The questionable role of digoxin in atrial fibrillation

Let's start with a patient case.  An elderly patient is admitted to the hospital with complaints of intermittent shortness of breath and a fluttering feeling in his chest.  He has a past medical history of hypertension, atrial fibrillation, and heart failure (EF 6 months ago = 30%).  He is currently taking ramipril 10 mg daily, metoprolol succinate 50 mg daily, and warfarin 6 mg M/W/F and 3 mg the rest of the week.  Other findings include a BP of 106/56 mm Hg, a creatinine clearnace of 40 mL/minute, an INR of 1.28, and atrial fibrillation with a heart rate in the 80s but a rapid ventricular response intermittently into the 120s bpm.  What should be recommended at this time to control this patient's atrial fibrillation and what is the role of digoxin, if any?

2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation1

When deciding to proceed with a "rate control" strategy over a "rhythm control" strategy, there are several factors which affect the ideal agent.  Generally, beta blockers or nondihydropyridine calcium channel blockers are considered first line and can be given intravenously in the acute setting (level of evidence: B).  In the AFFIRM study2 (the largest prospective atrial fibrillation trial to compare rate versus rhythm control), beta blockers were used more than the calcium channel blockers (taken by 68.1% of rate-control patients at some point in the study) but about the same frequency as digoxin (taken by 70.6% of rate-control patients).  The downsides of beta blockers and calcium channel blockers are that their negative inotropic and chronotropic effects can cause hypotension, bradycardia, and worsening of decompensated heart failure.  These guidelines recommend that nondihydropyridine calcium channel blockers should not be used in decompensated heart failure as these may lead to further hemodynamic compromise (level of evidence: C).1

No randomized prospective trial has ever been performed assessing the use of digoxin in atrial fibrillation (unlike the DIG study for heart failure).  Per the 2014 AHA/ACC/HRS guidelines, digoxin is not recommended as a first line agent due to its long onset of action, its drug-drug interactions, the need to monitor serum concentrations in certain patients, poor rate control during exercise, and possible negative effects on mortality.  In a post hoc analysis of the AFFIRM study3, digoxin was actually associated with increased all-cause mortality regardless of the presence of heart failure or gender.  

The presence of comorbid heart failure is a factor when deciding the goal serum concentration.  In the DIG trial4 (the landmark prospective trial to compare digoxin versus placebo in heart failure (both preserved and reduced EF)), digoxin use did not reduce mortality.  However, in a DIG post hoc study5 that analyzed groups based on digoxin serum concentrations, a concentration <0.9 mcg/L was associated with lower mortality whereas higher concentrations showed either no difference or increased mortality compared to placebo.

Recent study of digoxin in atrial fibrillation - the TREAT-AF6 trial 

It was prudent to look at digoxin in atrial fibrillation again because these older studies (ie. AFFIRM - 2002, DIG - 1997) predate contemporary management of cardiovascular disease.  The TREAT-AF study was a retrospective analysis of a cohort of 122,465 Veterans Affairs patients who were newly diagnosed with atrial fibrillation.  Multiple analyses were performed to adjust for modifiers and sensitivity analyses were performed to determine if there were unmeasured confounders.  Digoxin treatment was associated with higher mortality across all subgroups and was independent of factors such as kidney function, heart failure, and use of other medications.

Results of the TREAT-AF study does not mean that the evidence is unanimous associating digoxin with mortality in atrial fibrillation but it is by far the largest to date.  Contrary to this study, there has been an additional post hoc analysis of the AFFIRM trial and an observational analysis of a Kaiser Permanente population that both found no association with mortality (but both studies only included a few thousand patients). 

About digoxin (some pharmacology and pharmacokinetics)7

Digoxin (extracted from the foxglove plant, shown in photo above) has multiple components to its mechanism of action.  It exhibits positive inotropic effects by increasing calcium movement into the cardiac myocytes (useful for heart failure).  Digoxin also has strong vagotonic effects (parasympathetic) which inhibits calcium movement in the AV node, resulting in hyperpolarization and increases AV nodal refractoriness (useful for arrhythmias).  This is the reason why states of high sympathetic activity (such as advanced heart failure, exercise, chronic lung disease, thyrotoxicosis, or heart transplant where the nerves are no longer innervated), digoxin is of limited value.

Digoxin can be administered orally or intravenously.  If given orally, the intestinal microflora of some patients will metabolize digoxin, reducing the bioavailability.  These patients may require higher doses and are at risk of toxicity if antibiotics are given at some point which disrupt the flora.  The volume of distribution is very large (several hundred liters usually) and digoxin takes about 6 hours to reach an equilibrium in distributing to this compartment.  This means that checking a digoxin concentration within 6 hours of a dose will result in a misleadingly high value.  Elimination is a combination of renal clearance plus p-glycoprotein so patients with impaired kidney function or use of p-glycoprotein inhibitors require monitoring of serum concentrations and should often be given reduced doses.  Notably, the interaction of amiodarone and digoxin is so predictable that many experts recommend halving the dose of digoxin immediately when amiodarone is started.

Medications that increase digoxin concentrations (not all inclusive)

Amiodarone Quinidine Verapamil Diltiazem Cyclosporine Itraconazole Propafenone Flecainide

Back to the patient case

There are several factors in this case that are pertinent for selecting a therapy to improve the patient's heart rate control.  First, the patient should be questioned about missing doses and when the last doses of his medications were.  The subtherapeutic INR suggests that the patient may have missed recent doses of warfarin so nonadherence in general may be an issue.  If the patient confirms that he has missed his beta blocker in the last few days, the atrial fibrillation may have been brought on by the now sensitized ectopic foci, and reinforcement of adherence may be all that is necessary.  As far as additional therapy, increasing the dose of the metoprolol succinate (which would be good considering the goal dose for heart failure with reduced EF is 200 mg daily) or adding a nondihydropyridine calcium channel blocker are not options because of the low blood pressure.  This leads us with the option of adding digoxin or considering antiarrhythmic therapy.  If digoxin is used, the low creatinine clearance needs to be recognized and a starting dose of 125 mcg daily with followup serum monitoring in a week is reasonable (with a goal concentration of <0.9 mcg/L because of the patient's concomitant heart failure).  If deciding against digoxin because of the association with increased mortality, amiodarone is the next recommended therapy (Class IIb, level of evidence: C) (although it hasn't been shown to reduce mortality either).

Take home points:

• The use of digoxin in atrial fibrillation is controversial and it should be reserved for those who cannot take or have maximized doses of beta blockers and nondihydropyridine calcium channel blockers
• Digoxin is subject to numerous drug interactions and its mechanism limits its usefulness in many patients, especially those with high sympathetic tone
• When checking serum digoxin concentrations, make sure the patient has not received a dose within the last 6 hours as the result may be falsely elevated
• Do not exceed a concentration of 0.9 mcg/L when the patient has concomitant heart failure

References:
1.  January CT, Wann L, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol  2014
2.  Wyse DG, Waldo AL, DiMarco JP, et al.  A comparison of rate control and rhythm control in patients with atrial fibrillation.  N Engl J Med  2002;347:1825-33.
3.  Whitbeck MG, Charnigo RJ, Khairy P, et al.  Increased mortality among patient taking digoxin - analysis from the AFFIRM study.  Eur Heart J  2013;34:1481-8.
4.  The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-34
5.  Rathore SS, Curtis JP, Wang Y, et al.  Association of serum digoxin concentration and outcomes in patients with heart failure.  JAMA  2003;289(7):871-8.
6.  Turakhia MP, Santangeli P, Winkelmayer WC, et al.  Increased mortality associated with digoxin in contemporary patient with atrial fibrillation.  J Am Coll Cardiol  2014;64(7):660-8.
7.  Sampson KJ, Kass RS.  Chapter 29.  Anti-Arrhythmic Drugs. In: Brunton LL, Chabner BA, Knollman BC. eds.  Goodman & Gilman's The Pharmacological Basis for Therapeutics, 12e.  New York, NY:McGraw-Hill;2011.

photo by THE Holy Hand Grenade!