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European Heart Journal Advance Access originally published online on August 30, 2009
European Heart Journal
2009 30(19):2327-2336; doi:10.1093/eurheartj/ehp357
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial

Aldo P. Maggioni1,*, Gianna Fabbri1, Donata Lucci1, Roberto Marchioli2, Maria Grazia Franzosi3, Roberto Latini3, Gian Luigi Nicolosi4, Maurizio Porcu5, Franco Cosmi6, Severo Stefanelli7, Gianni Tognoni2, Luigi Tavazzi8 and on behalf of the GISSI-HF Investigators{dagger}

1 GISSI-HF Coordinating Center, ANMCO Research Center, Via La Marmora, 34, 50121 Florence, Italy
2 Consorzio Mario Negri Sud, S Maria Imbaro, Italy
3 Istituto Mario Negri, Milano, Italy
4 Cardiology Unit, AO S Maria Angeli, Pordenone, Italy
5 Cardiology Unit, AO Brotzu-S Michele, Cagliari, Italy
6 Cardiology Unit, Ospedale Valdichiana Santa Margherita, Cortona, Italy
7 Cardiology Unit, Ospedale Ave Gratia Plena, San Felice a Cancello, Italy
8 GVM Hospitals of Care and Research, Cotignola, Italy

Received 23 July 2009; revised 5 August 2009; accepted 12 August 2009; online publish-ahead-of-print 30 August 2009.

* Corresponding author. Tel: +39 055 5101361, Fax: +39 055 5101310, Email: maggioni{at}anmco.it

See page 2302 for the commentary on this article (doi:10.1093/eurheartj/ehp362)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Aims: This ancillary analysis of the GISSI-HF database aims at assessing the effect of rosuvastatin on the occurrence of atrial fibrillation (AF) in patients with chronic heart failure (HF) who were not in AF at study entry.

Methods and results: GISSI-HF was a double-blind, placebo-controlled trial testing n-3 PUFA and rosuvastatin vs. corresponding placebos in patients with chronic HF. Atrial fibrillation occurrence was defined as the presence of AF in the electrocardiogram (ECG) performed at each visit during the trial or AF as a cause of worsening HF or hospital admission or as an event during hospitalization. Among the 3690 patients (80.7%) without AF on their baseline ECG, 15.0% developed AF during a median follow-up period of 3.7 years, 258 randomized to rosuvastatin (13.9%) vs. 294 allocated to placebo (16.0%). Although the difference was not significant at unadjusted analysis (P = 0.097) and multivariable analysis adjusting for clinical variables (P = 0.067), it became significant after adjustment for clinical variables and laboratory examinations (P = 0.039), and for clinical variables, laboratory examinations, and background therapies (P = 0.038).

Conclusion: This study shows that there is some evidence of a beneficial effect of rosuvastatin in terms of reduction of AF occurrence in patients with HF. Larger populations are needed to provide a definite answer to the question.

ClinicalTrials.gov Identifier: NCT00336336 [ClinicalTrials.gov]

Key Words: Atrial fibrillation • Heart failure • Rosuvastatin


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Atrial fibrillation (AF) is the most frequent form of arrhythmia in clinical practice, affecting 6% of people aged >65 years.1 A report from the EuroHeart Failure Survey I found that nearly one out of four patients with heart failure (HF) has AF.2

The traditional therapies, with antiarrhythmic drugs and/or cardioversion, are often able to restore the sinus rhythm but relapses are very frequent in particular when AF has been present for a long time and there are structural changes at both atrial and ventricular levels.3–8 Further, AF in the setting of HF or left ventricular hypertrophy is associated with marked atrial dilatation and increased fibrosis.9 The result is that AF may become resistant to antiarrhythmic drugs.

Although AF is a recognized precipitating factor of acute HF, whether it is an independent predictor of an increased risk of death in chronic HF patients remains controversial being some studies supporting this conclusion,10–12 whereas others show no independent effect.13,14 Irrespective of its prognostic role, the development of AF is clearly undesirable in HF, and treatments that may prevent it are theoretically interesting.15

The use of statins had been suggested to protect against AF in some experimental studies.16 Observational studies provided evidence supporting a protective role of statins in terms of prevention of AF.16–18 However, insufficient data are available at this time to allow recommendations for prevention of AF with statins in patients with HF.

In the GISSI-HF study, the effect of rosuvastatin (10 mg daily) compared with placebo was evaluated in patients with chronic HF.19 In the present report, we have analysed the effect of rosuvastatin on the incidence of new AF in the population of patients who were not in AF at the time of randomization.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Study population
The design and main results of the GISSI-HF trial have been previously described in detail.19–21

For the purpose of this analysis, the essential information can be summarized as follows. A total of 4574 patients were recruited by a national network involving 325 cardiology and 31 internal medicine centres across Italy. Men and women aged 18 years or older, with clinical evidence of HF of any cause classified according to the New York Heart Association (NYHA) class II–IV and with left ventricular ejection fraction (LVEF) measured within 3 months before enrolment, were randomly allocated to treatment with rosuvastatin (2285) 10 mg daily or placebo (2289). If LVEF was >40%, the patient had to have been admitted at least once to hospital for HF in the preceding year. Clinical visits were planned at 1, 3, 6, and 12 months and then every 6 months until the end of the trial. The institutional review committee at each participating centre approved the study, and all patients gave informed consent.

Regardless of their allocation, all patients who received the same strategies of care, including lifestyle recommendations and up-to-date interventions for chronic HF (e.g. angiotensin-converting enzyme inhibitors, beta-blockers, diuretic drugs, digitalis, and spironolactone), were recommended. As reported previously,19 rosuvastatin treatment did not affect the two co-primary endpoints of the study, all-cause death and the combined endpoint of all-cause death or hospitalizations for cardiovascular reasons.

Electrocardiogram examination was performed in each patient during each planned clinical visit. Atrial fibrillation was identified when rapid oscillations or fibrillatory waves, varying in size, shape, and timing and associated with an irregular ventricular response, were detected at the 12-lead electrocardiogram (ECG) as reported by the clinical investigator.

Definition of atrial fibrillation occurrence during the study
To evaluate the rate of occurrence of AF during the course of the study, we excluded from the analysis the patients with AF at the baseline ECG (Figure 1). Atrial fibrillation occurrence during the trial was defined as follows: the presence of AF in the ECGs performed at each visit during the trial or AF as a cause of worsening HF or of hospital admission or AF as an event occurring during a hospital admission.


Figure 1
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  		Figure 1 Patients' disposition.

 
Statistical analysis
Analyses were intention-to-treat. The differences in the baseline characteristics of patients between randomized groups and of patients with and without AF during the trial were compared by the {chi}2 test for categorical variables and by the t-test or Mann–Whitney U test for continuous variables. Plots of the Kaplan–Meier estimates of the curves of AF occurrence have been presented along with the results of the log-rank tests. To estimate treatment effect, the Cox proportional hazards models were used in patients without AF at baseline, taking into account the effect of potential baseline confounding variables. Linearity of the continuous variables was tested by piecewise polynomials (the restricted cubic spline) to represent the relationship between the predictor and the response in a Cox model where each single variable was introduced alone in the model. The plots of the log-relative-hazard of the continuous variables were visually inspected in order to identify reasonable cut-off values. Left ventricular ejection fraction, heart rate, QRS duration, white cell count, sodium, and estimated glomerular filtration rate (eGFR) had a significant non-linear relationship with the log-relative-hazard of the development of AF. As a consequence, these variables were included in the models using cut-offs suggested by the relative plot. Different Cox's proportional models were fitted: (i) adjusted for clinical variables, (ii) adjusted for clinical variables and laboratory examinations, and (iii) adjusted for clinical variables, laboratory examinations, and background therapy.

Changes over time (6 months from baseline) of LDL cholesterol in patients with/without AF were evaluated by analysis of covariance, controlling for their baseline value separately in rosuvastatin and in placebo. All probability values are two-sided and confidence intervals (CI) are 95%. Data were analysed using the SAS statistical package (SAS Institute Inc.) and R statistical packages.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
Among the 4574 patients randomized to rosuvastatin or placebo, 884 (19.3%) had AF reported on the baseline ECG and were excluded from the analysis. Therefore, this evaluation focuses on 3690 patients without AF on the baseline ECG, 1855 randomized to rosuvastatin, and 1835 to placebo (Figure 1).

Table 1 shows the baseline characteristics of these patients according to randomized treatments, including details of background medical treatment. Mean age was 67 (SD 11) years, and 1484 (40%) patients were older than 70 years. Eight hundred and twenty-three (22%) patients were women. The aetiology of HF was ischaemic in 1555 (42%) patients. Mean LVEF was 32.6% (SD 8.2). Background treatment included a blocker of the renin–angiotensin–aldosterone system in 3465 (94%) of the patients, a beta-blocker in 2384 (65%), and spironolactone in 1462 (40%) (Table 1). No statistically significant differences were observed between the patients randomized to rosuvastatin or placebo with the exception of the baseline NYHA class, of the left ventricular hypertrophy at the ECG, and of haemoglobin.


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  		Table 1 Baseline characteristics of patients

 
The effect of rosuvastatin in terms of all-cause death fully mirrored the data observed in the total population of the trial: rosuvastatin 26.9% vs. placebo 25.7% (P = 0.37).

Baseline characteristics of patients who developed atrial fibrillation
A total of 552 patients (15.0%) were reported to have experienced at least one episode of AF during the median 3.7 [inter-quartile range (IQR) 2.2–4.4] years of follow-up (mean follow-up period 3.2 ± 1.5 years). The baseline characteristics of the study population divided between those who developed AF during the course of the study and those who did not are presented in Table 2.


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  		Table 2 Baseline characteristics of patients developing atrial fibrillation during the course of GISSI-HF

 
The patients who developed AF during the course of the GISSI-HF trial were older, with higher baseline systolic blood pressure, mean ejection fraction, body mass index, and, more often, with a history of hypertension and chronic obstructive pulmonary disease. As expected, a story of paroxysmal AF was significantly more frequent in patients in whom AF occurred during the trial. They also had more severe HF, as shown by a higher NYHA functional class, more frequent mitral insufficiency and hospital admissions for HF in the year preceding study enrolment. Patients who developed AF showed less frequently at the baseline ECG left ventricular hypertrophy. Patients with AF had higher bilirubin and fibrinogen, whereas eGFR, total cholesterol, and LDL cholesterol were lower. Diuretics, amiodarone, and anticoagulants were prescribed more frequently at baseline in patients who showed AF during the course of the trial, whereas in the No-AF group, more patients were treated with aspirin and beta-blockers.

Effects of rosuvastatin on atrial fibrillation occurrence
Among the 552 patients (15.0%) developing AF during the course of the study, 258 belonged to the group of 1855 patients randomized to rosuvastatin (13.9%) vs. 294 of the 1835 allocated to placebo (16.0%). Figure 2 shows the Kaplan–Meier curves for AF development stratified by study treatments. Curves started to diverge early and continued to diverge over the whole period of the study, showing a weak evidence of reduction of AF occurrence in the rosuvastatin group.


Figure 2
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  		Figure 2 Kaplan–Meier curves for time to new onset of atrial fibrillation.

 
The difference did not reach the conventional level of statistical significance at unadjusted analysis (P = 0.097) and multivariable analysis adjusted for clinical variables (P = 0.067) (Table 3, Model 1). The decrease in AF occurrence in the patients of the rosuvastatin group reached the conventional level of statistical significance after the adjustments for clinical variables and laboratory examinations (P = 0.039) (Table 3, Model 2), and for clinical variables, laboratory examinations, and background pharmacological therapy (P = 0.038) (Table 3, Model 3).


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  		Table 3 Effects of rosuvastatin on the occurrence of atrial fibrillation: unadjusted and multivariable analyses

 
The reduction of AF occurrence observed in the rosuvastatin group was similar in all analysed subgroups, with no evidence of heterogeneity of a treatment effect (Table 4). Specifically, the effect of rosuvastatin was similar irrespective of age, aetiology, history of prior paroxysmal AF, history of diabetes, NYHA class, level of LVEF, total cholesterol at baseline, and renal function.


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  		Table 4 Pre-defined subgroup analysis: time to new onset of atrial fibrillation

 
By the end of the study, 626 (34%) patients allocated to rosuvastatin and 660 (36%) allocated to placebo were no longer taking study drug for various reasons (P = 0.16). Of the patients who discontinued study treatment, 8 (0.4%) of the rosuvastatin group and 20 (1.1%) of the placebo group started an open-label statin treatment. In the per-protocol analysis of the 2309 fully compliant patients, who had taken experimental treatments for at least 80% of the time of observation and had no major protocol violations, the occurrence of AF was 12.3% (146 of 1187) in the rosuvastatin group and 14.6% (164 of 1122) in the placebo group [hazard ratio (HR) 0.85 (95% CI 0.67–1.06), P = 0.138]. Also in this per-protocol analysis, the decrease in the incidence of AF was statistically significant only after adjustment for clinical variables and laboratory examinations [HR 0.775 (95% CI 0.606–0.991), P = 0.042], and for clinical variables, laboratory examinations, and background pharmacological therapy [HR 0.765 (95% CI 0.597–0.981), P = 0.034].

Effects of rosuvastatin on low-density lipoprotein cholesterol and C-reactive protein
In the 1855 patients of the rosuvastatin group, concentrations of LDL cholesterol decreased from 122 mg/dL at baseline to 83 mg/dL after 1 year (–32%) and 89 mg/dL after 3 years (–27%). No significant change was noted in the 1835 patients of the placebo group, in which concentrations were 121 mg/dL at baseline, 130 mg/dL after 1 year, and 118 mg/dL after 3 years (interaction time vs. treatment, P < 0.0001).

An exploratory analysis was performed to assess whether the modification over time of LDL cholesterol levels was associated with the protective effect in terms of AF prevention. Irrespective of the study treatment (rosuvastatin or placebo), patients with AF or without AF during the course of the study showed similar reduction of LDL cholesterol. From baseline to 6 months after study entry, the median decrease in patients with AF was 10 mg/dL (IQR –39/+14) and in those without AF 13 mg/dL (IQR –47/+14), P = 0.17.

In a subgroup of 626 patients in whom we assayed high-sensitivity C-reactive protein, rosuvastatin lowered high-sensitivity C-reactive protein over 3 months by a median of 0.45 mg/L from a baseline of 2.71 mg/L (–17%), which was significantly different from the decrease of 0.10 mg/L from a baseline of 2.17 mg/L (–4%) that we noted in the placebo group (analysis of variance, P = 0.0195).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
The main findings of this ancillary analysis of the GISSI-HF database can be summarized as follows:

  1. the incidence of AF in patients with chronic HF treated according to the present evidence-based treatments remains relevantly high (15.0%);
  2. rosuvastatin treatment was associated with a decreased incidence of AF (13% relative risk reduction, 2.1% absolute risk reduction). The difference with respect to placebo reached the conventional level of statistical significance after adjustment for clinical variables, laboratory examinations, and background pharmacological therapy;
  3. the per-protocol analysis confirmed these findings;
  4. the results were homogeneous across the different subgroups, including patients with or without a history of previous episodes of AF.

Incidence of atrial fibrillation in patients with heart failure
The rate of occurrence of AF during the follow-up period of randomized clinical trials conducted in patients with HF is not always reported. In two recent trials testing angiotensin receptor blockers in patients with chronic HF, the incidence rate of AF in patients not showing AF at study entry was 6.5% over about 24 months of follow-up in the Val-HeFT trial22 and 6.1% over 37 months of follow-up in the CHARM trial.23 The higher rate of occurrence of AF observed in our study can be explained by the fact that AF occurrence was defined with a systematic assessment of the ECGs during the course of the study and both causes of hospitalization and reasons for worsening HF were centrally validated. In the Val-HeFT and CHARM trials, no systematic evaluation of the ECGs was performed, being AF occurrence defined when reported as an adverse event in Val-HeFT22 and with a specific case report form, but used just at the final or closing visit of the study in the CHARM trial.23 In an analysis of the SOLVD trial, conducted in a limited number of patients, AF episodes occurred in 14% of the cases during 3 years of follow-up,24 a rate of AF occurrence very similar to that observed in the present analysis. In this subanalysis of the SOLVD study, an intensive and systematic ECG recording was performed. Considering that a relevant number of episodes of AF can occur without any symptom, the actual rate of AF occurrence in patients with HF is probably higher with respect to that shown in our and other studies, confirming that AF remains a frequent relevant problem in this clinical setting.

Effect of rosuvastatin on atrial fibrillation occurrence
Some observational studies had indicated that there was an association between statin use and lower risk of AF.25,26 Randomized trials comparing a statin vs. a control regimen reported inconclusive (and somewhat contradictory) findings.27–29 Two recent overviews of randomized trials assessed the effects of statin therapy on AF as a primary or secondary endpoint. One of them concluded that statins may reduce the risk of AF by 61% (95% CI 15/82),18 and the second showed a moderate non-statistically significant rate reduction (24%, 95% CI –5/+45).30 These meta-analyses were relatively small and included heterogeneous populations.

Several studies have also investigated the potential mechanisms by which statins might prevent AF. Inflammation seems to be involved in the development and recurrence of AF.31 Based mainly on the observation that AF is associated with raised C-reactive protein32 and that statins significantly lower C-reactive protein,33 it has been suggested that statins may prevent AF. Accordingly, in the subgroup of patients enrolled in our study in whom C-reactive protein was measured (and in other studies conducted with the same drug in patients with HF34), rosuvastatin significantly decreased C-reactive protein. This might explain the potential beneficial effect of statins against AF. However, we were not able to establish a clear relationship between the decrease in C-reactive protein with statin use and the benefit obtained against AF.

Since statins improve lipid profile, a protective role against AF development could be advocated through the anti-atherogenic properties of statins.16 Even if, in this study, the favourable effect of rosuvastatin has been observed in a context of a significant reduction of LDL cholesterol, patients with/without AF during follow-up showed a similar decrease in LDL cholesterol levels. Further, a greater favourable effect of rosuvastatin in terms of AF prevention was not observed in patients with HF due to an ischaemic aetiology, in whom an anti-atherogenic effect could have been more likely to be observed.

It has also been proposed that other observed effects of statins, such as their ability to improve endothelial function, to reduce oxidative stress, and to modulate the neurohumoral system, may have anti-arrhythmic effects specifically in patients with HF, in whom all these potential favourable mechanisms could be particularly relevant.35 These mechanisms were not specifically investigated in this ancillary analysis of the GISSI-HF trial.

Our study confirmed that patients with a history of prior AF have more frequently new episodes of AF over time. However, the subgroup analysis for the presence/absence of prior episodes of AF did not show any difference in terms of rosuvastatin effect, not supporting the finding that statins can be more effective in secondary than in primary prevention of AF.18

Limitations
Our study was not designed to test the effect of rosuvastatin on AF occurrence. Therefore, a specific search for AF episodes was not planned, in particular Holter or trans-telephonic monitoring was not performed in our patients. In this way, most cases of asymptomatic, paroxysmal AF could not be detected, relevantly reducing the likelihood of defining the actual rate of AF occurrence. For this reason, the definition of AF used in our analysis has a limited sensitivity. However, differently from other studies,22,23 a systematic collection of electrocardiographic findings was foreseen by the GISSI-HF study protocol allowing the detection of a relevant number of AF episodes. This methodological approach together with the relatively long follow-up duration should have increased the reliability of the evaluation of the effects of the tested drug.

In the present analysis, different models were tested to assess the influence of treatment on recurrence of AF and different results have been obtained. Treatment effect was always not significant in Model 1 and significant in Models 2 and 3 only when LDL was added to the list of the independent variables. In all models, the P-values associated with treatment effect were <0.1 and close to the significant level P = 0.05. The progressively increasing divergence of the Kaplan–Meier curves and the weak evidence of benefit observed in the described statistical models suggest a possible role of rosuvastatin in the prevention of AF, but additional specific studies are required to get definite conclusions.

Conclusion and clinical implications
In patients with chronic HF, the presence of AF and new onset of AF are common complications which could have important clinical implications. In this setting of patients treated with an optimized, updated pharmacological therapy, our ancillary analysis showed that rosuvastatin might be superior to placebo in terms of reduction of AF occurrence.

However, considering the neutral effects of rosuvastatin on mortality,19,34 atherothrombotic events,19,34 and cardiovascular hospitalizations19 in patients with HF, in our view, some evidence of a weak favourable effect in the prevention of AF occurrence shown by this post hoc analysis of the GISSI-HF trial should not lead to a specific recommendation of prescription of statins to patients with HF. The effect of a statin treatment conducted for a longer period of time or in a larger population of patients should be evaluated to confirm the findings of our study.

The reported results do not challenge the use of statins in all the cardiovascular disorders for which they are strongly recommended.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
The study was planned, conducted, and analysed by the GISSI group which has full ownership of the data, in complete independence from AstraZeneca that concurred to fund the study. AstraZeneca also provided the experimental treatment.

GISSI is endorsed by Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Firenze, Italy; by Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; and by Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

Conflict of interest: L.T., G.T., A.P.M., R.M., G.F., and M.G.F. received research support and honoraria for lectures from AstraZeneca. R.L. and D.L. received research support from AstraZeneca. G.L.N. and M.P. received honoraria for lectures from AstraZeneca. F.C. and S.S. declare that they have no conflict of interest.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
The most important acknowledgement is to the participants in the study and to the cardiologists, nurses, ethical committees, and administrative staff in hospitals who assisted with its conduct.

All members of the Steering and Writing Committees had full access to the database. All members reviewed the paper and unanimously agreed to submit it to the European Heart Journal.


   Footnotes
 
{dagger} The complete list of the GISSI-HF Investigators has been already published as Appendix of refs 19 and 21. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 

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Primary prevention of atrial fibrillation by statins: still unresolved?
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Primary prevention of atrial fibrillation by statins: still unresolved?
Eur. Heart J., October 1, 2009; 30(19): 2302 - 2303.
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