Digoxin, Dig-ya think I was gone? Not yet!

Digoxin, Dig-ya think I was gone? Not yet!
Ann K. E. Nagle, PharmD, Pharmaceutical Care Leadership PGY1 Resident

BackgroundThe 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guideline for the Management of Heart Failure (HF) describes a strong correlation between HF and atrial fibrillation (AFib).These conditions often perpetuate one another by reducing cardiac function, worsening scarring of cardiac tissue, and activating the renin-angiotensin and vasopressin systems. While beta blockers are first-line therapy for both AFib and HF, digoxin also has a place in therapy for both conditions. Despite this, digoxin is only used when all other medications have been exhausted or optimized in patients with HF. 

Digoxin has been a treatment option for many years, yet remains understudied both clinically and in patient-reported outcomes, especially in patients with comorbid HF and Afib. The only significantly powered study examining the morbidity and mortality benefit of digoxin in HF (DIG trial) found that while it lacked mortality benefit, digoxin did significantly reduce hospitalizations in patients with HF. Patients in the DIG trial had normal sinus rhythm; however, this may not be applicable to all patients with HF and AFib. Notably, the DIG Trial was conducted before treatment guidelines included beta blockers. Other observational studies have shown mixed results for digoxin and mortality, therefore its clinical benefit is inconclusive.

Patient-reported outcomes, such as symptom improvement and quality of life, are also important considerations for choosing therapies. However, patient experience measures have not been well-researched in patients where Afib and HF overlap. The recently published RATE-AF trial focuses on these patients and evaluates the place of digoxin in therapy.

EvidenceThe RATE-AF trial is the first trial to exclusively study patients with AFib and HF comorbidities. It is a randomized, open-label, blind endpoint study that examined 160 patients in the UK. Participants were 60 years of age or older and had diagnoses of both AFib and HF (New York Heart Association [NYHA] class II or above). Baseline characteristics of patients included: average age 76 years, 46% female, heart rate 100 bpm with a majority having moderately troubling Afib symptoms (European Heart Rhythm Association [EHRA] class 2b), 19% had left ventricular ejection fraction (LVEF) of <50%, and median N-terminal pro b-type natriuretic peptide (NT-proBNP) was 1,057 pg/mL. Patients were randomized 1:1 into digoxin and bisoprolol with the average dose of digoxin being 161 mcg (average serum level 0.78 ng/mL) and average bisoprolol dose of 3.2 mg.

Primary endpoints were patient-reported quality of life improvements using the 36-Item Short Form Survey (SF-36) physical component summary (Physical Function, Role-Physical, Bodily Pain and General Health) at 6 months. Secondary endpoints at 6 and 12 months included mental and general health status, symptom and functional capacity, and NT-proBNP levels.

No statistical difference was reported in the primary outcomes; however, secondary outcomes did show some benefit to the digoxin group. At 12 months, those patients randomized to digoxin had significant improvement in vitality (P=0.01), general health (P=0.05), physical function (P=0.05) and role limitations due to physical health problems (P=0.05). AFib Effect on Quality of Life scores were not statistically different between digoxin and bisoprolol groups at 6 or 12 months. Post hoc analysis found that daily activities and treatment satisfaction were higher in the digoxin group and symptomatic improvement (EHRA class) was found to be substantially better in the digoxin group. LVEF improved similarly in both groups, but NT-proBNP levels were significantly improved at 12 months with treatment of digoxin. Post hoc analysis also found NYHA class improvement at 6 and 12 months in the digoxin group, with fewer adverse events.

Discussion & Clinical ImpactBeta blockers remain as a Class I, Level A recommendation to reduce mortality for patients with HF. The only significant clinical improvement in the RATE-AF trial was reduction in NT-proBNP levels in the digoxin group. While patient-reported outcomes (general health, treatment satisfaction, and physical limitation improvement) in the RATE-AF trial were significant, these findings are not clinical outcomes that would suggest digoxin be prioritized in treatment algorithms. Though secondary outcomes of the RATE-AF trial were significant, they should be interpreted with caution. A major limitation of these secondary endpoints is that this was a small cohort and multiple hypotheses were tested at once, which increases the risk of incorrectly detecting a difference between digoxin and bisoprolol groups. In practice, the results of this trial can only be used to consider digoxin as similar to beta blockers in patients with AFib and HF for improvements in quality of life and satisfaction of treatment. Digoxin may be an important tool for our patients who remain symptomatic after being optimized on guideline-driven therapy. 



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