By Michael Crawford, MD
Professor of Medicine, Associate Chief for Education, Division of Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: In a large older patient heart failure with reduced ejection fraction hospitalizations database, the outcome of withdrawing digoxin vs. continuing digoxin was examined at 30 days and up to four years of follow-up. Withdrawing preadmission digoxin in hospital resulted in higher mortality at 30 days and more readmissions at six months, one year, and four years.
SOURCES: Malik A, Masson R, Singh S, et al. Digoxin discontinuation and outcomes in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol 2019;74:617-627.
Uretsky BF, Vallurupalli S. Is the digitalis leaf still withering? J Am Coll Cardiol 2019;74:628-630.
Digoxin therapy in heart failure with reduced left ventricular ejection fraction (HFrEF) is indicated to prevent recurrent hospitalizations. Discontinuation has been shown to increase the risk of adverse outcomes in certain patients. The objective of this study was to examine the effects of discontinuing digoxin in patients hospitalized for an episode of HFrEF.
Malik et al used the OPTIMIZE-HF registry, which includes information about more than 48,000 HF hospitalizations in 259 hospitals in 48 U.S. states, and the corresponding Medicare database to identify 3,499 patients with an EF ≤ 45% who received digoxin before hospitalization. Among these patients, 721 discontinued digoxin during hospitalization. The authors used propensity score matching to derive a cohort that discontinued digoxin and a cohort that continued digoxin; these subjects were balanced on 50 key baseline characteristics. The final study population included 698 in each group. Also, the authors conducted a sensitivity analysis on acute kidney injury, a common reason for digoxin discontinuation. The 1,396 matched patients averaged 76 years of age and left ventricular ejection fraction of 28%; 41% were women.
At four years after discharge, the digoxin discontinuation group exhibited significantly higher rates of heart failure (HF) readmission (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.05-1.39; P = 0.007) and the combined endpoint of HF readmission or all-cause mortality (HR, 1.2; 95% CI, 1.07-1.34; P = 0.002), but not all-cause mortality alone. These results were evident at six months and one year after discharge. At 30 days after discharge, the digoxin discontinuation group showed a greater risk of all-cause mortality (HR, 1.8; 95% CI, 1.26-1.57; P = 0.001) but not HF readmission. The authors concluded that in older patients admitted for a HFrEF episode, discontinuing preadmission digoxin therapy was associated with poor outcomes.
I learned the hard way as a trainee not to stop drugs prescribed by another physician before admission unless you thought the drug was harming the patient. Soon after discontinuing the drug, one may learn quickly why the patient was taking the drug in the first place. The results of this study were not a surprise to me, but rather reinforced my prior experiential learning. What is interesting about this study was that in the face of modern pharmacologic and device therapy for HFrEF, we may have stopped using digoxin prematurely.
Recently, I treated two elderly women with a HFrEF exacerbation in the hospital who either could not tolerate all our modern pharmacologic therapy or it just did not work. A resident asked about digoxin; after a couple of days of digoxin therapy, the patients started to improve and were discharged shortly thereafter. In the 1990s, we learned from the work of the Digitalis Investigation Group (DIG) that digoxin in HFrEF patients can reduce readmissions but does not increase longevity.1 Although not currently listed as a first-line therapy option, digoxin still may play a role in HFrEF treatment — and not just for atrial fibrillation. The results of the Malik et al study suggest who might benefit most.
Why this retrospective propensity score-matched study when we have seen results from two randomized, controlled digoxin withdrawal studies (RADIANCE and PROVED)?2,3 These were small studies published in the early 1990s that showed that discontinuing digoxin in stable outpatients was associated with reduced functional class and ejection fraction and an increase in symptoms. Thus, there was a perceived need for a withdrawal study in hospitalized patients on modern neurohormonal-blocking therapy. Malik et al showed that digoxin withdrawal was associated with increased mortality for 30 days to one year and more readmissions from six months to four years. The subgroup analyses shed some light on the possible reason for these results. The adverse effects of digoxin withdrawal were most evident in those not on beta-blockers, with an EF > 25%, with coronary artery disease, and with a heart rate ≥ 70 bpm. These data suggest that the known suppression of sympathetic activity by digoxin may be important in certain patients, such as those with ischemic heart disease or those intolerant to beta-blockers.
The strengths of this study were its large size, use of contemporary therapy, and matching for 50 baseline variables. Some weaknesses included its retrospective, observational design where not all potential confounders were measured. Further, there were no data on digoxin or other drugs after hospitalization. Also, the OPTIMIZE-HF data are from the early 2000s; there have been a few advances in HF therapy since then. Perhaps appropriately, the use of digoxin in HFrEF today has decreased to 10% of patients; it was about 33% in the OPTIMIZE-HF database. However, for those on digoxin when admitted to the hospital, it may not be a good idea to stop the therapy, especially in patients with coronary artery disease or who are intolerant to beta-blockers. This was the case in both my recent elderly women with HFrEF who responded to digoxin.
If one decides to initiate digoxin in HFrEF patients, it is important to remember that in the DIG trial, adverse effects of digoxin were minimized if the serum level was kept < 1.0 ng/mL. In the Malik et al study, reduced renal function did not diminish the benefits of digoxin. Thus, digoxin can be used in patients with reduced renal function with proper dose adjustment.
- Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533.
- Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993;329:1-7.
- Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: Results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993;22:955-962.