Post hoc analyses of the Digitalis Investigation Group (DIG) trial indicate that digoxin
at low (0.5 to 0.9 ng/ml) serum digoxin concentration (SDC) reduces mortality, which
is eliminated at higher (>or=1 ng/ml) SDC, and that low-dose digoxin (<or=0.125 mg/day)
predicts low SDC. In the DIG trial, patients with ambulatory chronic systolic and
diastolic heart failure (HF) (n = 7,788) in normal sinus rhythm receiving angiotensin-converting
enzyme inhibitors and diuretics were randomized to receive placebo (n = 3,899) or
digoxin (n = 3,889). The median dose of digoxin (0.25 mg/day) and the target SDC (0.8
to 2.5 ng/ml) were higher than what are currently recommended, which in part may explain
the lack of long-term mortality benefit of digoxin in the DIG trial. To test this
hypothesis, we examined the effect of digoxin on short-term outcomes; 1-year all-cause
mortality occurred in 392 and 448 patients respectively in the digoxin and placebo
groups (hazard ratio for digoxin 0.87, 95% confidence interval [CI] 0.76 to 0.995,
p = 0.043). Respective hazard ratios for cardiovascular and HF deaths were 0.87 (95%
CI 0.76 to 1.01, p = 0.072) and 0.66 (95% CI 0.52 to 0.85, p = 0.001). All-cause hospitalization
occurred in 1,411 and 1,529 patients receiving digoxin and placebo respectively (hazard
ratio 0.89, 95% CI 0.83 to 0.96, p = 0.002). Respective hazard ratios for cardiovascular
and HF hospitalizations were 0.82 (95% CI 0.75 to 0.89, p <0.0001) and 0.59 (95% CI
0.52 to 0.66, p <0.0001). In conclusion, digoxin reduced 1-year mortality and hospitalization
in patients with chronic HF receiving angiotensin-converting enzyme inhibitors and
diuretics. Randomized clinical trials are needed to determine the effect of low-dose
digoxin in contemporary patients with chronic HF.