Digoxin

Recent data suggest that the target dose (and serum concentration) of digoxin therapy should be lower than traditionally assumed. Although higher doses may be necessary for maximal hemodynamic effects,94 beneficial neurohormonal and functional effects appear to be achieved at relatively low serum digoxin concentrations (SDC) typically associated with daily doses of 0.125 to 0.25 mg.94,103,108 A retrospective analysis of the relationship of SDC to outcomes in the DIG trial demonstrated a strong direct relationship between the risk of death and SDC, with concentrations >1.2 ng/mL being associated with harm, whereas concentrations <1.0 ng/mL were associated with favorable outcomes.109 These findings supporting the efficacy of low SDC are reinforced by a retrospective cohort analysis of the combined PROVED and RADIANCE databases indicating that patients with a low SDC (<0.9 ng/mL) were no more likely to experience worsening symptoms of HF on maintenance digoxin than those with a moderate (0.9-1.2 ng/mL) or high (>1.2 ng/mL) SDC.93,109 All SDC groups were significantly less likely to deteriorate during follow-up compared with patients withdrawn from digoxin.

Therefore, patients with reduced LVEF and normal sinus rhythm should be started on a maintenance dose of digoxin (no loading dose) of 0.125 or 0.25 mg once daily based on ideal body weight, age, and renal function. For young patients with normal renal function, a dose of 0.25 mg/day will be typical. Most patients with HF are older and have reduced renal function and should begin at 0.125 mg daily. Patients with a baseline conduction abnormality, or who are small in stature or elderly, should be started at 0.125 mg/day, which can be up-titrated if necessary. Updated dosing nomograms have been published in light of the recognized benefits of digoxin at lower serum concentrations, and they may be useful to clinicians in selecting appropriate an appropriate digoxin dose.110 After dosing has continued for a sufficient period for serum concentration to reach steady state (typically 5 daily doses), some clinicians consider the measurement of a SDC, especially in elderly patients or those with impaired renal function where the digoxin dose often is not predictive of SDC. SDC measurements may be considered when (1) a significant change in renal function occurs; (2) a potentially interacting drug (amiodarone, quinidine, verapamil, itraconazole, erythromycin, clarithromycin, ritonavir, propafenone, or cyclosporine, and others) is added or discontinued; or (3) confirmation of suspected digoxin toxicity is necessary in a patient with signs/symptoms or electrocardiogram changes consistent with this diagnosis. Samples for trough SDC should be drawn more than 6 hours after dosing; otherwise, the result is difficult to interpret because the drug may not be fully distributed into tissues.

Adequate ventricular rate control is important in patients with atrial fibrillation. During chronic therapy, the recommendations followed in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) trial are a reasonable starting point.111 These recommendations include: a resting heart rate <=80 bpm, an average heart rate by Holter monitor of <=100 bpm, and no heart rate >110% of the age-predicated maximum or a heart rate <=110 bpm during a 6-minute walk test. Digoxin alone is often inadequate to control ventricular response in patients with atrial fibrillation. Digoxin slows ventricular response to atrial fibrillation through enhancement of vagal tone. However, with exertion or other increases in sympathetic activity, vagal tone may diminish and ventricular rate accelerate. Addition of a beta blocker complements the pharmacologic action of digoxin and improves rate control. When beta-adrenergic blockers cannot be used, amiodarone has been used by some physicians, but chronic use has potentially significant risks, including thyroid disease and lung toxicity. If amiodarone is added, the dose of digoxin should be reduced by half and the SDC should be monitored to maintain the serum concentration in the desired range. Short-term, intravenous administration of diltiazem or amiodarone has been used for the acute treatment of patients with very rapid ventricular response, especially if the rapid rate is felt to be contributing to hemodynamic compromise. The negative inotropic effects of nondihydropyridine calcium channel blockers (diltiazem and verapamil) must be considered if these agents are used. Digoxin does not lower blood pressure; thus, it may be particularly valuable when hypotension from other agents is a concern.

Although digoxin continues to play a role in some patients with HF and atrial fibrillation, the traditional practice of arbitrarily increasing the dose and SDC of digoxin until ventricular response is controlled should be abandoned, because the risk of digoxin toxicity increases as well.