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Digoxin discontinuation associated with worse outcomes in HFrEF
Literature - Malik A, Masson R, Singh S, et al. - J Am Coll Cardiol 2019;74:617–27,

Introduction and methods

The ACC/AHA guideline for management of heart failure (HF) recommends that digoxin may be used, unless contraindicated, to decrease HF hospitalizations in patients with HFrEF [1]. The Digitalis Investigation Group randomized controlled trial showed that use of digoxin resulted in reduced risk of all-cause and HF hospitalizations in HFrEF patients, but did not reduce all-cause mortality [2-4]. Lack of mortality benefit combined with new guideline-directed medical therapies (GDMT) have resulted in a dramatic decline in use of digoxin [5]. Some studies have suggested that discontinuation of digoxin therapy is associated with increased risk of adverse outcomes in ambulatory patients with HFrEF [6-8]. Patients in these studies received ACE inhibitors, but not beta-blockers or MRAs.

The Medicare-linked OPTIMIZE-HF registry [9] was used to examine the relationship between discontinuation of pre-admission digoxin and outcomes in hospitalized HFrEF patients who receive more contemporary GDMT.

The OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry was a national web-based registry of acute HF between March 1, 2003 and December 31, 2004. Before admission 3449 patients received digoxin and in 721 of these patients digoxin was discontinued before discharge. Propensity score matching was applied to patients with continuation and discontinuation of digoxin therapy, resulting in groups of 698 patients. Outcomes were HF readmission, all-cause readmission, all-cause mortality and combined endpoint of HF readmission or all-cause mortality at 30 days, 6 months, 1 year and 4 years after hospital discharge.

Main results

  • Before propensity score matching, patients in the digoxin discontinuation group were older, had higher LVEF and fewer patients received GDMT for HFrEF.
  • After 4 years, digoxin discontinuation was associated with increased risk of HF readmission (HR: 1.21; 95% CI: 1.05-1.39; P=0.007), all-cause readmission (HR: 1.16; 95% CI:1.04-1.31; P= 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; P=0.002), but not with all-cause mortality (HR: 1.09; 95% CI: 0.97-1.24; P=0.163) compared to digoxin continuation.
  • At 6 months and 1 year after hospital discharge, digoxin discontinuation was associated with increased risk of HF readmission, all-cause readmission, all-cause mortality, and combined endpoint of HF readmission or all-cause mortality compared to digoxin continuation.
  • At 30 day post-discharge, digoxin discontinuation was not associated with HF of all-cause readmission, but risk of all-cause mortality was higher (HR: 1.80; 95% CI: 1.26 to 2.57; P=0.001), as well as the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; P=0.007) for those who discontinued digoxin compared to those who stayed on digoxin.
  • In the pre-matching cohort of HFrEF patients were discharge prescriptions of ACE inhibitors or ARBs, beta-blockers, loop diuretics, and nitrates associated with lower odds of digoxin discontinuation. Odds of digoxin discontinuation were also lower among patients with orthopnea, anemia, and chronic obstructive pulmonary disease, but higher among those with lower extremity edema.


In a cohort of hospitalized HFrEF patients who received more contemporary GDMT including ACEi/ARBs, beta-blockers and MRAs, discontinuation of digoxin was associated with worse outcomes after 30 days, 6 months, 1 year and 4 years after hospital discharge compared to continuation of digoxin. These results suggest that it may be premature to discontinue digoxin therapy in HFrEF patients even though they take more contemporary GMDT.


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failure: a report of the American College of Cardiology Foundation/American Heart Association

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2. The Digitalis Investigation Group Investigators. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33.

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6. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-convertingenzyme inhibitors. RADIANCE study. N Engl J Med 1993;329:1–7.

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. J Am Coll Cardiol 1993;22:955–62.

8. Ahmed A, Gambassi G, Weaver MT, et al. Effects of discontinuation of digoxin versus continuation at low serum digoxin concentrations in chronic heart failure. Am J Cardiol 2007;100:280–4.

9. Zhang Y, Kilgore ML, Arora T, et al. Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data. Int J Cardiol 2013;166:230–5.

Find this article online at JACC

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