D: Randomized, double-blind, placebo-controlled trial (1997)

P N = 6800, HF and LVEF < 45%, NSR
302 clinical centers in US and CanadaExcluded: afib/flutter, cardiac surgery or PCI within previous 4 weeks or need for cardiac surgery or PCI in near future
I Digoxin
C Placebo
O Efficacy:

  • NSS for death
  • Hospitalizations for worsening HF – RR: 0.72 (0.66-0.79, p<0.001)
  • Subgroup analysis: high risk patients – those with lower EF or enlarged hearts and those in NYHA III or IV – benefit appeared greater


  • Most common reasons for suspected digoxin toxicity: ventricular fibrillation or tachycardia, supraventricular arrhythmia, 2nd or 3rd degree AV block

**Retrospective Analysis: Relationship of serum digoxin concentration to mortality and morbidity in the DIG trial** (2005):

For women:

  • 0.5-0.9ng/mL: Beneficial effect of digoxin on morbidity and no excess mortality
  • > 1.2ng/mL (= 1.5 nmol/L): Risk for mortality was greater than placebo

**Association of serum digoxin concentration and outcomes in patients with heart failure (2003): Post-hoc analysis of the DIG trial

For men:

  • 0.5-0.8ng/mL: associated with reduction in mortality
  • 0.9-1.1ng/mL: not associated with reduction in mortality
  • > 1.2ng/mL (= 1.5 nmol/L): higher mortality in men

Take-home messages:

  • Efficacy of digoxin in heart failure:
    • Reducing risk for hospitalizations for worsening HF
  • Monitor digoxin trough levels (30min prior to dose)
    • Levels should at least be 8-12 hours after dose
    • CCS AF guidelines: maximum trough digoxin serum concentration: 1.5 nmol/L
      • DIG trial suggests that > 1.5 nmol/L associated with greater mortality in HF
    • CCS compendium for HF
      • Digoxin trough level in HF patients with severe renal dysfunction: <1nmol/L
      • If rapid deterioration in renal fx, hold digoxin and R/A when stable
      • Role of digoxin: in patients who are in SR + moderate to severe symptoms, despite optimized HF therapy → relieve symptoms + reduce hospitalizations
  • Concurrent atrial fibrillation:
    • Digoxin – target HR of <100bpm
    • Not as effective as controlling HR vs BB or CCBs during exercise
      – should not be used as monotherapy for active patients
    • CCS guidelines for atrial fibrillation:
      If used for treating patients with concomitant LV systolic dysfunction, its use should be dictated by the recommendations of the CCS HF Clinical Guidelines

1.0ng/mL = 1.3 mmol/L – associated with increased mortality in HF