European Heart Journal Advance Access originally published online on June 7, 2006
European Heart Journal 2006 27(13):1630-1631; doi:10.1093/eurheartj/ehl046
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Digoxin and reduction in mortality and hospitalization in systolic and diastolic heart failure at low serum digoxin concentrations: reply
University of Alabama at Birmingham and VA Medical Center
1530 3rd Avenue South, CH19
Birmingham, AL 35294-2041
USA
E-mail address: aahmed{at}uab.edu
Washington University School of Medicine
St Louis, MO
USA
University of Alabama at Birmingham
Birmingham, AL
USA
Northwestern University
Chicago, IL
USA
We appreciate Dr Rahimtoola's comments regarding our recent report1 based on the Digitalis Investigation Group (DIG) trial. Our analysis, which included both men and women with systolic (ejection fraction 
45%: main trial) or diastolic (ejection fraction >45%; ancillary trial) heart failure (HF), confirmed one of the key findings of the DIG trial that digoxin significantly reduces hospitalizations due to worsening HF in a broad population of HF patients with sinus rhythm.2
Our study also demonstrated that digoxin reduced HF hospitalization regardless of serum digoxin concentrations (SDC). Furthermore, we observed that in patients who achieved low SDC (0.5–0.9 ng/mL), digoxin was associated with reduction in all-cause mortality and all-cause hospitalizations.1 In a subgroup analysis, we found no significant interaction between digoxin and any major patient characteristic, including sex and ejection fraction.
Our subgroup analysis based on low SDC and placebo patients included 4843 patients: 982 patients receiving digoxin who had low SDC and 3861 patients receiving placebo. Of these, 602 (12%) had diastolic HF: 108 patients with low SDC and 494 patients receiving placebo. The magnitude of the absolute and relative reductions in total mortality was comparable between patients with systolic and diastolic HF, and there was no significant heterogeneity in the effect of digoxin between these two groups (adjusted P for interaction 0.834).1
Among systolic HF patients, low SDC was associated with a 3% absolute reduction (compared to 34% mortality in the placebo group, 31% of patients with low SDC died during the study) and a 22% relative reduction (adjusted hazard ratio 0.78, 95% CI, 0.68–0.87; P<0.0001) in all-cause mortality. Similarly, among diastolic HF patients, low SDC was associated with a 4% absolute reduction (compared to 23% mortality in the placebo group, 19% of patients with low SDC died during the study) and a 25% relative reduction (adjusted hazard ratio 0.75, 95% CI, 0.43–1.31; P=0.313) in all-cause mortality. Thus, although Dr Rahimtoola is correct that the mortality difference in the diastolic HF group did not achieve conventional statistical significance, we believe that the overall study findings are most consistent with the view that digoxin at low SDC reduces mortality by about 20–25%, independent of ejection fraction.
To further clarify this issue, a more detailed analysis of the DIG ancillary trial, including Kaplan–Meier curves, will be the subject of a future report.3
References
- Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF, Gheorghiade M. (2006) Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J 27:178–186.
[Abstract/Free Full Text] - The Digitalis Investigation Group. (1997) The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336:525–533.
[Abstract/Free Full Text] - Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF, Gheorghiade M. (2006) Effects of digoxin on morbidity and mortality in diastolic heart failure: The Ancillary Digitalis Investigation Group Trial. Circulation In Press.
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