JAMA December 22, 2020

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial

Dipak Kotecha et al. (RATE-AF Team)

Bottom Line

In older patients with permanent atrial fibrillation and symptoms of heart failure, low-dose digoxin compared with bisoprolol resulted in no significant difference in quality of life at 6 months, but it was associated with significantly fewer adverse events and better functional improvements at 12 months.

Key Findings

1. Primary Outcome: There was no significant difference in the normalized SF-36 physical component summary score at 6 months between the digoxin and bisoprolol groups (mean, 31.9 vs 29.7; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P=0.28).

2. Adverse Events: Digoxin was associated with significantly fewer total adverse events (29 vs 142) and serious adverse events (16 vs 37) compared with bisoprolol. Only 25% of patients in the digoxin group experienced at least one adverse event, compared to 64% in the bisoprolol group (P<0.001).

3. Heart Rate Control: Both drugs effectively reduced resting heart rate from a baseline of approximately 100 bpm to the mid-70s at 12 months (mean 75.4 bpm for digoxin vs 74.3 bpm for bisoprolol), with no significant difference between the groups.

4. Secondary Endpoints: At 12 months, patients receiving digoxin demonstrated significantly greater reductions in NT-proBNP levels and more substantial improvements in modified European Heart Rhythm Association (EHRA) symptom class compared to those receiving bisoprolol.

Study Design

Design

RCT

Open-Label

Sample

160

Patients

Duration

12 mo

Median

Setting

Multicenter, UK

Population Patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association (NYHA) class II or higher.

Intervention Low-dose Digoxin (dose range, 62.5-250 μg/d; mean dose, 161 μg/d).

Comparator Bisoprolol (dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d).

Outcome Patient-reported quality of life assessed by the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months.

Study Limitations

• The open-label design introduces potential bias, particularly for subjective, patient-reported secondary outcomes.

• The modest sample size (N=160) limits statistical power to detect differences in hard clinical outcomes such as mortality, stroke, or heart failure hospitalizations.

• The follow-up duration of 12 months precludes the assessment of long-term comparative efficacy and safety.

• The study population was restricted to older patients (mean age 76) with permanent AF and dyspnea (NYHA class II or higher), meaning findings may not be generalizable to younger, asymptomatic patients, or those with paroxysmal/persistent AF.

Clinical Significance

The RATE-AF trial challenges the modern paradigm of defaulting to beta-blockers for rate control in older patients with permanent AF and heart failure. While low-dose digoxin did not significantly improve the primary quality-of-life endpoint at 6 months, it achieved equivalent heart rate control while demonstrating a vastly superior side-effect profile and better functional improvements (e.g., NT-proBNP reduction) at 12 months. This rehabilitates digoxin—a centuries-old drug previously plagued by safety concerns stemming from confounded observational data—as a highly viable, and potentially preferable, first-line rate-control agent for this demographic.

Historical Context

Digoxin (derived from the foxglove plant) has been used in cardiology since William Withering described it in 1785. Despite its long history, randomized trials evaluating digoxin in atrial fibrillation were notably lacking. In recent decades, retrospective observational studies suggested digoxin was associated with increased mortality, driving a shift in guidelines toward beta-blockers as first-line rate control agents. However, these observational data were heavily limited by confounding by indication (digoxin was frequently given to sicker patients). The RATE-AF trial was designed to rigorously compare digoxin and beta-blockers head-to-head in a modern randomized framework to resolve this evidence gap.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the differing mechanisms of action between digoxin and bisoprolol explain the potentially superior functional outcomes seen at 12 months in older patients with permanent AF and heart failure symptoms?

Key Response

Digoxin increases vagal tone at the AV node for rate control and has mild positive inotropic effects without lowering blood pressure. Bisoprolol is a negative inotrope and chronotrope, which can exacerbate fatigue and limit exercise tolerance in older adults with heart failure.

Resident

Given that the RATE-AF trial utilized low-dose digoxin, what are the practical monitoring requirements and clinical thresholds you would use when initiating digoxin in an elderly patient with permanent AF and concurrent kidney disease?

Key Response

Residents must know that digoxin has a narrow therapeutic index and is renally cleared. Low doses target serum levels below 1.2 ng/mL. Monitoring requires checking renal function, electrolytes because hypokalemia increases toxicity risk, and serum digoxin levels, contrasting with the relatively easier monitoring of bisoprolol.

Fellow

In the RATE-AF trial, the majority of patients had preserved ejection fraction (HFpEF). How does the hemodynamic profile of HFpEF make these patients particularly vulnerable to the negative chronotropic and inotropic effects of beta-blockers compared to the vagotonic effects of digoxin?

Key Response

HFpEF patients rely heavily on heart rate to augment cardiac output during exertion due to a fixed, stiff stroke volume. Beta-blockers blunt this chronotropic response, leading to chronotropic incompetence and fatigue. Digoxin controls resting rate via vagal tone but allows for some physiological rate response during exercise.

Attending

Despite historical observational data associating digoxin with increased mortality, this randomized trial showed fewer adverse events with digoxin compared to bisoprolol. How should this RCT data reframe our risk-benefit discussions and influence deprescribing cascades in older, frail patients with permanent AF?

Key Response

Attendings need to weigh flawed historical observational data, which suffered from confounding by indication, against modern RCTs. This trial supports low-dose digoxin as a safe alternative that minimizes polypharmacy side effects like fatigue and falls from beta-blocker-induced hypotension, challenging the paradigm that beta-blockers are always first-line.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The RATE-AF trial used an open-label, blinded-endpoint design and found no significant difference in its primary endpoint at 6 months, but found significant secondary differences at 12 months. How does this design introduce potential bias in patient-reported outcomes, and how should researchers account for delayed treatment effects?

Key Response

An open-label design with patient-reported outcomes like the SF-36 is vulnerable to performance bias. Furthermore, designing a primary endpoint at 6 months when physiological adaptation takes longer highlights statistical challenges; a repeated-measures mixed-model approach is necessary to properly evaluate these longitudinal trajectories.

Journal Editor

The investigators reported significant findings at 12 months across numerous secondary endpoints despite missing the primary endpoint at 6 months. As a reviewer, how would you interrogate the risk of Type I error inflation and the handling of missing data for the patient-reported metrics at the 12-month mark?

Key Response

Editors must flag the emphasis on secondary outcomes when a primary outcome is neutral. Analyzing 12-month data requires stringent multiple-testing corrections. Furthermore, patient-reported quality of life trials often suffer from informative censoring, requiring robust sensitivity analyses for missingness.

Guideline Committee

Current AHA/ACC and ESC guidelines generally recommend beta-blockers or non-dihydropyridine calcium channel blockers as first-line for rate control in AF. Based on the RATE-AF trial, what specific class of recommendation and level of evidence should be proposed for low-dose digoxin as a first-line agent in older patients with permanent AF and HFpEF?

Key Response

Guidelines currently prioritize beta-blockers as Class I based largely on extrapolated data. The RATE-AF trial provides Level B-R evidence suggesting low-dose digoxin could be elevated to a Class IIa or IIb recommendation for first-line therapy specifically in the older, permanent AF demographic with HFpEF to prioritize symptom control.

Clinical Landscape

Noteworthy Related Trials

1997

DIG Trial

n = 6,800 · NEJM

Tested

Digoxin

Population

Patients with heart failure and left ventricular ejection fraction of 45% or less

Comparator

Placebo

Endpoint

All-cause mortality

Key result: Digoxin did not reduce overall mortality but significantly reduced the rate of hospitalizations for worsening heart failure.

2002

AFFIRM Trial

n = 4,060 · NEJM

Tested

Rate control strategy

Population

Patients with atrial fibrillation and high risk for stroke or death

Comparator

Rhythm control strategy

Endpoint

All-cause mortality

Key result: There was no significant difference in overall mortality between rate control and rhythm control, but rate control was associated with fewer adverse drug effects.

2010

RACE II Trial

n = 614 · NEJM

Tested

Lenient rate control (resting HR < 110 bpm)

Population

Patients with permanent atrial fibrillation

Comparator

Strict rate control (resting HR < 80 bpm)

Endpoint

Composite of cardiovascular death, heart failure hospitalization, stroke, systemic embolism, bleeding, and life-threatening arrhythmia

Key result: Lenient rate control was found to be non-inferior to strict rate control for preventing major cardiovascular events.

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