Efficacy of digitoxin according to left ventricular ejection fraction in DIGIT-HF
U Bavendiek, D Berliner, N H Thomas, J Schwab, A Rieth, L S Maier, X Liu, M Zdravkovic, M Huelsmann, C Veltmann, S Stoerk, M Boehm, A Koch, A Grosshennig, J BauersachsAbstract
Background
The DIGIT-HF trial recently demonstrated that digitoxin reduced the primary composite outcome of all-cause death (ACD) or first hospitalization for worsening heart failure (HFH) in patients with heart failure (HF) and a reduced ejection fraction (HFrEF) receiving a well-implemented guideline-recommended HF therapy. Post-hoc analyses of the DIG trial indicated a potential benefit of digoxin particularly in a prespecified population with a left ventricular ejection fraction (LVEF) <25%. The present analysis of DIGIT-HF evaluated the effects of digitoxin on the primary outcome time to ACD or HFH and its components across the range of LVEF at baseline.
Methods
DIGIT-HF was a double-blind, randomized, multicenter trial, enrolling patients with symptomatic HFrEF (New York Heart Association [NYHA] class ≥II and left ventricular ejection fraction [LVEF] ≤30%, or NYHA class ≥III and LVEF ≤40%). Patients were randomized to digitoxin or placebo on top of standard of care. For the present analysis patients were categorized into tertiles of LVEF documented at baseline: <26%, 26-30%, and 31-40%. Treatment effects of digitoxin vs. placebo were calculated for the primary outcome ACD or HFH and its components (for details see Table and Figure). Patients are analyzed as randomized. As these are post-hoc analyses, p-values are considered descriptive.
Results
Of the 1212 patients included in the intention to treat population, at baseline 420 patients (34.7%) had a LVEF of <26% (21.1±3.9%), 366 (30.2%) a LVEF of 26-30% (29.0±1.3%), and 426 (35.2%) a LVEF of 31-40% (35.2±2.7%). 20% of patients were female and 27% of patients had a history of atrial fibrillation at baseline with no significant difference between LVEF categories. Baseline characteristics of the patients were well balanced between treatment groups in all LVEF categories. In the ITT population, digitoxin significantly reduced the time to the primary outcome ACD or HFH. Both components of the primary endpoints contribute to the overall treatment effect of digitoxin. Efficacy of digitoxin on the primary outcome ACD and HFH as well as on its components was consistent with no statistically significant interaction between LVEF tertiles (Table). Restricted cubic spline plot analysis across a continuous LVEF range indicated a greater reduction of the primary outcome by digitoxin among patients with a markedly reduced LVEF (<20%) at trial entry (Figure). This was supported by specific analysis of patients with LVEF <20% (digitoxin n=52/placebo n=46; primary outcome ACD and HFH: Hazard Ratio (HR) 0.45 [95% Confidence Intervall (CI) 0.23 to 0.89], ACD: HR 0.67 [95% CI 0.25 to 1.75], HFH: HR 0.59 [95% CI 0.28 to 1.25]).
Conclusions
Digitoxin reduced the risk of the composite outcome of ACD or HFH in patients with HFrEF across the entire LVEF range with a treatment effect that appeared to be more pronounced in patients with a markedly reduced LVEF.Outcomes according to baseline LVEF tertilesOutcomes across continuous LVEF range