John Mandrola, MD


August 30, 2020

Researchers in atrial fibrillation (AF) focus mostly on paroxysmal and persistent AF. Permanent AF is largely ignored.

The reason is obvious: nonpermanent forms of AF may be treated with ablation. Procedures lead to profits. Where there are profits, there are research dollars. This is unfortunate because nearly half of all patients with AF have permanent AF.

A central question in the treatment of these patients is how best to control the ventricular response. We use three classes of drugs for rate control: β-blockers, calcium-channel blockers, and digoxin. There are no randomized controlled trials (RCTs) comparing these agents.

That is, until now. In a late-breaking presentation at the European Society of Cardiology (ESC) Congress 2020, Dipak Kotecha, PhD, from the University of Birmingham, reported the surprising results of the RATE-AF trial.


The trial compared bisoprolol to digoxin in older patients with permanent AF and breathlessness (New York Heart Association [NYHA] class 2 or higher). The primary endpoint was patient-reported quality of life at 6 months as measured by the physical component of the SF-36 questionnaire. This includes 10 questions on the degree of limitations for typical activities, such as climbing stairs, carrying groceries, and walking.

Key secondary endpoints included heart rate, N-terminal pro B-type natriuretic peptide (NTproBNP), left ventricular ejection fraction, other components of the SF-36, and adverse clinical events.

The mean age of the 160 patients in the trial was 76 years, and about half were women. Both groups had good adherence to the assigned drug. A few key results:

  • Heart rate responses were nearly identical in the two groups.

  • For the primary outcome at 6 months—physical functioning as reported by patients—there were no significant difference between digoxin and beta-blockers.

  • More than 50% of patients receiving digoxin compared with less than 10% on β-blockers improved more than two classes in the modified European Heart Rhythm Association (EHRA) symptom score (mEHRA for AF is similar to NYHA for heart failure and ranges from I to IV).

  • Over 6 to 12 months, improvement in NYHA class and NTproBNP level was significantly greater in the digoxin arm. Left ventricular ejection fraction remained unchanged in both arms.

  • While the trial was not powered for clinical events, there were fewer all-cause deaths (4 vs 7), cardiovascular deaths (3 vs 15), and adverse events (29 vs 142) in the digoxin arm.

The authors concluded that digoxin could be considered as a first-line approach for rate control for patients with permanent AF.

The Backstory on Digoxin and β-Blockers

These data stem from a 9-minute presentation. A complete critical appraisal requires a published peer-reviewed manuscript, which we don't have yet (one should be forthcoming).

But these are provocative and surprising findings given the backstory on digoxin.

First, digoxin has fallen from favor, largely because of observational studies that report associations between its use and increased mortality. I've defended digoxin on the grounds that the observational data are confounded by selection bias. A reanalysis of the placebo-controlled DIG trial strongly supports this notion.

Second, I, like many of my colleagues, favor β-blockers for rate control. This bias may stem from the favorable effects of β-blockers in patients with heart failure with reduced ejection fraction or myocardial infarction. But AF may mitigate these positive effects.

For instance, the principal investigator, Kotecha, was also first author on a patient-level meta-analysis of 10 RCTs of β-blockers vs placebo in heart failure that found β-blockers did not reduce mortality in patients who were in AF. The P value for interaction of .002 strongly suggested a heterogenous effect.

Third, I often wonder whether patients with AF are symptomatic because of the rhythm or because of the drugs we use to treat it. Adrenergic blockade comes with well-known side effects, although placebo-controlled data hint at a nocebo effect of β-blockers.  

Strengths and Cautions

The strengths of this trial are twofold:

It is a welcome addition in an evidence-free zone. Many days, nearly half the patients I see in clinic are older people with permanent AF who report breathlessness.

The results strongly favor digoxin. Surrogate measures (heart rate and BNP), clinical events (cardiovascular death and adverse events), and patient-reported outcomes all favored digoxin. Given the current fear of digoxin among U.S. clinicians, I was particularly struck by the substantially lower number of adverse effects.

But, as with any conference presentation, there is ample reason for caution:

I worry about the open-label nature of the trial. One of the ways placebo and nocebo effects can lead to clinical improvement or worsening is through social learning. Here, social lore holds that β-blockers cause side effects. In a trial with patient-reported outcomes, knowing your treatment assignment is problematic.

Digoxin may be unfairly villainized, but its use requires effort. Clinicians have to consider drug interactions, renal adjustments, and comorbidities and be vigilant about checking levels. In a trial, this is easy; in real-world practice, it is harder. The external validity of RATE-AF could be debated.

Another problem is that the investigators excluded calcium-channel blockers. In patients without substantial systolic impairment, calcium blockers are reasonable rate-controlling drugs. As a class of drugs, they don't carry the same social stigma of β-blockers. While I don't often prescribe calcium-channel blockers, RATE-AF would have been stronger with a third arm.

The baseline heart rate of included patients was about 100 beats/min. That is important. Many patients with permanent AF have higher rates. A person with a resting ventricular response of 140 to 150 beats/min is unlikely to be controlled on digoxin alone.


RATE-AF raises the possibility that digoxin may be superior to β-blockers in some patients with permanent AF. The trial makes me question my long-held practice. I love this part of clinical science.

The authors' conclusion might go too far. Upgrading digoxin to first-line therapy will require careful review of a published manuscript.

And, in a perfect world, RATE-AF would lead to more study. A confirmatory trial—with a calcium-channel-blocker arm—would be ideal.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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