomized trials are needed to definitively evaluate the role of different statins in patients with AF, especially on AF recurrence after EC. (Int Heart J 2009; 50: ) Key words: Atrial fibrillation, Atorvastatin, Simvastatin, Pleiotropic effects, Electrical cardioversion, Sinus rhythm RECENT data have revealed that drugs, which are not basically considered as antiarrhythmic drugs (for example highly selective beta blockers, ACE inhibitors, angiotensin receptor blockers and statins), can influence atrial fibrillation From the 1 Department of Cardiology and Angiology, University Clinical Centre Maribor, Maribor, 2 Department of Vascular Diseases, University Clinical Centre Ljubljana, Ljubljana, Slovenia. Address for correspondence: Franjo Naji, MD, Department of Cardiology and Angiology, University Clinical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia. Received for publication July 23, Revised and accepted November 6,

2 154 NAJI, ET AL Int Heart J March 2009 (AF). 1-5) This is also emphasized in patients after successful cardioversion of AF. While ACE inhibitors and angiotensin receptor blockers are evidently effective to a certain extent, the beneficial effects of statins on AF prevention are still controversial. Statins may exert antiarrhythmic effects through an effect on endothelial function as well as inflammation. 6) However, data in this regard are still conflicting. In the CARAF study the investigators showed that statins reduce the AF recurrence rate after successful pharmacological or electrical cardioversion (EC), but only when combined with beta blockers. 7) The data from the AR- MYDA-3 study strongly supports the fact that statins reduce the incidence of AF in patients after elective cardiac surgery. 8) In a systematic analysis of 14 trials, Patel, et al found that statin therapy was associated with reduced odds of developing AF. 9) Another meta-analysis performed by Liu, et al, on the other hand, suggested that statins may be effective in AF prevention mainly in patients after cardiac surgery. Favorable effects of statins were confirmed in observational studies, but no such effect could be noted in the analysis of randomized clinical trials (RCT). 10) In all these studies, different statins were used, based on the theory that their beneficial or antiarrhythmic effects are to some extent similar. On the other hand, there are data that indicate that the so-called pleiotropic effects between different statins can differ considerably. 11) We hypothesized that patients treated with a more potent statin therapy (atorvastatin) would be less prone to AF recurrence than those treated with a less potent statin therapy (simvastatin). To the best of our knowledge, no similar study has yet to be published. Methods A retrospective analysis of data concerning the patients referred to our Department of Cardiology and Angiology for planned EC between January 2000 and December 2004 was performed. Patients diagnosed with persistent AF and treated with atorvastatin or simvastatin were included. Exclusion criteria were: paroxysmal AF, AF of less than one month duration, age > 85 years, heart surgery or an electrophysiologic procedure prior to EC or during the followup period, and an implanted pacing device. After EC all included patients were examined regularly and followed for a period of two years. Data collection and analysis were performed according to hospital ethics policy. On admission, the medical history was taken and physical examination performed. Standard laboratory measurements including serum cholesterol level, CRP, and 12-lead ECG were obtained. Transthoracic echocardiography was performed prior to EC in all patients. Patients were properly anticoagulated with a minimum treatment period of 4 weeks before the procedure. If adequate antico-

3 Vol 50 No 2 STATINS IN PREVENTION OF ATRIAL FIBRILLATION 155 agulation was not achieved, we performed a transesophageal echocardiogram in order to rule out possible thrombi in the cardiac cavities. EC was performed under sedation with intravenous propofol. Up to 3 synchronized external monophasic shocks (200 J, 300 J, 360 J) with electrodes placed in the right parasternal and apical position were delivered. After successful EC the patients were monitored for 24 hours, following which another 12-lead ECG was recorded. Patients without sinus rhythm at that point were excluded from further analysis. After a period of one month and with present sinus rhythm and low thromboembolic risk, anticoagulant treatment was discontinued. Statin therapy was prescribed according to the guidelines for patients with hyperlipidemia and/or elevated cardiovascular risk. Patients were monitored during regular visits in our outpatient clinic every 3 to 6 months and at 1 and 2 years, when a 12 lead ECG was recorded. They were also instructed to visit the emergency department immediately in case of symptoms suggestive of recurrent AF. Liver and muscle enzymes were controlled every 4 to 6 months. The endpoint was documented AF in a 12-lead ECG. Statistical analysis: The patients were divided in two groups according to statin treatment (atorvastatin group and simvastatin group). Continuous data are given as the mean ± SD, whereas categorical variables are expressed as percentages. Differences between continuous variables were evaluated using Student s t-test, and the chi-square test was used for categorical variables. We used simple logistic regression to assess the correlation between the recurrence of AF after two years and treatment with statins. Multivariable logistic regression with the enter method was used to adjust the influence of statin therapy for other clinical variables. The model was tested with the Hosmer-Lemeshow goodness-of-fit test. Statistical analysis was performed using the SPSS 13.0 statistical package (SPSS; Chicago, IL). Results After the inclusion criteria were met, 65 patients were included. Of these, 29 were treated with atorvastatin and 36 with simvastatin. In the simvastatin group, 26 patients were treated with a 20 mg dose and 10 patients with a 40 mg dose (median dose, 26 ± 9 mg). In the atorvastatin group, 21 patients were treated with a 10 mg dose and 8 patients with a 20 mg dose (median dose 13 ± 4 mg). In 39 patients, statin therapy was started in the period of one month before inclusion, whereas in 26 patients statins were prescribed for a longer period prior to cardioversion. Treatment with simvastatin was discontinued in 1 patient due to elevated liver enzymes, while atorvastatin was discontinued in 1 patient due to myalgia. The dose of simvastatin was elevated in 1 patient. In 1

4 156 NAJI, ET AL Int Heart J March 2009 Table. Clinical Characteristics of Patients Recruited Into the Simvastatin Group and the Atorvastatin Group Patient characteristics Atorvastatin group (n = 29) Simvastatin group (n = 36) P value Age (years) Sex (male) Duration of AF (months) LA diameter (mm) Ejection fraction (%) Mitral regurgitation (stage 2 or higher) Ischemic heart disease Arterial hypertension Diabetes mellitus Medication Beta-blocker Verapamil ACE inhibitor Amiodarone Sotalol Propafenone Angiotensin receptor blocker (ARB) Cholesterol (mmol/l) CRP (mg/l) 62 ± 3 20 (69.0%) 4.1 ± ± 5 55 ± 5 5 (17.2%) 5 (17.2%) 25 (86.2%) 8 (27.6%) 10 (34.5%) 4 (13.8%) 21 (72.4%) 21 (72.4%) 2 (6.9%) 6 (20.7%) 3 (10.3%) 5.8 ± ± ± (47.2%) 5.4 ± ± 6 53 ± 8 6 (16.7%) 8 (22.2%) 31 (86.1%) 10 (27.8%) 10 (27.8%) 3 (8.3%) 26 (72.2%) 28 (77.8%) 0 (0%) 6 (16.7%) 5 (13.9%) 6.0 ± ± Data are presented as the mean ± SD (ranges) or numbers (percentages). atorvastatin-treated patient the dose was elevated and in another atorvastatin was changed to rosuvastatin. Amiodarone was discontinued prior to AF recurrence in 2 simvastatin treated patients and in 2 atorvastatin treated patients, while it was added in 1 atorvastatin treated patient. ACE inhibitors were discontinued in 1 atorvastatin treated patient and in 2 simvastatin patients. All other medications were taken regularly throughout the observation period. There were no significant differences in patient age, sex, duration of AF, medications, or concomitant diseases between the 2 groups. We did not find any significant differences in left atrium dimension, ejection fraction, or mitral regurgitation. There were also no significant differences in cholesterol and CRP levels between the groups, which were evaluated prior to EC during the hospital stay. The data are presented in the Table. After a period of two years, AF reoccurred in 11 (38.0%) patients in the atorvastatin group and in 24 (66.7%) patients in the simvastatin group. Using a logistic regression model, the unadjusted odds ratio (OR) of having an AF recurrence for patients on atorvastatin versus those on simvastatin was 0.31 (95% CI , P = 0.02). After adjustment for other potentially confounding variables - including age, sex, hypertension, diabetes, ischemic heart disease, treatment with ACE inhibitors, ARBs, beta-blockers, antiarrhythmic therapy, dura-

5 Vol 50 No 2 STATINS IN PREVENTION OF ATRIAL FIBRILLATION 157 tion of AF, CRP, and echocardiographic characteristics, the OR was 0.20 (CI 0.04 to 0.698, P = 0.048). Discussion The results of the present study suggest that atorvastatin and simvastatin exert different effects on the AF recurrence rate after successful EC. To the best of our knowledge, this is the first study comparing the effects of different statin treatments in this clinical setting. We did not find any significant differences in patient characteristics that could in any way explain the different outcome after successful EC. Cholesterol levels, obtained at least one month after initiation of treatment with statins, were similar in both groups. The CRP levels at the time of EC were lower in the atorvastatin group, although the difference was not statistically significant. Since patients were already treated with statins for at least 1 month, it could be speculated that this happened through a greater antiinflammatory effect of atorvastatin. It might be hypothesized that the greater antiarrhythmic effect of atorvastatin occurred due to modulation of inflammation and endothelial function as well as due to the greater antioxidative effect. This could lead to faster or more sustained reversal of atrial remodeling and better restoration of atrial function. There is a substantial amount of data stating that statins, in addition to their lipid-lowering action, also modulate inflammation, 12) nitric oxide-dependent endothelial function, 13) and oxidative stress. 14) However, there is limited evidence indicating that different statin treatment regimens exert different pleiotropic effects. Few studies addressed this issue and the results are somewhat conflicting. Hognestad, et al conducted a prospective study on 97 patients randomized to conventional lipid-lowering treatment with simvastatin 20 mg or aggressive treatment with atorvastatin 80 mg. They found significant decreases in hs-crp and fibrinogen in the aggressive treatment arm compared to the conventional treatment arm. The nitric oxide-total was significantly increased in both groups, although the effect was more pronounced in the atorvastatin group. 15) On the other hand, Mulder, et al found in their prospective study that in patients with documented cardiovascular disease, aggressive lipid lowering-therapy with atorvastatin did not provide any additional effect on inflammation markers as compared to conventional treatment with simvastatin. 16) However, the authors do admit that target LDL in the aggressively treated group was not achieved. Turner, et al compared the effects of different statins on invasion and proliferation of smooth muscle cells cultured from the human saphenous vein. They demonstrated the antiproliferative effect of atorvastatin was greater than that of simvastatin. 11)

6 158 NAJI, ET AL Int Heart J March 2009 In AF, inflammation as well as neurohormonal activation undoubtedly plays an important role. A number of studies have addressed this issue, showing a clear relationship between elevated CRP levels, oxidative stress or BNP, and AF incidence and recurrence. 17,18) Despite the amount of data showing their antiinflammatory effects, the evidence that statins reduce the risk of AF incidence is conflicting. Two meta-analyses of existing observational studies and RCTs were performed. Patel, et al analyzed 14 trials and found that statin use was associated with reduced odds of developing new-onset AF, recurrent AF, recurrent AF after successful cardioversion, and postoperative AF. 9) The metaanalysis performed by Liu, et al includes 6 RCTs and 10 observational studies. The authors demonstrated that statins may be effective in AF prevention mainly in patients after cardiac surgery. The favorable effects of statins were mainly seen in observational studies, but no such effect could be noted in the analysis of RCT. They suggested that larger RCTs are needed, with longer follow-up periods studying different forms of AF and in different clinical settings. 10) Only a few studies have attempted to demonstrate the favorable effect of statin therapy in patients after successful cardioversion of AF. In their retrospective study, Siu, et al hypothesized that statins reduce the recurrence rate of AF after successful EC in patients with lone AF and hyperlipidemia. 4) Ten patients treated with statins received atorvastatin or simvastatin for 32 ± 6 weeks before EC. After an observation period of 2 years, there was a significant decrease in the AF recurrence rate in the statin treated group. Ozaydin, et al conducted a small prospective randomized open label study trying to prove that atorvastatin prolongs the AF free survival period after successful EC. 19) Forty-eight patients with AF lasting longer than 48 hours were randomized to either an atorvastatin or no atorvastatin group. Atorvastatin was given 48 hours prior to EC. After 3 months of follow-up, treatment with atorvastatin was associated with reduced risk of developing AF as well as with a significant decrease in high sensitivity CRP level. In a similar study conducted by Tveit, et al, 114 patients were randomized to receive pravastatin treatment for a period of 3 weeks before EC or no drug. 20) No beneficial effect of pravastatin treatment was observed after a 6-week observation period. It was suggested that the lack of an effect of pravastatin treatment could be due to the open label design of the study, underrepresentation of patients with coronary disease, and short duration of statin treatment prior to EC. The CARAF study was the biggest study performed in this clinical setting. In this multicenter observational study, 625 patients after successful pharmacological or EC were followed for a period of one year. The researchers observed a significant 74% reduction in the odds of recurrent AF, but only in patients also taking beta-blockers. They hypothesized that an interaction between both drugs was only apparent and that patients on beta-blockers were

7 Vol 50 No 2 STATINS IN PREVENTION OF ATRIAL FIBRILLATION 159 more likely to benefit from statin therapy due to their clinical characteristics. However, a statistical analysis which would compare the clinical characteristics of patients on beta-blockers and other patients was not performed. 7) Limitations: Our study was retrospective and nonrandomized. It is also possible that short paroxysms of AF were not reported since patients often do not experience symptoms connected to paroxysmal AF. We were also not able to obtain any laboratory data which would further prove that atorvastatin decreased lipid values to a greater extent than simvastatin. Patients in both groups were also treated with other drugs that could influence the AF recurrence rate. However, the distribution of those medications was similar in both groups, reducing the possibility for their unrecognized effect after adjustment in multivariate analysis. Conclusion: In conclusion, our findings suggest that different statin treatments exert different effects on the AF recurrence rate after successful EC. Larger prospective randomized clinical trials are needed to further evaluate the role of statin therapy in patients with AF. References 1. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J 2003; 24: Komatsu T, Ozawa M, Tachibana H, et al. Combination therapy with amiodarone and enalapril in patients with paroxysmal atrial fibrillation prevents the development of structural atrial remodeling. Int Heart J 2008; 49: Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002; 106: Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003; 92: Ishiguro H, Ikeda T, Abe A, et al. Antiarrhythmic effect of bisoprolol, a highly selective beta 1-blocker, in patients with paroxysmal atrial fibrillation. Int Heart J 2008; 49: Tamargo J, Caballero R, Gómez R, Núñez L, Vaquero M, Delpón E. Lipid-lowering therapy with statins, a new approach to antiarrhythmic therapy. Pharmacol Ther 2007; 114: (Review) 7. Humphries KH, Lee M, Sheldon R, et al. Statin use and recurrence of atrial fibrillation after successful cardioversion. Am Heart J 2007; 154: 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: Patel AA, White CM, Shah SA, Dale KM, Kluger J, Coleman CI. The relationship between statin use and atrial fibrillation. Curr Med Res Opin 2007; 23: Liu T, Li L, Korantzopoulos P, Liu E, Li G. Statin use and development of atrial fibrillation: a systematic review and meta-analysis of randomized clinical trials and observational studies. Int J Cardiol 2008; 126: Turner NA, Midgley L, O Regan DJ, Porter KE. Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion. J Cardiovasc

8 160 NAJI, ET AL Int Heart J March 2009 Pharmacol 2007; 50: Strandberg TE,Vanhanen H, Tikkanen MJ. Effect of statins on C-reactive protein in patients with coronary artery disease. Lancet 1999; 353: Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: Rosenson RS. Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities. Atherosclerosis 2004; 173: (Review) 15. Hognestad A, Aukrust P, Wergeland R, et al. Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation. Clin Cardiol 2004; 27: Mulder DJ, van Haelst PL, Wobbes MH, et al. The effect of aggressive versus conventional lipidlowering therapy on markers of inflammatory and oxidative stress. Cardiovasc Drugs Ther 2007; 21: Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol 2007; 50: (Review) 18. Yamada T, Murakami Y, Okada T, et al. Plasma brain natriuretic peptide level after hybrid therapy with pulmonary vein isolation and antiarrhythmic drugs for atrial fibrillation. Int Heart J 2008; 49: 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: 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: