Expert Review: Arrhythmia, Heart Failure

Eplerenone and Atrial Fibrillation in Mild Systolic Heart Failure: Results From the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) Study

Background

Atrial fibrosis has been recognized as a pathophysiologic substrate for atrial fibrillation or flutter (AFF) occurrence. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been shown to reduce the incidence of atrial fibrillation in patients with heart failure (HF) in small prospective or retrospective studies.

Knowledge Gap

Aldosterone antagonists belong to another pharmacotherapy class that block the renin-angiotensin-aldosterone system axis. However, it is unclear if their use is associated with a reduction in AFF incidence especially in HF patient who are already treated with an ACE-inhibitor or ARB.

Aim of the Study

The present study investigated if the use of eplerenone is associated with a reduction of AFF in HF patients already treated with ACE-inhibitor or ARB and beta-blocker. Furthermore, the investigators assessed the effect of eplerenone in patients with and without AFF at baseline and the relationship between baseline AFF and subsequent events.

Methods

The present study hypothesis was a pre-specified secondary endpoint in the EMPHASIS-HF study. EMPHASIS-HF clinical trial was a prospective, randomized placebo-controlled clinical trial which assessed the efficacy and safety of eplerenone use in systolic HF patients (ejection fraction< 35%) with mild symptoms (New York Heart Association functional class II) who were already treated with the recommended or maximally tolerated dose of  an ACE inhibitor (or an ARB or both) and a beta-blocker (unless contraindicated). The present analysis included 1,794 patients who had no AFF at baseline and 934 patients with AFF at baseline.

Results

New onset AFF was significantly reduced by eplerenone and occurred in 25 of 911 eplerenone-treated patients (2.7%) versus 40 of 883 patients (4.5%) in the placebo group (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.35 to 0.96; p = 0.034). An adjusted analysis with co-variables reduced the magnitude of the effect slightly (HR: 0.713, 95% CI: 0.485 to 1.050; p = 0.087).The effect of eplerenone on the primary endpoint (cardiovascular mortality or hospitalization for HF) was similar among patients with and without AFF at baseline (HR: 0.60, 95% CI: 0.46 to 0.79 vs. HR: 0.70, 95% CI: 0.57 to 0.85, respectively; p for interaction = 0.411). The risk of the primary and secondary mortality and morbidity endpoints according to baseline AFF status (for both treatment groups combined) was not significantly higher in subjects with and without baseline AFF (HR: 1.13, 95% CI: 0.96 to 1.33; p = 0.152).

Conclusion

In patients with systolic HF and mild symptoms, addition of eplerenone to recommended therapy reduced the incidence of new onset AFF. The effects of eplerenone on the risk of major cardiovascular events were similar in patients with and without AFF at baseline.

Perspective-Clinical Impact

The present study showed that eplerenone use in patients with systolic HF and mild symptoms is associated with a reduction in the incidence of new onset AFF on top of ACE-inhibitors / ARBs and beta-blockers.

The magnitude of the observed effect was however marginally significant in adjusted analysis. From a clinical perspective, the prognostic importance of atrial fibrillation per se is unclear, as in the present analysis the authors could not find an independent prognostic risk for cardiovascular events or death by AFF over and above other risk factors in HF. Furthermore, the clinical benefit of eplerenone was also similar in patients with or without baseline AFF.

These additional findings minimize the clinical benefit from the observed additional effect of eplerenone regarding the incidence of AFF. Nevertheless, its occurrence in HF is commonly associated with symptom deterioration, and in addition increases the risk of stroke, necessitating treatment with anticoagulation with its associated inconvenience, cost, and bleeding hazard.

The present study is in addition inherent to certain limitations according to the authors. Firstly, the findings should not be implemented to all HF patients with mild symptoms since the specific study participants although with mild symptoms, were characterized by a severely reduced left ventricular ejection fraction, were relatively aged and had a previous hospitalization for HF. Secondly, no ambulatory monitoring for new AFF episodes was carried out therefore it is likely that the incidence of new onset AFF could have been underestimated.

Corresponding author from the original article:  Dr. Karl Swedberg, Department of Medicine, Sahlgrenska University Hospital/Östra, 41685 Göteborg, Sweden.

E-mail: Karl.swedberg@gu.se.

Citation: J Am Coll Cardiol 2012 59: 1598-1603.

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