CHADS 2 Score, Statin Therapy, and Risks of Atrial Fibrillation

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1 CLINICAL RESEARCH STUDY CHADS 2 Score, Statin Therapy, and Risks of Atrial Fibrillation Chen-Ying Hung, MD, a Ching-Heng Lin, PhD, b El-Wui Loh, PhD, c Chih-Tai Ting, MD, PhD, a,d Tsu-Juey Wu, MD, PhD a,d,e a Cardiovascular Center and b Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; c Institute of Population Health Sciences, National Health Research Institutes, Taiwan; d Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan; e School of Medicine, Chung Shan Medical University, Taichung, Taiwan. ABSTRACT OBJECTIVE: Little is known about the effectiveness of statins on primary prevention of atrial fibrillation in elderly patients. This study aimed to evaluate the efficacy of statin treatment for atrial fibrillation prevention in elderly patients with hypertension, and to determine if comorbidity or CHADS 2 (Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack) score can predict the effectiveness of statin treatment. METHODS: Patients aged 65 years with hypertension were identified from a National Health Insurance research database (a systemic sampling from 2000 to 2009 with a total of 1,000,000 subjects). Medical records of 27,002 patients were used in this study, in which 2400 (8.9%) were receiving statin therapy. Risk of new-onset atrial fibrillation in statin users and nonusers was analyzed. RESULTS: During the 9-year follow-up period, 2241 patients experienced new-onset atrial fibrillation. Statin users were younger than nonusers (72.4 vs 73.4 years) but had a higher prevalence of ischemic heart disease, diabetes mellitus, stroke, and chronic renal disease. Overall, statin therapy reduced the risk of atrial fibrillation by 19% (adjusted hazard ratio 0.81; 95% confidence interval, ; P.009). Subgroup analysis showed that statin use was beneficial in patients with or without a particular comorbidity. The effectiveness of statins was significant in patients with CHADS 2 score 2 (adjusted hazard ratio 0.69; 95% confidence interval, ; P.001). However, statin therapy was not as beneficial in hypertensive patients without other cardiovascular comorbidities (CHADS 2 score 1). CONCLUSION: Statin therapy in elderly patients with hypertension reduces the risk of new-onset atrial fibrillation. Statins are more beneficial in patients with CHADS 2 score 2 than in those with score of Elsevier Inc. All rights reserved. The American Journal of Medicine (2013) 126, KEYWORDS: Atrial fibrillation; Hypertension; CHADS 2 score; Statins Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data. Dr Hung, Dr Lin, and Dr Wu collaborated closely on designing the study, developing the analytic protocols, interpreting the statistical output, and writing the article. Dr Loh and Dr Ting helped interpret the results and reviewed and refined the article draft. Requests for reprints should be addressed to Ching-Heng Lin, PhD, and Tsu-Juey Wu, MD, PhD, Cardiovascular Center, Taichung Veterans General Hospital, 160, Section 3, Chung-Kang Road, Taichung 407, Taiwan. address: tjwu@vghtc.vghtc.gov.tw Atrial fibrillation is the most common arrhythmia and is associated with increased cardiovascular morbidity, mortality, and economic burden. 1 Old age, male sex, hypertension, congestive heart failure, ischemic heart disease, pulmonary diseases, diabetes mellitus, and valvular heart disease have been reported as risk factors for the development of atrial fibrillation. 2-5 Among them, age and hypertension are responsible for more atrial fibrillation than any other risk factor. 4 Therefore, a major current focus in population management is how to prevent the occurrence of new-onset atrial fibrillation in these high-risk groups. Owing to the inefficacy and side effects of classic antiarrhythmic drugs, current focus of atrial fibrillation primary prevention has shifted to drugs that target atrial fibrillation substrate, such as statins, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), and aldosterone antagonists. 6 Animal experiments and clinical studies have proven the concept /$ -see front matter 2013 Elsevier Inc. All rights reserved.

2 134 The American Journal of Medicine, Vol 126, No 2, February 2013 of primary prevention of atrial fibrillation with statins, 6 and recent guidelines suggested that statins could be used for atrial fibrillation prevention in patients undergoing cardiac surgery or those with heart failure. 7 However, little is known about the effectiveness of statins on primary prevention of atrial fibrillation in elderly patients or other high-risk groups. CHADS 2 (Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack) scoring system includes many cardiovascular diseases related to atrial fibrillation, and was recently found to be related to the atrial fibrillation recurrence after ablation 8 and the electroanatomical remodeling of the left atrium. 9 However, no studies have focused on the ability of this score to predict the effect of statin treatment on atrial fibrillation prevention. The purpose of the present study was to evaluate the effect of statin treatment on primary prevention of atrial fibrillation in elderly patients with hypertension in a nationwide cohort. We also wanted to determine if atrial fibrillation-related cardiovascular comorbidity or CHADS 2 score could predict the effectiveness of statin treatment on primary atrial fibrillation prevention. CLINICAL SIGNIFICANCE MATERIALS AND METHODS Research Database The National Health Insurance program in Taiwan has been operating since 1995 and it covers about 99% of Taiwanese population. The National Health Research Institute (NHRI) has established a National Health Insurance research database. For the current analysis, we used a systemic sampling of patient data from 2000 to 2009 with a total of 1,000,000 subjects, which was released by the NHRI. These random samples have been confirmed by the NHRI to be representative of the general Taiwanese population. The NHRI safeguards the privacy of individuals and provides the data to researchers after ethical approval has been obtained. The NHRI made data at the individual level available to us in an anonymous format, in which specific individuals cannot be identified. Retrospective register studies do not require ethical approval from the ethics committees in Taiwan. Statin therapy in elderly patients with hypertension reduces the risk of newonset atrial fibrillation by 19%. In addition to the usefulness in predicting strokes, CHADS 2 (Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack) score could predict the preventive effect of statins on atrial fibrillation. Statins are more beneficial in patients with CHADS 2 score 2 than in those with score of 1 in atrial fibrillation primary prevention. Patient Selection Patients aged 65 years with hypertension were identified according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code To ensure the diagnostic validity and avoid any potential for misclassifications, only patients who had a diagnosis of hypertension and had used at least 1 antihypertensive drug were selected. Patients were not eligible for enrollment in this cohort study if they had a history of cardiac dysrhythmias (including atrial fibrillation) or conduction disorders, thyrotoxicosis, rheumatic heart disease, pulmonary heart disease, valvular heart disease, or cardiomyopathy. This study included 27,002 patients for analysis. Definitions of Drug Use Statin use records were retrieved from ambulatory and inpatient claims data. Patients were divided into statin users group and nonusers group according to their statin use in This allowed inclusion of patients who used statins on an intermittent basis. According to the payment regulations of National Health Insurance program in Taiwan, statins can only be used for treatment of hypercholesterolemia with laboratory evidence of elevated total cholesterol or low-density lipoprotein. Thus, the statin users were elderly patients with hypercholesterolemia and hypertension, while nonstatin users were elderly patients with hypertension. Other cardiovascular drugs such as aspirin, ACEIs and ARBs, aldosterone antagonists, beta-blocking agents, and calcium channel blockers were identified by the same method. Definitions of the Clinical Endpoints and Follow-up The study endpoint was defined as new-onset atrial fibrillation (ICD-9-CM: ) or death during the 9-year follow-up period ( ). All occurrences of atrial fibrillation were confirmed by the claims data. To ensure the diagnostic validity, only patients with at least 3 consensus atrial fibrillation diagnoses at an outpatient department (to avoid misclassification due to those with tentative diagnosis for examinations and retrieving examination reports) or at least 1 inpatient hospitalization atrial fibrillation diagnosis were identified. Other comorbidities such as ischemic heart disease, congestive heart failure, diabetes mellitus, stroke or transient ischemic attack, chronic obstructive pulmonary disease, and chronic renal disease were identified by the same approach. The CHADS 2 score was calculated for each patient by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years, and diabetes mellitus, and 2 points for a history of stroke or transient ischemic attack. The cutoff values of CHADS 2 score for analysis were determined according to a previous study on the risk of stroke. 10

3 Hung et al CHADS 2 Score, Statins, and Atrial Fibrillation 135 Table 1 Baseline Characteristics Variable Total (n 27,002) Nonusers (n 24,602) Statin Users (n 2400) P Value Age at entry, mean (SD), 73.3 (5.5) 73.4 (5.6) 72.4 (4.8).001 years 65-74, n (%) 17,114 (63) 15,436 (63) 1678 (70) 75, n (%) 9888 (37) 9166 (37) 722 (30) Male, n (%) 12,883 (48) 11,997 (49) 886 (37).001 Comorbidities, n (%) Ischemic heart 4628 (17) 3982 (16) 646 (27).001 disease Congestive heart 609 (2) 557 (2) 52 (2).759 failure Diabetes mellitus 5165 (19) 4466 (18) 699 (29).001 Stroke or transient 3284 (12) 2906 (12) 378 (16).001 ischemic attack Chronic obstructive 2697 (10) 2469 (10) 228 (10).403 pulmonary disease Chronic renal disease 1158 (4) 1017 (4) 141 (6).001 Medications, n (%) Aspirin 6313 (23) 5501 (22) 812 (34).001 ACEIs & ARBs 10,728 (40) 9558 (39) 1170 (49).001 Aldosterone 554 (2) 499 (2) 55 (2).385 antagonists Beta blocking agents 12,316 (46) 11,023 (45) 1293 (54).001 Calcium channel 15,576 (58) 13,956 (57) 1620 (68).001 blockers CHADS 2 score, mean (SD) 1.8 (0.9) 1.8 (0.9) 1.9 (1.0).001 1, n (%) 12,070 (45) 11,090 (45) 980 (41) 2-3, n (%) 12,986 (48) 11,770 (48) 1216 (51) 4-6, n (%) 1946 (7) 1742 (7) 204 (8) 2, n (%) 14,932 (55) 13,512 (55) 1420 (59) ACEIs angiotensin-converting enzyme inhibitors; ARBs angiotensin-receptor blockers; CHADS 2 Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack. Statistical Analysis The data are presented as the mean values and SDs for continuous variables, and proportions for categorical variables. The differences between continuous values were analyzed by using t-test for continuous variables, and chi-squared test for categorical variables. The atrial fibrillation-free survival curves were plotted via the Kaplan-Meier method, with statistical significance examined by the log-rank test. Multivariable Cox proportional hazard models were used to identify independent factors contributing to atrial fibrillation occurrence. All statistical analyses were carried out by SAS software version 9.2 (SAS Institute, Inc., Cary, NC). A P value of.05 was considered statistically significant. RESULTS Clinical Characteristics A total of 27,002 hypertensive patients aged 65 years were enrolled in this study. These patients were followed-up for 9 years (average years) to evaluate the preventive effect of statins therapy on new-onset atrial fibrillation. The mean age of the study population was years, with 37% of them aged 75 years. Males accounted for 48% of the population. Among the patients, 24,602 (91.1%) had never used statins, and 2400 (8.9%) had used statins in The average CHADS 2 score of the cohort was , and 55% of the study subjects had a score 2. Table 1 summarizes the baseline characteristics of the statin users and nonusers. Among the study subjects, 17% had ischemic heart disease, 2% had congestive heart failure, 19% had diabetes mellitus, 12% had stroke or transient ischemic attack, 10% had chronic obstructive pulmonary disease, and 4% had chronic renal disease. Statin users were younger than nonusers ( vs years; P.001) and the percentage of male statin users was lower than that of male nonusers (37% vs 49%; P.001). Statin users also had a higher prevalence of ischemic heart disease (P.001), diabetes mellitus (P.001), stroke or transient ischemic attack (P.001), and chronic renal disease (P.001). In regard to the drug

4 136 The American Journal of Medicine, Vol 126, No 2, February 2013 Table 2 Multivariate Analysis for New-onset Atrial Fibrillation Variable Hazard Ratio* 95% CI P Value Statins users (yes/no) Age 75 years (yes/no) Male (yes/no) Comorbidities (yes/no) Ischemic heart disease Congestive heart failure Diabetes mellitus Stroke or transient ischemic attack Chronic obstructive pulmonary disease Chronic renal disease Medications (yes/no) Aspirin ACEIs and ARBs Aldosterone antagonists Beta blocking agents Calcium channel blockers ACEIs angiotensin-converting enzyme inhibitors; ARBs angiotensin-receptor blockers; CI confidence interval. *Controlled all variables listed in this table. use history, the statins group had a higher rate of aspirin- (P.001), ACEIs and ARBs (P.001), beta-blocking agents (P.001), and calcium channel blockers (P.001) usage than the nonstatins group. Statin users also had higher CHADS 2 scores ( vs ; P.001) than nonusers. Statins Effect on Primary Prevention of Atrial Fibrillation Table 2 demonstrates the adjusted hazard ratio (HR) for the development of atrial fibrillation in the cohort. During the 9-year follow-up, 2241 patients (8.3% of the study population) developed new-onset atrial fibrillation. Atrial fibrillation occurred less frequently among statin users compared with nonusers before and after an adjustment for variables between the 2 cohorts (adjusted HR 0.81; 95% confidence interval [CI], ; P.009). The annual incidence of atrial fibrillation decreased from 1.05% per year to 0.85% per year after statin use. Among the cardiovascular comorbidities, age 75 years (adjusted HR 1.72; 95% CI, ; P.001), ischemic heart disease (adjusted HR 1.20; 95% CI, ; P.001), congestive heart failure (adjusted HR 1.91; 95% CI, ; P.001), stroke or transient ischemic attack (adjusted HR 1.20; 95% CI, ; P.004) significantly increased the risk of new-onset atrial fibrillation in the study population. Diabetes mellitus, chronic obstructive pulmonary disease, chronic renal disease, and other cardiovascular medications had no significant impacts on the occurrence of new-onset atrial fibrillation in this cohort. CHADS 2 Score and Treatment Outcome Figure 1 displays the hazard ratio plot of atrial fibrillation occurrence based on Cox proportional hazards analysis with statin use as a covariate. The relationships of baseline comorbidities and CHADS 2 score and the risk of atrial fibrillation were evaluated in statin users and nonusers. There were no significant differences in atrial fibrillation hazard risk ratios between statin users and nonusers for different age groups and any comorbidity (ranged from 0.71 to 0.86). Statins were significantly effective in patients with CHADS 2 score 2 (adjusted HR 0.69; 95% CI, ; P.001) after an adjustment for sex, ischemic heart disease, chronic obstructive pulmonary disease, chronic renal disease, and the use of medications in multivariate Cox regression analysis. However, no significant benefit was found in patients with a CHADS 2 score of 1 (adjusted HR 0.91; 95% CI, 0.71 to 1.19; P.500). The Kaplan-Meier survival plot presented in Figure 2 shows the protective effect of statins on occurrence of atrial fibrillation according to CHADS 2 score. In patients with CHADS 2 score of 1, no significant difference in protective effect was found between statin users and nonusers (log rank P.870). On the other hand, there was a significant difference between statin users and nonusers (log rank P.001) among those with CHADS 2 score 2. The survival curves began to separate early and continued to separate throughout the course of the study. Patients with CHADS 2 score 2 had a higher risk of new-onset atrial fibrillation but also benefited more from statins protective effect than those with CHADS 2 score of 1. Further analyses for patients with higher CHADS 2 score ( 3) failed to show

5 Hung et al CHADS 2 Score, Statins, and Atrial Fibrillation 137 Figure 1 Specific subgroup analysis for new-onset atrial fibrillation. CHADS 2 Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack; CI confidence interval; HR hazard ratio. a significant effect due to the relatively small patient number (data not shown). DISCUSSION Main Findings This nationwide cohort study is the largest (enrolled 27,002 subjects) and longest (from 2001 to 2009) study for analysis of the protective effects of statins on the atrial fibrillation occurrence among hypertensive elderly patients. The main results of this study were that the risk of atrial fibrillation was lower in statin users than nonusers, especially for those with CHADS 2 score 2. Even though the statin users had more cardiovascular comorbidities than the comparison cohorts, statin therapy remained a protective factor against new-onset atrial fibrillation before and after adjusting for variables. To our knowledge, this is the first study to explore the relationship between the atrial fibrillation protective effect of statins and the CHADS 2 score. Our study showed that CHADS 2 score represents not only a clinical risk factor for stroke, but also predicts the primary preventive effect of statins on atrial fibrillation in hypertensive elderly patients. Effectiveness of Statins on Primary Prevention of Atrial Fibrillation in Hypertensive Elderly Although statins have been found to be effective for atrial fibrillation prevention in patients with heart failure or those who received cardiac surgery, there is very little evidence to support the potency of statins effect on primary prevention of atrial fibrillation in elderly patients with hypertension. In a brief report (included 2304 patients with a 3.5-year follow-up), statin therapy was shown to have a protective

6 138 The American Journal of Medicine, Vol 126, No 2, February 2013 Figure 2 Atrial fibrillation-free survival rate according to statins use and CHADS 2 score. (A) CHADS 2 score of 1, (B) CHADS 2 score 2. CHADS 2 Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack. effect on hypertensive patients with a 54% risk reduction. 6 However, there was no significant difference in the incidence of atrial fibrillation between the statins group and the control group in the Antihypertensive and Lipid Lowering treatment to prevent Heart ATtack (ALLHAT) trial; included 8582 patients with a 4.8-year follow-up) 2 or the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial; included 5804 patients with a 3.2-year follow-up). 3 Because of these conflicting data, studies with larger populations and longer follow-up periods in patients with hypertension are needed to confirm the effect of statins. In the present study, we showed that there was an overall 19% atrial fibrillation risk reduction in hypertensive elderly patients treated with statins. However, statin therapy in those without other cardiovascular comorbidities (CHADS 2 score 1) did not provide any significant protective effect. This result may explain the different results in the previous studies statins effectiveness may be confounded by other cardiovascular comorbidities. The PROSPER trial included individuals aged years with a history of risk factor or vascular disease. The CHADS 2 score of this population was around 1.45 (calculated from the available data of this trial 3 ), much lower than our study. Possibly for this reason, the atrial fibrillation protective effect of statins was not so obvious in the trial. On the other hand, evaluation of atrial fibrillation was an ancillary study to ALLHAT, and 20% of participants did not receive atrial fibrillation measurement during the follow-up period. 2 The ignorance had possibly created certain biases in homogeneity of the samples. Furthermore, the racial difference, as shown in the ALLHAT study, may explain the difference in our results (included mainly Taiwanese) compared with other trials. Ability of CHADS 2 Score to Predict Treatment Outcome Statin treatment has been suggested for atrial fibrillation prevention in some high-risk patients, such as individuals undergoing cardiac surgery or those with heart failure. 7 However, we do not know if this therapy provides similar benefits in other high-risk groups. Herein, our study demonstrated that CHADS 2 score was a convenient and useful scoring system for predicting the effectiveness of statins. Patients with a CHADS 2 score 2 had a good statin treatment outcome, with a 31% reduction of atrial fibrillation risk. On the other hand, those with CHADS 2 score of 1 gained no significant benefits from statin therapy in atrial fibrillation prevention. Those with CHADS 2 score 2 had a

7 Hung et al CHADS 2 Score, Statins, and Atrial Fibrillation 139 higher risk of new-onset atrial fibrillation, but they also benefited more from statins protective effect than those with a CHADS 2 score of 1. This implies that the CHADS 2 score can be used to guide the upstream therapy of atrial fibrillation in elderly patients with hypertension. Possible Mechanisms of Our Findings Increasing evidence supports the concept of primary prevention of atrial fibrillation with statins. Several biological mechanisms other than improvement of lipid metabolism have been proposed, such as anti-inflammatory and antioxidant effects, modulation of endothelial function, altered membrane fluidity, and ion channel function. 6,11,12 While this is the first study to explore the relationship between the atrial fibrillation protective effect of statins and the CHADS 2 score, further research is needed to confirm this relationship and to identify the exact mechanism. However, a recent analysis from the Justification for the Use of statins in primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) can give us a hint for the possible mechanism. 13 In the JUPITER trial, patients with higher high-sensitivity C-reactive protein got a better atrial fibrillation protective effect from statin therapy. High-sensitivity C-reactive protein represents the status of systemic inflammation. 14 Recent studies also showed that CHADS 2 score was related to this biomarker. 15,16 Therefore, those with higher CHADS 2 scores are in a more severe inflammation status, and the antiinflammatory effect of statins may be more obvious in these patients. Study Limitations There were several limitations in the present study. First, the study population was a selective group that included mainly Taiwanese population. The cohort excluded patients with any cardiac dysrhythmias or conduction disorders, thyrotoxicosis, and many heart diseases related to atrial fibrillation. Second, details of duration of each atrial fibrillation episode and types of atrial fibrillation were not available in the National Health Insurance research database. Third, statin use was defined at baseline, so patients that started statins during the follow-up period were classified as nonusers. This method may underestimate the protective effect of statin therapy. Even though this method allowed inclusion of patients who used statins on an intermittent basis, the mean cumulative statin using time was significantly higher in statin users than nonusers ( vs years; P.001). The prevalence of statin usage also was significantly different between statin users (62%, 54%, and 48%, respectively) and nonusers (9%, 13%, and 14%, respectively) at the 3 rd,6 th, and 9 th year of follow-up, respectively (Supplementary Table 1). Finally, our study included only patients with hypertension. All our patients had CHADS 2 scores 1, so we could not evaluate whether this finding was applicable to those without hypertension. CONCLUSIONS Statin therapy in elderly patients with hypertension reduces the risk of new-onset atrial fibrillation. In addition to the usefulness in predicting strokes, our study showed that CHADS 2 score could predict the preventive effect of statins on atrial fibrillation in this population. Further studies to confirm the relationship between CHADS 2 score and the effect of statins in atrial fibrillation primary prevention in other categories are warranted. ACKNOWLEDGMENTS This study is based in part on data obtained from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes. References 1. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med. 1998;158: 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: 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: Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82:2N-9N. 5. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med. 1995;98: 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: 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). Europace. 2010;12: Chao TF, Cheng CC, Lin WS, et al. Associations among the CHADS(2) score, atrial substrate properties, and outcome of catheter ablation in patients with paroxysmal atrial fibrillation. Heart Rhythm. 2011;8: Park JH, Joung B, Son NH, et al. The electroanatomical remodelling of the left atrium is related to CHADS2/CHA2DS2VASc score and events of stroke in patients with atrial fibrillation. 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8 140 The American Journal of Medicine, Vol 126, No 2, February Goonasekara CL, Balse E, Hatem S, Steele DF, Fedida D. Cholesterol and cardiac arrhythmias. Expert Rev Cardiovasc Ther. 2010;8: Calo L, Martino A, Sciarra L, et al. Upstream effect for atrial fibrillation: still a dilemma? Pacing Clin Electrophysiol. 2011;34: Pena 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: Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem. 2001;47: Maehama T, Okura H, Imai K, et al. Usefulness of CHADS2 score to predict C-reactive protein, left atrial blood stasis, and prognosis in patients with nonrheumatic atrial fibrillation. Am J Cardiol. 2010;106: Crandall MA, Horne BD, Day JD, et al. Atrial fibrillation and CHADS2 risk factors are associated with highly sensitive C-reactive protein incrementally and independently. Pacing Clin Electrophysiol. 2009;32:

9 Hung et al CHADS 2 Score, Statins, and Atrial Fibrillation 140.e1 Supplementary Table 1 Mean Cumulative Statins Using Time and Prevalence of Statins Usage Variable Total (n 27,002) Nonusers (n 24,602) Statin Users (n 2400) P Value Cumulative statin using 3.5 (2.4) 0.9 (1.7) 5.5 (2.8).001 time, mean (SD), years Prevalence of usage, n (%) (9) 0 (0) 2400 (100) (11) 1372 (6) 1634 (68) (14) 2235 (9) 1495 (62) (16) 2855 (12) 1445 (60) (16) 2873 (12) 1349 (56) (16) 3097 (13) 1300 (54) (17) 3323 (14) 1268 (53) (17) 3401 (14) 1211 (51) (17) 3527 (14) 1161 (48).001