Digoxin Use in Patients with Atrial Fibrillation – Should We Desist?

Digoxin is FDA-approved for the treatment of mild to moderate heart failure (HF) as well as the control of resting ventricular rate in adult patients with chronic atrial fibrillation (AF).¹ Current guidelines recommend digoxin to control resting heart rate in patients with AF when they have concurrent HF.² But does digoxin improve outcomes in patients with AF? The available data are conflicting and observational.^3-6 Does the recently published TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study provide additional insights?⁷

The TREAT-AF study was a retrospective cohort study that examined the association between digoxin use and mortality in patients newly diagnosed with AF. The study was conducted utilizing pharmacy and medical claims for patients treated in the Veterans Affairs (VA) healthcare system.  Patients were included in the analysis if they had a confirmed diagnosis of AF and received any outpatient prescription and had at least one outpatient visit within 90 days of diagnosis. The study excluded patients with prior diagnosis of AF who had catheter or surgical ablation in the previous 4 years; cardiac surgery in the previous 30 days; a history of valvular disease, repair, or replacement; thyroid disease; or a kidney transplant. The primary outcome of the study was time to death, beginning 90 days after the initial AF diagnosis. Study investigators performed an intention-to-treat analysis adjusting for age, race, hypertension, HF, stroke, Charlson comorbidity score, CHADS₂ score, cardiovascular medications, eGFR stratification, and antiarrhythmic medications.

This study cohort included 122,465 patients (mean age = 72.1± 10.3 years) and, as would be expected among older veterans, the majority were men (98.4%).  Approximately 25% received digoxin therapy within 90 days of diagnosis.  Slightly more than a third of the patients had an eGFR less than 60ml/min or were on dialysis during the study. The majority of patients had a CHADS₂ scores of 0-1 (47.2%) or 2-3 (45.7%).

In the unadjusted analysis, digoxin use was associated with a very significant increase in all-cause mortality when compared to non-digoxin use  (95 vs. 67 per 1,000 person-years; p<0.001). After multivariate adjustment, digoxin use was independently associated with higher mortality (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.23-1.29, p<0.001).  Propensity matching (HR: 1.21, 95% CI: 1.17-1.25, p<0.001) and adjustment for drug adherence (HR: 1.31, 95% CI: 1.27-1.36, p<0.001) further confirmed the association. These findings were consistent across all subgroups and were independent of renal function, HF status, and concomitant therapy. The authors concluded that the results challenge current recommendations regarding the use of digoxin in AF.^2,7

This is the largest cohort study to date addressing the safety of digoxin use in patients with AF. Additionally, the time frame studied [2003-2008] is more contemporary than many previous studies.^5,8 Furthermore, because the study cohort was from within the VA Healthcare system, the study was not limited to a particular geographical area.

However, the retrospective and observational nature of this study make these findings far from robust.  Additionally, the patient population consisted almost entirely of male patients, which limits its generalizability to women.  It is also noteworthy that patients in the digoxin-treated group were more likely to be diagnosed with HF at baseline when compared to patients who did not receive digoxin (21.3% vs. 14.1%). Appropriately, the authors attempted to account for the differences in HF status through multivariate adjustment and propensity matching.

Most importantly, the study did not report nor adjust for potential differences in left ventricular ejection fraction or New York Heart Association functional class. Therefore, it is difficult to determine whether all-cause mortality is attributable to differences in HF severity or digoxin use alone. While mortality rates are high for all functional classes of chronic HF, 1-year mortality rates exceed 50% in patients with advanced stages of HF compared to 20-30% in those with mild to moderate disease.⁹ Lastly, the investigators did not report digoxin concentrations and this too could have impacted mortality.  Higher digoxin serum concentrations (e.g. historically therapeutic concentrations of 1-2 ng/mL) do not result in clinical improvement and may increase mortality.¹⁰

The results of the TREAT-AF should be examined in the context of previous studies.

The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study compared rate-control therapy with rhythm-control therapy in patients with AF. A secondary analysis of the AFFIRM study originally found an increase in mortality with digoxin use (HR: 1.41, 95% CI: 1.19-1.67).⁵  However, a more recent post-hoc analysis of this data found no association between digoxin exposure and mortality after matching patients based on propensity scores.⁶

Similarly, the Stockholm Cohort study initially found that patients receiving digoxin had a markedly higher mortality (51% versus 31%, p<0.001). However, after adjustment for covariates, digoxin use was not associated with an increased risk of mortality. Digoxin was more commonly prescribed to patients who were older and had a greater disease burden, which likely explains the association with increased mortality.³

In a post-hoc analysis of the Rate Control Efficacy in Permanent AF: A Comparison between Lenient versus Strict Rate Control II (RACE II) study, the 3-year estimated cumulative incidence for CV outcomes was similar in the digoxin and non-digoxin groups (12.9% vs. 13.4%; unadjusted HR 0.97, 95% CI: 0.62-1.52). The RACE II investigators concluded that lower serum concentrations of digoxin and the exclusion of patients with severely impaired left ventricular dysfunction might explain these findings.⁴

Bottom line – numerous confounders complicate the interpretation of these studies.  These disparate findings serve as a reminder that even the most complex statistical methods cannot replace prospective, randomized studies.¹¹

Digoxin dosed to attain concentrations in the range of 0.5-0.9 ng/mL appears to have a superior safety profile, improves left ventricular function, reduces hospitalizations, and may improve survival in patients with HF, particularly in high risk patients with NYHA class III-IV or a left ventricular ejection fraction less than 25%.^12,13  Additionally, based on the RADIANCE and PROVED studies, it may be unwise to discontinue the use of digoxin in patients with HF with reduced ejection fraction.^14,15  Admittedly, whether this risk holds true in the contemporary setting of β-blockers and other proven therapies for HF with reduced ejection fraction is unknown.

TREAT-AF and one analysis from the AFFIRM trial suggest that digoxin therapy is associated with increased all-cause mortality.  Other studies suggest there is no relationship between mortality and digoxin therapy. While TREAT-AF raises questions regarding digoxin and increased mortality in patients with AF, prospective studies are needed. Until such data are available, there may be circumstances (such as AF with concomitant HF) where digoxin is still useful, particularly when dosed to attain serum concentrations in the range of 0.5-0.9 ng/mL and only after exhausting other options, such as beta blockers (for all patients with HF) or nondihydropyridine calcium channel antagonists (for patients with HF and preserved ejection fraction).

Given the conflicting data, what do you think? Would you recommend digoxin for a patient with AF without HF? What about patients with AF and concomitant HF?