In the Digitalis Investigation Group (DIG) trial 1, conducted from 1991 to 1995, patients with a left ventricular ejection fraction of 0.45 or less were randomly assigned to digoxin (n=3 397) or placebo (n=3 403) in addition to diuretics and angiotensin-converting-enzyme inhibitors. Then mean age was 63 years, and 27% of the participants were older than 70 years. The median dose of digoxin was 0.25 mg per day and the average follow-up 37 months. Blood samples were obtained from 1 485 patients in the digoxin group. The mean serum digoxin levels at 1-month visit are shown in table T1. Digoxin did not reduce overall mortality (RR 0.99, 95% CI 0.91 to 1.07), but it reduced the rate of hospitalization both overall and for worsening heart failure (RR 0.72, 95% CI 0.66 to 0.79). The risk of death from any cause or hospitalization for worsening heart failure was lower in the digoxin group (RR 0.85, 95% CI 0.79 to 0.91).
| Dosage of digoxin | Mean serum digoxin level |
|---|---|
| 0.125 mg/day | 0.76 ng/ml |
| 0.250 mg/day | 0.89 ng/ml |
| 0.375 mg/day | 0.88 ng/ml |
| 0.500 mg/day | 0.88 ng/ml |
A post hoc analysis of the DIG trial 2 examined the clinical outcomes associated with digoxin therapy at different serum digoxin concentrations (SDCs). The main analysis was restricted to men (n = 3 782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and > or =1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2 611). Patients with higher digoxin concentrations were older, had greater number of heart failure signs or symptoms, and had lower median BMIs and estimated glomerular filtration rates.
Higher SDCs were associated with increased crude all-cause mortality rates (table T2). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% CI 2.1% to 10.5%) lower mortality rate compared with patients receiving placebo, whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI 5.7% to 18.0%) higher absolute mortality rate than patients receiving placebo. The association between lower SDC and mortality persisted after multivariable adjustment (table T2).
| Digoxin concentration | Crude all-cause mortality rate (%) | HR (95% CI) for crude all-cause mortality | HR (95% CI) for adjusted all-cause mortality |
|---|---|---|---|
| Placebo | 36.2% | HR 1.00 (reference) | HR 1.00 (reference) |
| 0.5-0.8 ng/mL | 29.9% | HR 0.72 (0.61 to 0.85) | HR 0.80 (0.68 to 0.94) |
| 0.9-1.1 ng/mL | 38.8% | HR 0.99 (0.82 to 1.19) | HR 0.89 (0.74 to 1.08) |
| >or =1.2 ng/mL | 48.0% | HR 1.34 (1.12 to 1.61) | HR 1.16 (0.96 to 1.39) |
| P = 0.006 for trend |
There were 330 women with SDCs measured; women also exhibited a pattern of increased all-cause mortality rates at higher SDCs. Compared with the 756 women randomly assigned to placebo, higher SDCs were associated with all-cause mortality after multivariable adjustment, although the findings were not statistically significant.
Another study 3 using retrospective data from the DIG trial included 4 944 subjects with HF due to systolic dysfunction. Continuous multivariable analysis demonstrated a significant linear relationship between SDC and mortality in women and men. There was a suggestion of reduced mortality in men (HR 0.80, 95% CI0.70 to 0.92) and no effect on mortality in women (HR 0.84, 95% CI0.62 to 1.13) at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentration HASH(0x2fcaf98)1.2 ng/ml seemed harmful in both genders (HR in men 1.18, 95% CI 0.99 to 1.39 and HR in women 1.33, 95% CI1.001 to 1.76). Digoxin reduced the risk of hospital stay for worsening heart failure and the risk of the combined end point of mortality and heart failure hospital stay in women and men at low SDCs (0.5 to 0.9 ng/ml), and there was no reduction in the risk of the combined end point at higher serum concentrations.
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