During my residency, I dutifully memorized when and how to use the 6 different digitalis preparations then in use: acetylstrophanthidin, ouabain, digitalis leaf, digitoxin, acetyl digitoxin, and digoxin. Today, only digoxin remains in use and then, only occasionally. When I was in training, digitalis preparations were given to patients with heart failure, atrial fibrillation, and other supraventricular arrhythmias. Currently, digoxin is rarely used in the management of heart failure because we have so many other effective and evidence-based medications that improve both morbidity and mortality in heart failure patients.1 In the American Heart Association/American College of Cardiology update on the management of heart failure, digoxin is not even listed in the table of potentially useful drugs for patients with heart failure.1 The fact that digitalis therapy is not commonly prescribed for patients with heart failure is largely the result of the Digitalis Investigation Group (DIG) trial, a randomized, double-blind clinical trial published in The New England Journal of Medicine in 1997.2 In this trial, digoxin neither reduced nor increased overall mortality, although it did reduce hospitalizations both overall and for worsening heart failure. Subsequently, it was demonstrated that higher blood levels of digoxin in this trial were associated with worse outcomes compared with placebo, while lower blood levels were associated with better outcomes.3 As noted above, the introduction of a variety of effective evidence-based medications that improved morbidity and mortality as well as quality of life led to the gradual disappearance of digoxin as a therapeutic agent in heart failure.
Other studies prior to and subsequent to the publication of the DIG trial sought to examine whether digitalis therapy benefited or harmed patients.4 In a number of these investigations, digoxin therapy was observed to increase cardiac output and decrease pulmonary capillary wedge pressure in patients with heart failure, resulting in improved symptoms and signs of heart failure. In addition, a number of investigations re-examined data from previously concluded trials, including the DIG trial, and came to opposing conclusions, that is, digoxin therapy either increased or decreased mortality in patients given this drug. Recently, Ali et al at the Birmingham Alabama Veterans Affairs Hospital and the University of Alabama Birmingham performed 2 re-analyses of the DIG trial that led to publications in The American Journal of Medicine.5,6 The conclusions from these latter 2 studies were that digoxin therapy did not increase or decrease mortality, but it did reduce re-admissions for heart failure in older individuals with systolic heart failure. However, in patients with diastolic heart failure, digoxin therapy did not reduce long-term repeat hospitalizations. Recently, clinical investigators from the Netherlands reported the results of a new study, the Rate control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial, in which digoxin or a beta-blocker, bisoprolol, was given for rate control in atrial fibrillation patients during a 1-year follow-up. Heart rate control was the same with both therapies, but patients who received digoxin had fewer heart failure symptoms, lower natriuretic peptide levels (a marker of volume overload), and had fewer adverse events and fewer admissions to the hospital.7,8 It is possible that the results of this trial will rejuvenate digoxin therapy for heart rate control in patients with atrial fibrillation. Despite the results of the RATE-AF trial, I am sure that the debate over the benefits vs the risks associated with this 200-year-old drug will continue.
So, when, if ever, do I use digoxin in my own inpatient and outpatient practice? First, let me say that I do use digoxin in my practice for both inpatients and outpatients. However, I rarely, if ever, use it for heart failure, preferring agents that have been shown in randomized, double-blind clinical trials to reduce morbidity and mortality, that is, beta-blockers, renin-angiotensin blockers, mineralocorticoid blockers, and Entresto (Novartis AG, Basel, Switzerland), when the patient can afford the co-pay for the latter agent. And, of course, I prescribe diuretics to relieve volume overload. When these measures fail to improve signs and symptoms of heart failure, I refer such patients to our heart failure specialists, who have access to experimental drugs and innovative invasive techniques. I do not consider myself a heart failure specialist. Rather, I am a general cardiologist who can recognize when standard guideline-directed attempts are not successful. However, on occasion, when I see a heart failure patient already taking digoxin, I do not discontinue this medication.
The situation is quite different when I see patients with atrial fibrillation. These individuals are usually inpatients, elderly, often frail, and with tachycardia in excess of 140 beats per minute. Because many of these patients will also have ischemic heart disease, I usually prefer controlling the heart rate with beta-blockers such as metoprolol as long as arterial blood pressure is maintained. At times, the emergency physicians will already have started intravenous diltiazem or esmolol rather than beta-blockade. Once heart rate is controlled, I start oral (PO) beta-blockade in the patients who have been receiving intravenous (IV) esmolol or metoprolol and PO diltiazem in patients who have been receiving this latter drug IV. Of course, most of these atrial fibrillation patients have CHA2DS2-VASc scores (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, Sex category) that mandate anticoagulation. In a moderate number of atrial fibrillation patients, heart rate remains high, with blood pressures that are borderline low despite adequate doses of beta-blocker or diltiazem. A recent example was a frail 84-year-old woman with a history of coronary artery disease and previous coronary bypass surgery whose heart rate was controlled with IV, followed by oral, metoprolol. With metoprolol therapy, her heart rate in atrial fibrillation was 80-90 beats per minute and her arterial blood pressure was 105/70 mm Hg. She reported orthostatic symptoms when standing at her bedside. In such patients, one should not give additional doses of metoprolol or diltiazem, fearing dangerous hypotension. In such patients, I reduce the dose of the beta-blocker and add digoxin to the patient’s medical regimen. On our busy inpatient cardiology consultation service, this scenario is observed nearly every week. If heart rate control is chosen as the short- or long-term strategy for these individuals, they are discharged on a modest dose of oral metoprolol and whatever dose of digoxin was needed to maintain a satisfactory heart rate, usually 0.125 to 0.25 mg daily. There is no need to monitor serum digoxin levels as long as the patient’s resting heart rate remains at a reasonable level, for example, between 70 and 90 beats per minute. When these individuals are subsequently seen in the outpatient clinic, the dose of digoxin is adjusted so that the heart rate in atrial fibrillation is as just described. Anticoagulation is initiated or continued, and the possibility of cardioversion and anti-arrhythmic medication therapy is discussed with the patient. The results of the RATE-AF trial, once published and digested, may well cause me to initiate digoxin therapy sooner and in many more of my atrial fibrillation patients.
As always, I look forward to hearing from readers at jalpert@shc.arizona.edu or on our blog at amjmed.org.
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-Joseph S. Alpert, MD
