WASHINGTON – New onset atrial fibrillation more than doubled the rate of adverse outcomes in patients with heart failure with reduced ejection fraction in a review of more than 15,000 such patients.

In 9,934 patients with heart failure with reduced ejection fraction (HFrEF) and no history of atrial fibrillation (AF), development of new-onset AF was linked with a greater than twofold increased risk of cardiovascular disease death or hospitalization for heart failure during follow-up, compared with HFrEF patients who did not initially have or later develop heart failure, after adjustment for several demographic and clinical variables, John J.V. McMurray, MD, said at the annual meeting of the American College of Cardiology. This difference for the primary endpoint of his analysis was statistically significant.

The HFrEF patients with incident AF also had a greater than twofold increased rate of all-cause death and of stroke compared with HFrEF patients without preexisting or incident AF, said Dr. McMurray, professor of medical cardiology at the University of Glasgow, Scotland. He characterized the HFrEF patients who develop new-onset AF as a “remarkably high-risk group,” and that this was his study’s “most surprising finding.”

The 1,645 patients with paroxysmal AF at the start of their follow-up also had a significantly increased rate of cardiovascular death or heart failure hospitalization, but their increased risk when compared with HFrEF patients who didn’t develop AF was a much more modest 20% in his fully adjusted analysis. The patients who began follow-up with paroxysmal AF also had a relatively increased relative stroke rate of 33% when compared with HFrEF patients without AF at baseline who remained AF free, but the all-cause mortality rate among those with paroxysmal AF wasn’t significantly elevated, compared with the comparator group.

The 3,770 patients with persistent or permanent AF at baseline showed no statistically significant spike in their adverse event rates, compared with patients without AF, for any of the examined endpoints. The study group also included 66 patients with an undefined form of AF who weren’t included in these analyses.

“It’s the first episodes and paroxysmal episodes that cause trouble, and the trouble they cause is stroke,” Dr. McMurray said in an interview. Their stroke risk gets exacerbated in clinical practice, because these patients often don’t receive the stroke prevention they need in the form of anticoagulation treatment.

“We find over and over that patients with paroxysmal AF are not anticoagulated as frequently as they should be,” Dr. McMurray said. And HFrEF patients with a first AF episode need anticoagulation, too, as soon as AF is diagnosed, he advised.

He went a step further and speculated that the reason why HFrEF patients with new onset AF did so poorly in his analysis was because they already had several prior, brief AF episodes that had gone undetected. “Many of these patients probably had undiagnosed, clinically unapparent AF episodes” that then resulted in strokes, he suggested.

The upshot is that patients with HFrEF may need more aggressive monitoring for new-onset AF, possibly in the form of small, implanted arrhythmia-detection devices. Dr. McMurray said that he and other researchers are currently testing whether this hypothesis is correct. “We and others are now looking at this because these new data are convincing that new-onset AF is bad news [for HFrEF patients].”

In the analysis, “we looked only at clinically recognized and adjudicated new-onset AF. Goodness knows how many HFrEF patients are having unrecognized paroxysmal AF. Almost certainly there is a lot that is unrecognized” that potentially could be detected using a small implanted arrhythmia monitor, which could then lead to earlier anticoagulant treatment as well as possible treatment with antiarrhythmic drugs or with catheter ablation, Dr. McMurray said. Looking for undetected AF in HFrEF patients “is where the science is moving.”

A potentially important clue from his analysis is that the baseline blood level of N-terminal pro brain natriuretic peptide (NT-proBNP) averaged 1,535 pg/mL among patients who later developed new onset AF, compared with an average baseline level of 1,037 pg/mL among patients who never developed AF. The relatively higher blood level of NT-proBNP among the patients who later had incident AF more closely matched the levels of patients who had persistent of permanent AF at baseline, who averaged a NT-proBNP level of 1,631 pg/mL. This pattern suggests that implanted monitoring for new-onset AF could possibly focus on the subgroup of HFrEF patients without diagnosed AF but with a high NT-proBNP level, Dr. McMurray suggested. But he cautioned that this hypothesis requires testing before introducing this approach into practice.

The findings that Dr. McMurray reported are “something we should act on,” commented Adrian F. Hernandez, MD, professor of medicine and a cardiologist at Duke University in Durham, N.C. The comorbidity of AF in HFrEF patients requires “aggressive anticoagulation, and also a review of their heart failure medical treatment to be sure that is optimized, because AF could be a sign of worsening heart failure,” Dr. Hernandez said in an interview. “We may need to more aggressively get HFrEF patients with AF into normal sinus rhythm.”

When Mikhail Kosiborod, MD, treats HFrEF patients with a high risk for AF, such as patients with lower ejection fractions, a dilated left ventricle, or a dilated atrium, “I frequently do 30-day loop recordings in these patients because of their risk for incident AF,” Dr. Kosiborod said in an interview. “We don’t yet have convincing evidence for this, but it makes sense.”

The analysis that Dr. McMurray presented used data collected from two recent drug-treatment trials in HFrEF patients, PARADIGM-HF and ATMOSPHERE, a total group of 15,415 HFrEF patients. The median duration of follow-up was 27 months in PARADIGM-HF and almost 37 months in ATMOSPHERE.

Another finding from his analysis was that the HFrEF patients enrolled in these two trials did not get treatment with a mineralocorticoid receptor antagonist – spironolactone or eplerenone – “as often as they should,” with treatment rates of 44%-48%, compared with use of a beta-blocker in 92%-95% of patients. Treatment with eplerenone (Inspra) “has been shown to reduce the risk for new onset AF, so adding eplerenone or spironolactone is an important step that could be taken to try to prevent AF as well as treat the HFrEF and reduce mortality,” Dr. McMurray said.

PARADIGM-HF and ATMOSPHERE were funded by Novartis. Dr. McMurray has been a consultant to and has received travel and research support from Novartis, and he has received research and travel support from Amgen. Dr. Hernandez has received honoraria from Amgen, AstraZeneca, Janssen, Merck, and Novartis, and has received research support from Amgen, Bayer, Merck, and Portola. Dr. Kosiborod has been a consultant to several drug companies, and he has received research funding from AstraZeneca, Boehringer Ingelheim, Gilead, and Sanofi-Aventis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

New-onset AF boosts bad HFrEF outcomes