Digoxin a 'Viable Alternative' in AF With HF: RATE-AF Published

Susan Jeffrey

December 23, 2020

A randomized trial shows no significant difference in the primary endpoint of quality of life at 6 months between treatment with digoxin vs the beta-blocker bisoprolol (Zebeta) in patients with atrial fibrillation (AF) and symptoms of heart failure (HF).

At 12 months, however, 8 of 20 secondary outcomes significantly favored digoxin, and adverse events were less common with digoxin than bisoprolol. 

"These findings support potentially basing decisions about treatment on other endpoints," the authors conclude.

Lead author Dipak Kotecha, MD, PhD, University of Birmingham, UK, previously presented results of the RATE-AF trial at the virtual European Society of Cardiology (ESC) Congress 2020. The findings are now published in the December 22/29 issue of the Journal of the American Medical Association.

AF is considered permanent when patients and physicians jointly decide not to pursue a plan to restore sinus rhythm, the researchers write. These patients accounted for 50% of patients with AF in a global registry reported in 2010, they note, "yet there is almost no robust evidence to support clinical decision making."

"Guidance is particularly needed for heart rate control in patients with AF and heart failure because inadequate heart rate control may worsen heart failure," the investigators warn, "and the combination of these conditions increases the risk of hospital admission and mortality."

These patients are generally treated with a beta-blocker, digoxin or a combination of the two, they note. Beta-blockers are more widely used "due to experience in cardiovascular conditions and in heart failure with reduced ejection fraction in particular because prognosis is improved in patients with sinus rhythm regardless of age or sex. However, this finding was not replicated in the subgroup of patients with AF."

Digoxin is "usually a second-line option due to neutral mortality effects" in randomized clinical trials of patients with heart failure, reduced left ventricular ejection fraction and sinus rhythm, they write. "Although there have been safety concerns from observational studies, digoxin is more commonly used in patients who have a greater comorbidity burden, require additional therapy, or are unable to tolerate beta-blockers; all factors associated with a higher risk of adverse events."

RATE-AF was a randomized, open-label, blinded end point trial including 160 patients recruited from three hospitals and primary care practices in England from 2016 through 2018. Eligible patients were 60 years or older with permanent AF, and dyspnea classified as New York Heart Association class II or higher.

They received either low-dose digoxin (dose range 62.5-250 μg/day; mean dose, 161 μg/day) or bisoprolol (dose range, 1.25-15 mg/day; mean dose, 3.2 mg/day) for heart rate control.  

The primary end point was patient-reported quality of life using the 36-item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months, with higher scores being better (range 0-100), with a minimal clinically important difference of 0.5 SD.

Seventeen secondary endpoints were assessed at 6 months, including resting heart rate, modified European Heart Rhythm Association (EHRA) symptom classification, and N-terminal pro-brain natriuretic peptide (NT-proBNP) level. There were 20 secondary endpoints assessed at 12 months. Adverse events (AE) were collected at each visit by asking patients if they had experienced any of the common AEs listed for each drug and via review of the medical record.

They found no significant difference between treatment groups on the primary outcome of normalized SF-36 PCS at 6 months, with a mean score of 31.9 for digoxin vs 29.7 for bisoprolol (adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8], P = .28).

Of the 17 secondary outcomes measured at 6 months, there was no significant difference between the groups on 16 of these, including resting heart rate (mean 76.9/min with digoxin vs 74.8/min for bisoprolol, P = .40).

Only the modified EHRA class was significantly different between the groups at 6 months, with 53% of patients on digoxin reporting a 2-class improvement vs 9% in the bisoprolol group (adjusted odds ratio 10.3; 95% CI, 4.0 - 26.6;, P < .001).

At 12 months, 8 of 20 outcomes now significantly favored digoxin, including NT-proBNP levels (median 960 pg/mL with digoxin vs 1250 pg/mL with bisoprolol; ratio of geometric means, 0.77; 95% CI, 0.64 - 0.92;, P = .005). The other 12 outcomes were "null," with no significant differences between treatments.

"Adverse events were less common with digoxin," the authors write; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). "There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group."

"The secondary endpoints should be considered exploratory and hypothesis generating," they caution.

"Viable Alternative"

In an accompanying editorial, Gregory Curfman, MD, deputy editor of JAMA, notes that this is the first randomized trial comparing low-dose digoxin with the beta-blocker bisoprolol for heart rate control in patients with permanent AF.

He points out that current clinical practice guidelines in both the US and Europe recommend beta-blockers or calcium channel blockers as first-line treatments. This new study "provides novel information on the use of digoxin for heart rate control in patients with atrial fibrillation."

"On the basis of these results, low-dose digoxin may be considered a viable alternative to beta-blockers to safely achieve heart rate control in patients with permanent AF," Curfman writes. "The relatively low dose of digoxin (mean, 161 μg/d) proved to be sufficient for heart rate control while avoiding the threat of digoxin toxicity."

Because this trial was small and open-label in design, he adds, "the results may not markedly change the current clinical practice guidelines for heart rate control in AF. Still, among patients with permanent AF who do not tolerate beta-blockers or calcium channel blockers, or who do not adequately respond to these drugs, digoxin may be useful to consider as a second-line agent."

Digitalis glycosides were first introduced into clinical use in 1785 by William Withering, a physician in Birmingham, England, Curfman writes.    

"A classic therapeutic intervention that had its beginnings over two centuries ago with the work of a physician in Birmingham has now been renewed by the work of a new generation of Birmingham physicians," he concludes. "With further research to confirm and extend the results of Kotecha et al, digitalis glycosides may once again find a valuable, albeit ancillary, place in the therapeutic armamentarium for treatment of patients with AF."

The RATE-AF trial was funded by the National Institute for Health Research as part of a career development fellowship awarded to Kotecha. The study was also supported by a British Heart Foundation accelerator award given to the University of Birmingham Institute of Cardiovascular Sciences. Kotecha reported receiving grants from the National Institute for Health Research, the British Heart Foundation, the European Union-European Federation of Pharma Industries and Associations Innovative Medicines Initiative BigData@Heart, the European Society of Cardiology (in collaboration with Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer Alliance, Bayer, Daiichi-Sankyo, and Boston Scientific), and the IRCCS San Raffaele/Menarini Research; and receiving personal fees from Bayer, AtriCure, Amomed, and Myokardia. Disclosures for coauthors appear in the paper. Curfman has disclosed no relevant financial relationships.

JAMA. Published online December 22, 2020. Abstract, Editorial

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