RATE-AF Trial Boosts Digoxin for Rate Control in Permanent AF

Bruce Jancin

August 30, 2020

Digoxin now deserves to be considered first-line therapy for long-term heart rate control in older patients with permanent atrial fibrillation and symptoms of heart failure, investigators on a new study conclude.

Dipak Kotecha, MBChB, PhD, MSc, presented the 12-month results of the Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) trial at the virtual European Society of Cardiology (ESC) Congress 2020.

In the trial, 160 seniors, mean age 76 years, with moderate or severe symptoms due to permanent atrial fibrillation (AF) as well as heart failure symptoms were randomly assigned to low-dose digoxin or the β-blocker bisoprolol, for rate control.

The open-label trial was designed to address a centuries-old unmet need: "Although digoxin has been in use since 1785, we have no longer-term clinical trials of digoxin in patients with AFib or AFib with heart failure," noted Kotecha, professor of cardiology at the University of Birmingham, United Kingdom.

Not only is digoxin greatly understudied in AF, but permanent AF — the most common form of the arrhythmia — has received only a tiny fraction of the research attention that's been devoted to paroxysmal or persistent AF, he added.

In RATE-AF, digoxin and bisoprolol proved similarly effective at reducing heart rate, from about 100 beats/min at baseline to the mid-70s at 6 and 12 months. Notably, only a handful of study participants required an additional rate control drug during the 12-month study.

Nor did the two drugs differ in terms of their effect on patient-reported quality of life at 6 months, as reflected by their Short Form-36 (SF-36) Physical Component Score, the primary study endpoint. And both drugs were well tolerated, with 96% of patients in the digoxin group still receiving the drug at a mean of 161 µg/day at 6 months, and 89% still receiving their β-blocker.

But that's pretty much where the similarities in outcomes ended.

For example, at 12 months, the digoxin group scored significantly higher than the β-blocker group on several domains of the SF-36 Physical Component Score, including vitality, physical function, and global health.

More than half of the digoxin group had a two-class improvement in modified European Heart Rhythm Association AF-related symptoms at 6 months, compared with 10% of the β-blocker group. At 12 months, nearly 70% of the digoxin group had a two-class improvement, vs 30% of patients receiving bisoprolol.

Heart failure symptoms in the digoxin group improved from a mean baseline New York Heart Association (NYHA) class of 2.4 to 1.5 at both 6 and 12 months; the improvement was more modest in the β-blocker group, going from NYHA 2.4 at baseline to 2.0 at both 6 and 12 months.

And while N-terminal pro B-type natriuretic peptide (NTproBNP) levels improved in the digoxin group from a baseline of 1095 pg/mL to 1058 pg/mL at 6 months and 960 pg/mL at 12 months, NTproBNP actually went up in the β-blocker group, from 1041 to 1209 to 1250 pg/mL at 12 months.

Moreover, Kotecha said, although RATE-AF was underpowered to assess clinical events, it's nevertheless noteworthy that a total of 29 adverse events occurred in 12 months in the digoxin group, compared to 142 with β-blocker therapy. There were 12 unplanned hospital admissions in the digoxin group and 28 in the β-blocker group, and 22 primary care visits for either AF or cardiovascular symptoms in patients receiving digoxin, vs 64 in the β-blocker group.

"Our results suggest a wider use of digoxin for stable patients with permanent AFib," Kotecha concluded.

β-Blocker Still First-Line?

However, in an interview, Jonathan Piccini, MD, had a different take on the study results. "I don't think this study should widely impact clinical practice in the US," said Piccini, director of cardiac electrophysiology at Duke University, Durham, North Carolina.

His reservations included RATE-AF's modest sample size as well as uncertainty as to the trial's generalizability, given that bisoprolol isn't much used in the United States. Moreover, these were elderly patients with shortness of breath, and it's unclear how effective digoxin would be for rate control in patients with permanent AF who are more active.

"The classic teaching is that digoxin is great for rate control at rest, but when people are active it's not nearly as good as β-blockers or calcium-channel blockers," he said.

"A β-blocker is still going to be my first-line rate control agent. But the results of RATE-AF do open my mind that for an older sedentary patient I may very well think twice now about using digoxin, because in that situation it looks like it achieves similar goals as a β-blocker," Piccini added.

On the plus side for RATE-AF, he said, "I am very pleased to see that we have a randomized controlled trial focused on rate control in permanent AFib. It also tickles me pink to see a randomized controlled study of digoxin. And I'm really excited to see a clinical trial that focuses on quality of life. It should give some confidence to know that from a quality of life perspective clinicians can consider using either digoxin or a β-blocker for rate control."

American College of Cardiology Vice President Dipti Itchhaporia, MD, said she'd need to see a much larger randomized trial that included a calcium-channel blocker as a third rate-control arm before she'd consider digoxin as first-line rate-control therapy in patients with AF with or without heart failure. In addition, she has reservations about drawing definitive conclusions from an open, unblinded study in which patient-reported outcomes are the primary endpoint.

"I think these were surprising findings given what we all think about digoxin in this country. In general, digoxin fell out of favor for rate control, mainly because of observational studies showing increased mortality. So most of us choose a β-blocker," she said in an interview.

But, of course, a randomized trial, even a 160-patient randomized trial, constitutes a higher level of evidence.

"I don't think I'm going to convert tomorrow and make digoxin my first-line rate-control therapy without more data. But RATE-AF does makes me stop and think about using it more than I did before in some of my permanent AFib patients," said Itchhaporia, director of disease management at Hoag Memorial Hospital in Newport Beach, California.

The study was supported by the UK National Institute for Health Research, the British Heart Foundation, and the EU. Kotecha reported having no financial conflicts regarding the study.

European Society of Cardiology (ESC) Congress 2020. Presented August 30, 2020.

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