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European Heart Journal Advance Access published online on May 13, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn192
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Beneficial effects of statin therapy for prevention of atrial fibrillation following DDDR pacemaker implantation

Anne M. Gillis*, Margaret Morck, Derek V. Exner, Andrea Soo, M. Sarah Rose, Robert S. Sheldon, Henry J. Duff, Katherine M. Kavanagh, L. Brent Mitchell and D. George Wyse

Libin Cardiovascular Institute of Alberta and Department of Cardiac Sciences, University of Calgary and Calgary Health Region, HSC Room 1634, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1

Received 23 May 2007; revised 8 April 2008; accepted 17 April 2008.

* Corresponding author. Tel: +1 403 220 6841, Fax: +1 403 270 0313, Email: amgillis{at}ucalgary.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Aims: Data suggest that atrial pacing, statins, angiotensin-converting enzyme-inhibitors and angiotensin receptor blocking drugs prevent atrial tachycardia/atrial fibrillation (AT/AF) in some patients. The clinical predictors of AT/AF recurrence following dual-chamber pacemaker insertion were examined in 185 consecutive patients with paroxysmal AF.

Methods and results: Predictors of AT/AF recurrence were evaluated in this observational cohort study. The time to first AT/AF recurrence and AT/AF burden (h/day) was retrieved at each follow-up visit by interrogating the pacemaker. AT/AF recurred following pacemaker implantation in 157 (85%) patients. At 1 year of follow-up, patients without recurrence were more likely to be on statin therapy (54%) when compared with patients without statin therapy (25%, {chi} = 12.31, P = 0.0004). Statin therapy was the only significant predictor of AT/AF recurrence in a multivariate logistic regression model (adjusted odds ratio 0.33, 95% confidence interval 0.14–0.74, P = 0.007). AT/AF burden was significantly lower in the group on statin therapy (median 0.10 h/day) when compared with the group not on statin therapy (median 0.39 h/day, P = 0.0059).

Conclusion: AT/AF recurs frequently following pacemaker implantation in patients with sinus node disease. The progression to permanent AF remains low over time. Statin therapy was significantly associated with AT/AF suppression.

Key Words: Atrial fibrillation • Dual-chamber pacing • Statins


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Atrial fibrillation (AF), atrial flutter, and atrial tachycardia (AT) occur frequently in pacemaker patients.1–3 In this population, atrial pacing compared with ventricular pacing reduces the likelihood of AF emergence.4 Data also suggest that hexamethyl glutaryl CoA reductase inhibitors (statins),5–10 angiotensin-converting enzyme (ACE)-inhibitors,11,12 and angiotensin receptor-blocking (ARB) drugs13 prevent AF in some patients. The mechanisms by which these drugs prevent AF are not completely understood. Inflammation14,15 and oxidative stress injury may play a role in the genesis of AF16–19 raising the possibility that statins, through anti-inflammatory or antioxidant effects, might prevent AF. ACE-inhibitors and ARB agents may prevent AF by preventing haemodynamic triggers for AF or through tissue-specific effects that prevent atrial structural remodelling and fibrosis.20

Some pacemakers have enhanced monitoring features that allow determination of the time of occurrence and overall burden of AT/AF over time.1–3 We examined the temporal characteristics of AT/AF and evaluated factors associated with AT/AF recurrence in a consecutive series of patients with a history of symptomatic bradycardia and paroxysmal AF who received a dual-chamber pacemaker that monitors the daily burden of AT/AF. We hypothesized that the use of statins and/or ACE-inhibitors/ARB agents would reduce the recurrence of AF in this population.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Patient selection and follow-up
For inclusion in this prospective cohort study, patients experienced at least three episodes of AF within the year prior to pacemaker implantation, at least one episode was electrocardiographically documented and they received a Medtronic AT 500/501 DDDR pacemaker (Medtronic Inc, Minneapolis, MN) This pacemaker was the device of choice for patients with paroxysmal AF during the study period as information on the daily frequency and burden of AT/AF could be stored in the pacemaker for up to 14 months.2,3 The only exclusion criterion was atrioventricular (AV) node ablation as the indication for pacemaker (three patients). All remaining and eligible patients (n = 185) were enrolled between November 1999 and June 2004. Recruitment stopped when the AT 500/501 pacemaker was replaced by new technology. No sample size calculation was made. All patients were followed prospectively for at least 1 year. Patients were assessed 4–8 weeks after pacemaker implant and every 6 months thereafter. This study was approved by the Conjoint Health Research Ethics Board at the University of Calgary.

Pacemaker programming
Pacing algorithms to suppress AF or treat atrial tachycardia/flutter were not programmed unless the patient had recurrence of multiple episodes of AT/AF. The AT 500/501 pacemaker provides information about the date, time of onset, duration, rhythm classification, and AT/AF burden (h/week) of AT/AF over time.2,3 The pacemakers were programmed to collect intracardiac atrial electrograms on the first 30 and the last five episodes of AT/AF. The pacemaker was programmed to detect atrial tachyarrhythmias if the atrial rate exceeded 167 b.p.m. The details of AT/AF classification have been published previously.2 (See the supplementary file for more details of pacemaker settings.)

Episode review
All AT/AF episodes with available intracardiac electrograms and marker channels were reviewed by the investigators for appropriate classification.1,2 The specificity of the detection algorithm for AT/AF in the Medtronic 500/501 pacemaker is 96%.2,21

Definitions
Sustained AT/AF was defined as an atrial tachyarrhythmia with a cycle length ≤360 ms lasting ≥5 min. AT/AF burden was defined as the quantity of AT/AF expressed in h/day retrieved from the device memory.2 Permanent AT/AF was defined as an AT/AF burden of 24 h/day for at least 6 months.

Data analysis
AT/AF burden and time to first recurrence of sustained AT/AF was determined from the pacemaker data logs. As longer episodes of AT/AF are more likely associated with adverse cardiovascular events,22 the time to first recurrence of AT/AF lasting ≥1 day, and ≥7 days were also determined. The clinical characteristics of patients experiencing AT/AF and those not experiencing AT/AF within the first year were compared. Variables assessed included age, gender, cardiac disease, history of heart failure, echocardiographic parameters, and baseline medication use including the use of antiarrhythmic, statins, β-blockers, ACE-inhibitors, or ARB drugs.

Statistical analysis
Statistical analyses were performed using Stata 8.0 (StataCorp LP, College Station, TX, USA). All P-values were two-sided and no adjustment was made for multiple P-values in this exploratory analysis. Data are expressed as median with inter-quartile ranges (IQR). Differences in median data for independent groups were compared using the Mann–Whitney U test.2 Differences in AF burden between 2 and 12 months were compared using a paired t-test. Differences in proportions were analysed using a {chi}2 test. Survival free from AT/AF was described using Kaplan–Meier estimates.23 The assumption of proportional hazards was tested based on Schoenfeld residuals.24 There was evidence against the proportional hazards assumption for statin therapy, which was the primary predictor variable of interest, in the multivariable model ({rho} = –0.18; {chi}12 = 5.28, P = 0.022). As all patients were followed for at least 1 year, differences between the proportion of patients experiencing AT/AF at 1 year were compared using a {chi}2 test and a multivariable logistic regression model was used to assess the effect of statins in the presence of other significant predictor variables. Univariate predictors with a P-value <0.1 (Table 1) were entered into the multivariable model. A propensity score analysis was undertaken to adjust for baseline differences in the statin and no-statin groups (see supplementary file for additional details).25,26 To generate the propensity score, a logistic regression analysis was used to remove as much confounding as possible; all variables from Table 2 were entered into the model until the highest value of the c-statistic was obtained. The variables included in the final propensity score model were age, gender, left ventricular (LV) ejection fraction (EF), β-blocker use, all Class I/II antiarrhythmic drugs, hypertension, and coronary artery disease (CAD). No interactions were included because of sample size limitations. The c-statistic in the final model was 0.73 indicating good discrimination and the Hosmer–Lemeshow test showed that there was no evidence against lack of fit ({chi}82 = 11.85, P = 0.16). The score was divided into quintiles from the combined groups26 and entered into the multivariable logistic regression model.


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  		Table 1 Characteristics of study population

 

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  		Table 2 Patient characteristics as a function of statin therapy

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 
Atrial tachycardia/atrial fibrillation following pacemaker implantation
The characteristics of the study population are shown in Table 1. The majority of patients had sinus node disease. Most subjects had normal LV systolic function. All patients were followed for at least 1 year and the average duration of follow-up was 2.77 ± 0.97 years. Most patients experienced AT/AF following pacemaker implantation. The overall probability of experiencing AT/AF at 1 year was 0.69 (95% CI 0.62–0.76). All patients experiencing AT/AF following pacemaker implantation experienced multiple episodes. At 1 year of follow-up, the probability of subjects experiencing episodes of AT/AF lasting ≥1 day and ≥7 days during follow-up was 0.31 (95% CI 0.25–0.39) and 0.12 (95% CI 0.08–0.17), respectively. The event-free survival from sustained AT/AF as a function of the duration of the episode is shown in Figure 1. The burden of AT/AF increased slightly but not significantly over time [median 0.034 h/day at 2 months vs. 0.17 h/day at 12 months (P = 0.068)]. After 3 years of follow-up, the burden of AT/AF remained <30 min/day in 58% of the study population. At 3 years, 7% of the patients had developed permanent AF.


Figure 1
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  		Figure 1 Kaplan–Meier survival curves showing event-free survival from atrial tachycardia/atrial fibrillation (AF) lasting ≥5 min (dotted line), lasting ≥1 day (solid line), and/or lasting ≥7 days (dashed line). Eighty-six percent of patients developed AF following pacemaker implantation and most experienced their first episode within 100 days of implantation.

 
Predictors of atrial tachycardia/atrial fibrillation recurrence
Patients who did not experience AT/AF recurrence at 1 year were significantly more likely to be receiving statin therapy (54%) than were those with AT/AF recurrence at 1 year (25%, Table 1, {chi}12 = 12.31, P = 0.0004). Event-free survival from any episode of sustained AT/AF over the first year of follow-up as a function of statin use is shown in Figure 2. Freedom from AT/AF was higher in the group receiving statin therapy. At 1 year follow-up, the probability of patients receiving statin therapy to experience AT/AF was 0.63 (95% CI 0.51–0.75) compared with 0.85 for those not on statin therapy (95% CI 0.77–0.91).


Figure 2
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  		Figure 2 Kaplan–Meier survival curves showing event-free survival from any episode of atrial tachycardia (AT)/atrial fibrillation (AF) ≥ 5 min. At 1 year patients on a statin (solid line) were significantly less likely to experience AT/AF during follow-up when compared with patients not on a statin (dashed line; {chi}2 = 12.31, P = 0.0004).

 
The characteristics of patients on statin therapy vs. no statin therapy are shown in Table 2. The dose and statin prescribed are summarized in Table 3. Patients on statin therapy were more likely to be male ({chi}12 = 2.99, P = 0.084), have CAD ({chi}12 = 7.67, P = 0.0056), and were more likely to be on a β-blocker ({chi}12 = 4.74, P = 0.030) or Class I/III antiarrhythmic drugs ({chi}12 = 3.56, P = 0.060). These variables, plus hypertension, age, and LVEF were used to construct the propensity score.


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  		Table 3 Statin use

 
The use of statin therapy remained a significant predictor of AT/AF suppression in the multivariable logistic regression model (Table 4) [adjusted odds ratio (OR) = 0.33, 95% CI 0.14–0.74, P = 0.007]. None of the other variables were significant in the multivariable model. The results of the multivariable analysis did not change if the linear term of the propensity score was used instead of the quintiles.


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  		Table 4 Logistic regression models

 
As longer lasting episodes of AT/AF may be associated with more morbidity, we examined event-free survival from AT/AF episodes lasting ≥1 day and ≥7 days. At 1 year of follow-up, freedom from longer episodes of AT/AF tended to be higher in patients receiving statin therapy when compared with those not receiving statin therapy (Figure 3). At 1 year of follow-up, the total burden of AT/AF during follow-up in patients receiving statin therapy was significantly lower than in those not receiving statin therapy (Mann–Whitney U test, P = 0.0059; Figure 4). This difference persisted over long-term follow-up.


Figure 3
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  		Figure 3 (A) Kaplan–Meier survival curves showing event-free survival from any episode of atrial tachycardia (AT)/atrial fibrillation (AF) lasting ≥1 day. Patients on a statin (solid line) tended to be less likely to experience AT/AF lasting ≥1 day during follow-up compared with patients not on a statin (dashed line; {chi}2 = 2.40, P = 0.13). (B) Kaplan–Meier survival curves showing event-free survival from any episode of AT/AF lasting ≥7days. Patients on a statin (solid line) were less likely to experience AT/AF ≥7days duration during follow-up compared with patients not on a statin (dashed line; {chi}2 = 3.89, P = 0.035).

 

Figure 4
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  		Figure 4 Boxplot showing atrial tachycardia (AT)/atrial fibrillation (AF) burden at 1 year in patients on a statin and those not on a statin. The horizontal solid line represents median data, the lower, and upper borders of the box represent the 25th and 75th percentiles, respectively; the bars indicate the range of the data. Patients on statin therapy had a significantly lower AT/AF burden (P = 0.0059).

 
Other drugs and atrial tachycardia/atrial fibrillation burden
At 1 year, AT/AF burden was not significantly different in patients on β-adrenergic-blocking agents (median 0.14 h/day) or not on β-adrenergic blocking agents (median 0.27 h/day, P = 0.93), in patients on Class I/III antiarrhythmic drugs (median 0.35 h/day) or not on Class I/III antiarrhythmic drugs (median 0.10 h/day, P = 0.33), patients on amiodarone (median 0.26 h/day) or not on amiodarone (0.16 h/day, P = 0.56) and in patients on ACE-inhibitors/ARB drugs (median 0.16 h/day) or not on ACE-inhibitors/ARB drugs (0.28 h/day, P = 0.64).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 Acknowledgements
 References
 
The major findings of the present study are: (i) AT/AF recurrences are common after pacemaker implantation for symptomatic bradycardia in patients with a prior history of paroxysmal AF but the progression to permanent AF is small; (ii) use of statin therapy was associated with a significant reduction in the probability of AT/AF recurrence and with a significantly lower overall burden of AT/AF.

Statins for prevention of atrial fibrillation
A number of studies has reported that statin use may prevent AF. One retrospective study reported that statin use was associated with a reduced prevalence of AF.5 Other studies have reported that statin use was associated with a significant reduction in the incidence of perioperative AF following thoracic or coronary artery bypass surgery.6,7 Statin use has been reported to prevent recurrence of AF following electrical cardioversion.8 This has been confirmed in one prospective trial of atorvastatin compared with placebo9 but not in a small, randomized, prospective study of pravastatin.27 More recently, Hanna et al.10 reported that lipid-lowering therapy in a large cohort of over 25 000 patients with LV dysfunction was associated with a significant reduction in the prevalence of AF. In the present study of patients receiving a pacemaker for bradycardia and paroxysmal AF, we have demonstrated that statin use is associated with a low burden of AT/AF which persists over long-term follow-up.

Statins may prevent AF through anti-inflammatory and/or antioxidant effects.14–19 C-reactive protein, a biomarker of inflammation, has been reported to be elevated in some patients with AF.14,15 However, in the case of perioperative AF, the beneficial effect of statins for suppression of AF was observed to be independent of changes in inflammation markers.6 Oxidative stress injury may contribute to the electrophysiological and structural remodelling that occurs in AF.15–18 Although statins have antioxidant effects, some, but not all, antioxidants have been reported to prevent AF.16,19 The exact mechanism(s) by which statins are antiarrhythmic requires further study.

Previous reports have suggested that ACE-inhibitors prevent the development of AF in patients with LV dysfunction.11,12 As well, the ARB, irbesartan, has been reported to reduce AF recurrence when used in combination with amiodarone.13 Hanna et al.10 reported that the use of lipid-lowering therapy (predominantly statin therapy) for prevention of AF was significantly greater than the effect of ACE-inhibitors or ARB agents. In the present study population, the majority of which had sinus node dysfunction and preserved LV function, neither ACE-inhibitors nor ARB drugs were associated with a lower probability of AT/AF recurrences. Healey et al.12 reported that the benefit of ACE-inhibition/ARB agents for prevention of AF was observed predominantly in those with LV systolic dysfunction or hypertrophy. Thus, the absence of significant systolic dysfunction in the majority of the study population may explain the absence of the benefit of ACE-inhibitors/ARB agents for prevention of AF. The majority of patients in this study were not on β-blockers. Higher utilization of β-blocker therapy, particularly carvedilol, might have been beneficial for prevention of AF in those with heart failure. One study suggests that β-blockers may not have such an effect in the elderly28 and the average age in the present study was over 70 years. Although AF is frequently associated with structural heart disease and systolic dysfunction, the majority of patients in the study either had primary electrical disease (sinus node dysfunction) or hypertension with normal systolic function as the underlying aetiology of paroxysmal AT/AF.

Progression of atrial tachycardia/atrial fibrillation over time
We previously reported that the burden of AT/AF progresses over time in the pacemaker population with sinus node disease.1 In the present study, the progression to persistent AF (7% at 3 years) was lower than that we reported previously (11% over 2 years in patients with sinus node disease). Overall, AT/AF burden remained <30 min/day in 58% of the study population at 3 years. Other investigators have reported a higher rate of progression to permanent AF. The differences in the rates of progression to permanent AF reported in different studies may reflect a number of factors including the burden of AF at baseline, more widespread use of cardiovascular drugs that modify AF recurrence including statins, ACE-inhibitors, and ARB agents as well as programming pacemakers to minimize ventricular pacing.29 The pacemaker technology employed in the present study lacked pacing algorithms to minimize ventricular pacing. In AT 501, the AV interval shortens during rate adaptation which may have increased the percentage of ventricular pacing. Whether antiarrhythmic effects of statins, ACE-inhibitors, ARB agents, or β-blockers would be increased or mitigated by minimizing ventricular pacing is unknown.

Our previous study was limited by the amount of data that could be stored in earlier generations of pacemakers. A strength of the present study is that the daily burden of AT/AF could be tracked over time and retrieved from the pacemaker diagnostics. Other studies have reported that atrial or dual-chamber pacing reduces or prevents AF recurrence compared with ventricular pacing.4 The dominant data analysis used in these previous studies was electrocardiographically documented AF. As many episodes of AT/AF are asymptomatic and also because not all episodes of AF will be detected by intermittent electrocardiography monitoring,30 the use of the pacemaker diagnostics to detect all episodes of AT/AF represents a significant advantage.

Study limitations
This was a prospective observational study. Patients were not randomized to statin therapy and the specific statins used and their dosages varied. The current analysis was based on statin use during follow-up and statin use changed over time in some patients. It is possible that the substrate and triggers for AT/AF and other unmeasured variables in the patient population receiving statin therapy differed from those not receiving statin therapy, making the expected recurrence of AT/AF probabilities different between the two groups. Finally, the present study population is unique consisting predominantly of patients with sinus node disease and normal ventricular systolic function. The association between statin use and AF recurrence may not apply to patients with systolic dysfunction and AF. The observations of the present study serve to generate the hypothesis that statins prevent AF in patients with sinus node disease.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 Acknowledgements
 References
 
Following dual-chamber pacemaker implantation in patients with bradycardia and a prior history of paroxysmal AF, the use of statin therapy was associated with AT/AF suppression. Randomized clinical trials are warranted to test the hypothesis that statins prevent AF in patient populations at risk of AF.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
Acknowledgements
 References
 
This study is supported by Canadian Institutes for Health Research and Heart and Stroke Foundation of Alberta.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
References
 
A.M.G. and H.J.D. are Medical Scientists and D.V.E. is a Scholar of the Alberta Heritage Foundation for Medical Research.

Conflict of interest: A.M.G. is a consultant to Medtronic Inc, has received speakers honoraria from Medtronic Inc and research support from Medtronic Inc. D.V.E. has received speakers honoraria from Medtronic Inc, St Jude and research funding from Medtronic Inc and St Jude. L.B.M. has received speakers honoraria from Medtronic Inc. D.G.W. is a member of a Medtronic Inc Advisory Panel. The Arrhythmia Program in the Calgary Health region has received fellowship support from Medtronic Canada and St Jude Canada.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgements
 References
 

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