Aldosterone Antagonist in HF Cuts Risk of New Atrial Fib

May 24, 2011

May 23, 2011 (Gothenburg, Sweden) — Aldosterone antagonist therapy in the EMPHASIS-HF trial, previously reported to significantly cut the risk of clinical events in patients with mild systolic heart failure, apparently also suppressed development of new atrial fibrillation (AF) or atrial flutter (AFL) in many patients.

In the trial's two-year average follow-up, the rate of new AF/AFL was 42% lower (p=0.034) among patients who received eplerenone (Inspra, Pfizer), compared with placebo, on top of standard HF medications, investigators reported here at the Heart Failure Congress 2010 sessions of the European Society of Cardiology Heart Failure Association.

Moreover, in the analysis, "the effects of eplerenone on the risk of major cardiovascular events were similar in patients with and without atrial fibrillation or flutter at baseline," said Dr Karl Swedberg (University of Gothenburg, Sweden) when presenting the results. Nor did baseline AF/AFL seem to increase the risk of "most major study outcomes," including the study's primary end point of cardiovascular death or heart-failure hospitalization.

EMPHASIS-HF had randomized 2737 patients in NYHA class 2 heart failure and an LVEF <30%, or 30% to 35% if the QRS exceeded 130 ms, to receive eplerenone or placebo on top of standard therapy [1]; as previously reported by heartwire , it was halted after a mean follow-up of 21 months after the emergence of a significant benefit in the eplerenone group.

At that point, the actively treated patients showed a 37% reduction in the primary end point (p<0.001), 24% reduction in cardiovascular death (p=0.01), and a 42% reduction in hospitalization for heart failure (p<0.001).

The current analysis of the effect of baseline and incident AF/AFL in EMPHASIS-HF was prospectively documented on specially designed case record forms; AF/AFL was considered present if apparent from any of the ECGs, heart-failure etiology reports, or medical history, according to Swedberg. At baseline, AF/AFL was absent in 1794 patients (65%) and present in 943 patients (35%).

Among those without baseline AF/AFL, 2.7% of the 911 eplerenone recipients developed new AF/AFL compared with 4.5% of the 883 controls, for a hazard ratio of 0.58 (95% CI 0.35–0.96, p=0.034) in patients who received the aldosterone blocker. The analysis adjusted for age, renal function, body-mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, hypertension history, MI history, and left bundle-branch block or wide-QRS complex.

Eplerenone was about as effective for the primary end point in patients with or without baseline AF/AFL.

Hazard Ratios (HR) for Effect of Eplerenone vs Placebo on Outcomes by Baseline Presence or Absence of AF/AFL

End point Patients without AF/AFL, HR p Patients with AF/AFL, HR p
CV death/HF hospitalization 0.70 <0.001 0.60 <0.001
All-cause hospitalization 0.83 <0.03 0.70 <0.01
HF hospitalization 0.65 <0.001 0.56 <0.001
All-cause death/all-cause hospitalization 0.81 <0.01 0.70 <0.001
HF death/HF hospitalization 0.65 <0.001 0.56 <0.001

As the featured discussant for Swedberg's presentation, Dr Lars Ryden (Karolinska Institutet, Stockholm, Sweden) observed that the guidelines require ECG confirmation for a diagnosis of AF, while in EMPHASIS-HF, less specific findings were allowed to indicate a presence of AF. "I think perhaps if this is a prespecified end point, why not [use] more accurate diagnostic criteria? Or why not further attempts to record it more accurately" using ECG, as recommended in the guidelines?

Still, he said, he believes the trial should have an impact on future guidelines, which now recommend ACE inhibitors or angiotensin-receptor blockers for prevention of new-onset AF in systolic HF--"in the next version, perhaps aldosterone antagonists will be added."

EMPHASIS-HF was funded by Pfizer; Swedberg discloses serving as a consultant for and receiving grants or contracts from Pfizer. Ryden had no disclosures.