Oral Digoxin in High-Risk Heart Failure Patients
Oral Digoxin in High-Risk Heart Failure Patients
The DIG trial was a placebo-controlled double-blind RCT of digoxin in HF. The detailed description of the rationale, design, implementation, patient characteristics, and results of the DIG trial has been reported previously. Briefly, the DIG trial enrolled 7788 ambulatory chronic HF patients in normal sinus rhythm from 302 centres in the USA and Canada from 1991 to 1993. Patients were randomized to receive either digoxin or placebo. Of these patients, 6800 had LVEF ≤45% (main study) and 988 had LVEF >45% (ancillary study). Most patients were receiving background therapy with angiotensin-converting enzyme (ACE) inhibitors and diuretics. Although data on beta-blocker use were not collected, the rate of beta-blocker use would be expected to be low, as these drugs were not yet approved for use in HF. The current study was based on a public-use copy of the DIG data obtained from the National Heart, Lung, and Blood Institute, which also sponsored the DIG trial.
High risk was defined as NYHA class III–IV symptoms, LVEF <25%, or cardiothoracic ratio (CTR) >55%. Although the NYHA subgroup was specifically mentioned in the DIG trial protocol, both the DIG report and FDA analyses included the other two subgroups. Because the FDA determines the requirements for drug packaging, including findings of subgroup analyses, we used all three high-risk subgroups for the purpose of the current study. Findings from the RADIANCE and PROVED trials suggested that discontinuation of digoxin tended to worsen NYHA class symptoms, reduce LVEF, and increase the CTR. Therefore, it was expected that digoxin would be most effective in HF patients with higher NYHA class symptoms, lower LVEF, and larger hearts. To compare the effect of digoxin in low-risk HF patients, we assembled a cohort that excluded patients with any of the three high-risk characteristics, namely NHYA class III–IV symptoms, LVEF <25%, or CTR >55%.
The primary outcome of the DIG trial was all-cause mortality during a median follow-up of 37.9 months. Vital status of all patients was collected up to 31 December 1995 and was 98.9% complete. Because the effect of digoxin was expected to be more pronounced in the first 2 years after randomization, the DIG trial protocol pre-specified separate analysis of the effect of digoxin on mortality and HF hospitalization during that period. Outcomes of interest for the current analysis were combined endpoints of HF mortality or HF hospitalization and all-cause mortality or all-cause hospitalization during the first 2 years after randomization.
Baseline characteristics of high-risk HF patients were compared using Pearson's χ and Wilcoxon rank sum tests. Kaplan–Meier analysis and Cox proportional hazards analyses were used to determine the effect of digoxin on various outcomes. Using a serum digoxin concentration (SDC) cut-off of 0.5–0.9 ng/mL and ≥1 ng/mL as low and high SDCs, respectively, we examined the association of low and high SDCs with the combined endpoints of 2-year all-cause mortality or all-cause hospitalization and 2-year HF mortality or HF hospitalization. We then repeated our analysis in low-risk HF patients. All statistical tests were two-tailed, with P-values <0.05 considered significant. SPSS-18 for Windows (Chicago, IL, USA) was used for statistical analysis.
Methods
Study Design and Patients
The DIG trial was a placebo-controlled double-blind RCT of digoxin in HF. The detailed description of the rationale, design, implementation, patient characteristics, and results of the DIG trial has been reported previously. Briefly, the DIG trial enrolled 7788 ambulatory chronic HF patients in normal sinus rhythm from 302 centres in the USA and Canada from 1991 to 1993. Patients were randomized to receive either digoxin or placebo. Of these patients, 6800 had LVEF ≤45% (main study) and 988 had LVEF >45% (ancillary study). Most patients were receiving background therapy with angiotensin-converting enzyme (ACE) inhibitors and diuretics. Although data on beta-blocker use were not collected, the rate of beta-blocker use would be expected to be low, as these drugs were not yet approved for use in HF. The current study was based on a public-use copy of the DIG data obtained from the National Heart, Lung, and Blood Institute, which also sponsored the DIG trial.
High-risk Patients
High risk was defined as NYHA class III–IV symptoms, LVEF <25%, or cardiothoracic ratio (CTR) >55%. Although the NYHA subgroup was specifically mentioned in the DIG trial protocol, both the DIG report and FDA analyses included the other two subgroups. Because the FDA determines the requirements for drug packaging, including findings of subgroup analyses, we used all three high-risk subgroups for the purpose of the current study. Findings from the RADIANCE and PROVED trials suggested that discontinuation of digoxin tended to worsen NYHA class symptoms, reduce LVEF, and increase the CTR. Therefore, it was expected that digoxin would be most effective in HF patients with higher NYHA class symptoms, lower LVEF, and larger hearts. To compare the effect of digoxin in low-risk HF patients, we assembled a cohort that excluded patients with any of the three high-risk characteristics, namely NHYA class III–IV symptoms, LVEF <25%, or CTR >55%.
Outcomes
The primary outcome of the DIG trial was all-cause mortality during a median follow-up of 37.9 months. Vital status of all patients was collected up to 31 December 1995 and was 98.9% complete. Because the effect of digoxin was expected to be more pronounced in the first 2 years after randomization, the DIG trial protocol pre-specified separate analysis of the effect of digoxin on mortality and HF hospitalization during that period. Outcomes of interest for the current analysis were combined endpoints of HF mortality or HF hospitalization and all-cause mortality or all-cause hospitalization during the first 2 years after randomization.
Statistical Analysis
Baseline characteristics of high-risk HF patients were compared using Pearson's χ and Wilcoxon rank sum tests. Kaplan–Meier analysis and Cox proportional hazards analyses were used to determine the effect of digoxin on various outcomes. Using a serum digoxin concentration (SDC) cut-off of 0.5–0.9 ng/mL and ≥1 ng/mL as low and high SDCs, respectively, we examined the association of low and high SDCs with the combined endpoints of 2-year all-cause mortality or all-cause hospitalization and 2-year HF mortality or HF hospitalization. We then repeated our analysis in low-risk HF patients. All statistical tests were two-tailed, with P-values <0.05 considered significant. SPSS-18 for Windows (Chicago, IL, USA) was used for statistical analysis.