From the Lown Cardiovascular Center and Research Foundation, Brookline, Massachusetts; Departments of Epidemiology and Nutrition, Harvard School of Public Health; Department of Medicine, Brigham & Women’s Hospital, and Harvard Medical School, Boston, Massachusetts
Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting approximately 2.2 million Americans1 and responsible for up to 30% of all ischemic strokes.2 It has a higher prevalence among elderly, hypertensive, and diabetic patients and among men, all of whom also have a higher prevalence of coronary artery disease (CAD). Clinical trials have shown that HMG-CoA reductase inhibitors (statins) are effective for the primary and secondary prevention of CAD.3,4 We hypothesized that statin therapy might have a beneficial effect on the prevention of atrial fibrillation in patients with CAD because of shared risk factors.
Patients and methods
We studied patients with stable chronic CAD, without a history of atrial fibrillation, enrolled in an ongoing observational study. The exposure was recorded as time spent on statin therapy of any brand during follow-up. The outcome was the occurrence of atrial fibrillation during follow-up, verified through a review of records and confirmed by 12-lead electrocardiogram (ECG) or ambulatory ECG monitoring.
We divided the study population into two mutually exclusive groups according to statin use: users and nonusers (of any cholesterol-lowering drugs). We compared the effects of statin use with no cholesterol therapy at all, as well as nonstatin cholesterol-lowering therapy, on the development of atrial fibrillation.
We calculated the relative risks of developing atrial fibrillation and their accompanying 95% confidence intervals (CIs), which were estimated from a Cox proportional hazards regression model. Fisher’s exact test was used to compare proportions, and the Student t test was performed to compare means. All statistical tests were two-sided, and all analyses were carried out using Stata 7.0 for Windows (Stata Corporation, College Station, Texas).
A total of 606 patients with at least 1 year’s worth of follow-up data, complete medication information, and information on history of atrial fibrillation were eligible for this study. Thirty-three patients with previous atrial fi-brillation were excluded, and 124 patients (20%) who had used nonstatin cholesterol-lowering drugs were excluded from the main analysis. The final study sample consisted of 449 men and women with stable CAD. Among these, 186 patients (41%) never used any cholesterol-lowering drugs during the study, and 263 patients (59%) used statins as their only cholesterol-lowering drugs. Average follow-up time was 5 years (range, 1—9 years). Completion rate for follow-up forms was 100%. Of 449 subjects, 18 (4%) voluntarily withdrew from the study during follow-up.
Statin users were younger, but included a larger proportion of patients who were current or past smokers compared with nonusers. They also had a larger proportion of patients who were treated with beta blocking agents, but had a smaller proportion of patients who were taking aspirin (table 1).
Among statin users, 9% developed atrial fibrillation. In contrast, 15% of nonusers developed atrial fibrillation. Corresponding incidence rates of atrial fibrillation per 1,000 person-years were 18 (95% CI, 11—26) for statin users and 37 (95% CI, 26–54) for nonusers (figure). The relative risk of developing atrial fibrillation for statin users compared with nonusers was 0.48 (95% CI, 0.28–0.83; table 2). The risk of developing atrial fibrillation was stratified for several known risk factors of atrial fi-brillation: advanced age, male sex, and hypertension (table 2). For all risk factors examined, statin use was consistently associated with a significant reduction in the risk of atrial fibrillation (figure and table 2).
We investigated whether the association between statin use and atrial fibrillation depended on baseline serum cholesterol levels and on changes in these cholesterol levels during follow-up. Within each of the groups of total cholesterol and each of the groups of change in total cholesterol, relative risks consistently indicated a reduced likelihood of developing atrial fibrillation (table 2). In a multivariate Cox proportional hazards model, we entered baseline cholesterol level and percentage of change in cholesterol level separately and then together, and found that inclusion of these variables did not alter the association between statin use and atrial fibrillation.
In addition, we calculated the total number of years a patient took statins during the study. We then divided patients into four groups according to the length of statin use (table 2). The relative risk of atrial fibrillation decreased as the total length of statin use increased (P = .03; table 2).
Of the 124 patients who had used nonstatin lipid-lowering agents (gemfibrozil, cholestyramine, clofibrate, colestipol, and probucol) and who were excluded from the main analysis, 17% developed atrial fibrillation during follow-up compared with 15% of nonusers of any lipid-lowering drugs and 9% of statin users. The incidence rate of atrial fibrillation was not statistically different from the incidence rate of atrial fibrillation among nonusers (34 versus 37 per 1,000 person-years, respectively; relative risk = 0.92; 95% CI, 0.56—1.50).
We examined the association between statin use and incidence of atrial fibrillation, adjusting for potential confounders, including age, systolic blood pressure, left ventricular ejection fraction (by echocardiogram), alcohol use (any versus none), history of heart failure, history of myocardial infarction, and total serum cholesterol level. The adjusted relative risk of atrial fibrillation according to statin use was 0.37 (95% CI, 0.18—
0.76) after controlling for these potential confounders. Additional analyses were performed to test the impact of other potential covariates by including them in the main multivariate model one at a time. These included sex; height; weight; smoking (past or current); self-assessed health status; diastolic blood pressure; history of hypertension; diabetes; left ventricular dysfunction; left ventricular hypertrophy; serum creatinine level; potassium level; use of angiotensin-converting enzyme inhibitors, beta blocking agents, calcium channel blocking agents, diuretics, antiarrhythmic drugs, warfarin, or aspirin; changes in total serum cholesterol level; and high-density lipoprotein cholesterol level. Each time, after one of these variables was entered into our main regression model, the relative risk between statin use and atrial fibrillation changed less than 5% and remained significant.
These findings support our hypothesis that statin use is protective against atrial fibrillation in a cohort of patients with chronic CAD. We used a multivariate Cox proportional hazards model that controlled for potential confounding factors, and statin use remained associated with a significant reduction in the onset of atrial fibrillation. The effect of statin therapy on the development of atrial fibrillation was independent of the changes in serum cholesterol levels over time and baseline cholesterol level.
The findings do not appear to be spurious because different definitions of exposure to statins were used, and a dose-response relationship between length of statin use and reduction of atrial fibrillation was found. Confounding is unlikely, as the associations persisted after adjustment for many known risk factors for atrial fibrillation, including age, sex, clinical characteristics, concomitant medications, and relevant cardiac diagnoses.
The mechanisms involved in the effects of statins on occurrence of atrial fibrillation are unclear. These effects might be related to the fact that mevalonic acid is a precursor not only of cholesterol synthesis but of other signaling intermediates, which are considered important for the cellular localization and intracellular trafficking of several membrane-bound proteins.5 One possible explanation for this effect might be related to the major role that the autonomic nervous system plays in the pathophysiology of atrial fibrillation.6,7 Recent reports suggest that statins can normalize autonomic tone and balance between the sympathetic and parasympathetic limbs of the autonomic nervous system, which in turn might decrease vagal tone and alter the electrophysiologic substrate, resulting in prevention of atrial fibrillation.8,9
Another plausible explanation for the beneficial effects of statin use might be related to their anti-inflammatory effects. A recent report from the Cardiovascular Health Study indicated that C-reactive protein is increased in patients 65 years and older with atrial fibrillation on one hand, and increased C-reactive protein is strongly associated with future development of atrial fibrillation in patients without previous atrial fibrillation on the other hand.10 Another recent report suggested that increased C-reactive protein is also associated with the development of hypertension, a major risk factor for atrial fibrillation.11 C-reactive protein has also been shown to be a potent determinant of successful cardioversion of paroxysmal atrial fibrillation to sinus rhythm.12 All of these findings suggest that inflammation could play an important role in developing atrial fibrillation and that the preventive benefit of statins might be related to their anti-inflammatory effects and suppression of
In a cohort of outpatients with stable CAD without prior atrial fi-brillation, we found that statin use was associated with a markedly reduced incidence of atrial fibrillation (50% to 60% reduction) over an average of 5 years of follow-up. This association, which appeared to be dose-dependent, remained significant after adjusting for potential confounders and was independent of serum total cholesterol level. The mechanisms behind this previously unreported effect of statins are not well defined and warrant further investigation.