Why to use digoxin in heart failure? Yves Juillière, Cardiology, ILCV, CHU Nancy-Brabois, France Digitalis purpurea Representation of the extracellular loops Binding orientation of digoxin and the transmembrane domain regions of the sheep α 1-subunit of Na + ,K + -ATPase From HEENAN SM et al, J Mol Graph Model 2005; 23: 465-75
Presenter Disclosure Information ✸ I declare having professional relationships with the following industrial companies: - AstraZeneca for financial support of the entire I-CARE program - Bayer, Servier and Novartis for participating to boards - Abbott Vascular, Bristol-Myers-Squibb, Novartis, Sanofi-Aventis, Schering-Plough for participation to investigational trials as French national coordinator and/or to meetings as speaker Digitalis purpurea
1950s - 1980s 1980s - 2000 Hemodynamic Model Neurohormonal Model Reduced contractility Progressive remodeling with impaired Pump dysfunction myocardial performance Treatment: Treatment: Positive inotropic drugs to stimulate Prevention of progression with contractility neurohormone blockers Vasodilators to « unload » the heart Conventional drugs Diuretics Conventional drugs Digitalis Diuretics Digitalis Emerging therapies Endothelin blockers Neutralendopeptidase inhibitors Heart Failure: a changing paradigm Chimeric atrial peptides Francis GS, Am J Med 2001; 110(7A): 37S-46S Cytokine inhibitors Matrix metalloproteinase inhibitors
Long-term digitalis therapy improves LV function in HF ARNOLD SB et al, N Engl J Med 1980; 303: 1443-1448 Acute readministration Discontinuation
Effect of digoxin withdrawal in pts with mild to moderate chronic CHF: the PROVED trial URETSKY BF et al. J Am Coll Cardiol 1993; 22: 955-962 Withdrawal of digoxin from pts with chronic HF treated with ACE inhibitors: the RADIANCE trial PACKER M et al, N Engl J Med 1993; 329: 1-7
DIG Study Digitalis Investigation Group, N Engl J Med 1997; 336: 525-533
Clinical benefits of low serum digoxin concentrations in heart failure ADAMS KF et al, JACC 2002; 39: 946-953 From PROVED and RADIANCE studies
Association of serum digoxin concentration and outcomes in patients with heart failure (DIG trial) RATHORE SS et al, JAMA 2003; 289: 871-878
Association of serum digoxin concentration and outcomes in patients with heart failure (DIG trial) RATHORE SS et al, JAMA 2003; 289: 871-878
Digoxin and reduction in mortality and hospitalization in HF: a comprehensive post-hoc analysis of the DIG trial AHMED A et al, Eur Heart J 2006; 27: 178-186
Relationship of serum digoxin concentration to mortality and morbidity in women in the DIG trial ADAMS KF et al, J Am Coll Cardiol 2005; 46: 497-504 HR for all-cause mortality or HR for all-cause mortality first hospitalization due to WHF
Heart rate as a risk factor in CHF (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial BÖHM M et al. Lancet 2010; 376: 886-894
Percentage of Digoxin in HF studies 92% 53% ELITE II MADIT 58% CONSENSUS CIBIS II 50% 33% 67% V-HeFT- I 100% CIBIS III Val-HeFT MADIT-II 57% ??% V-HeFT- II 100% AVID 46% MERIT-HF 63% VALIANT SOLVD T 66% CHARM-A SCD-HeFT 63% US Carv Trial 91% 45% SOLVD P 12% COMPANION ??% COPERNICUS 67% CHARM-I 58% SAVE 25% CARE-HF 43% CAPRICORN ??% CHARM-P 28% AIRE 12% SHIFT 22% SENIORS 39% I-Preserve 13% 26% TRACE A-HeFT 59% BEST 93% RALES 75% ATLAS ??% GESICA 77% 61% COMET EPHESUS ??% OVERTURE 59% CORONA 34% RECOVER 55% EMPHASIS 27% PEP-CHF 11% ANDROMEDA 31% RENAISSANCE 83% V-HeFT III 75% HF-Action 43% PRAISE 99% Between 11% and 100%, mean: 55%
Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction CASTAGNO D et al. Eur Heart J 2012; 33: 1137-1141
Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction CASTAGNO D et al. Eur Heart J 2012; 33: 1137-1141
Mortality and morbidity of HF treated with digoxin. A propensity-matched study ANDREY JL et al. Int J Clin Pract 2011; 65: 1250-1258 All-cause survival Mean F/U: 46.1±11.2 mths
Mortality and morbidity of HF treated with digoxin. A propensity-matched study ANDREY JL et al. Int J Clin Pract 2011; 65: 1250-1258 Cardiovascular mortality
Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure FREEMAN JV et al. Circ Cardiovasc Qual Outcomes 2013; in press. Mean daily dose of digoxin: 0.15±0.05 mg 0.14±0.04 mg among those who died 0.15±0.05 mg among those who did not die Serum digoxin concentration: never measured in 30% only once in 27% more than once in 43% Mean serum digoxin concentration: At the first one-month measurement: 0.93±0.21 ng/ml in men 1.12±0.32 ng/ml in women During F/U: 1.02±0.48 ng/ml 1.01±0.46 ng/ml in those who died 1.04±0.55 ng/ml in those who did not die
What is the economic value of digoxin therapy in CHF patients? (DIG trial) EISENSTEIN EL et al, J Card Fail 2006; 12: 336-342
✸ Number of pts needed to treat for 1 year to avoid 1 CV death or 1 hospitalization for HF:……. 25 ✸ Cost for Ivabradine: - Total French price: 63.35 € /mo 19000 € for 25 pts/yr ✸ Cost for Digoxin: - Total French price: 2.75 € /mo 825 € for 25 pts/yr
CONCLUSION ✸ One of the first cardiovascular agents used in medicine ✸ Large morbidity benefit: - at least as large as that seen for either ACE-inhibitors or ivabradine in heart failure ✸ Problematic underprescription of digoxin because of: - minimizing the very substantial benefit in morbidity - overlooking the role of background therapy in the most of large trials testing ACE-inhibitors or beta-blockers - Lack of an extensive marketing for a low cost generic drug ✸ Importance of a low serum digoxin concentration < 0.9 ng/ml
« After all, in spite of opinion, prejudice or error, time will fix the real value upon this discovery » Sir William WHITERING Birmingham, July 1, 1785 In: « An account of the foxglove and some of its medical uses with practical remarks on dropsy and other diseases »
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