Why to use digoxin in heart failure?

Transcription

1 Why to use digoxin in heart failure? Yves Juillière, Cardiology, ILCV, CHU Nancy-Brabois, France Digitalis purpurea Representation of the extracellular loops and the transmembrane domain regions of the sheep α1-subunit of Na +,K + -ATPase Binding orientation of digoxin From HEENAN SM et al, J Mol Graph Model 2005; 23:

2 Presenter Disclosure Information Digitalis purpurea 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

3 1950s s Hemodynamic Model Reduced contractility Pump dysfunction Treatment: Positive inotropic drugs to stimulate contractility 1980s Neurohormonal Model Progressive remodeling with impaired myocardial performance Treatment: Prevention of progression with neurohormone blockers Vasodilators to «unload» the heart Conventional drugs Diuretics Digitalis Heart Failure: a changing paradigm Francis GS, Am J Med 2001; 110(7A): 37S-46S Conventional drugs Diuretics Digitalis Emerging therapies Endothelin blockers Neutralendopeptidase inhibitors Chimeric atrial peptides Cytokine inhibitors Matrix metalloproteinase inhibitors

4 Long-term digitalis therapy improves LV function in HF ARNOLD SB et al, N Engl J Med 1980; 303: Discontinuation Acute readministration

5 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: 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

6 DIG Study Digitalis Investigation Group, N Engl J Med 1997; 336:

7 Clinical benefits of low serum digoxin concentrations in heart failure ADAMS KF et al, JACC 2002; 39: From PROVED and RADIANCE studies

8 Association of serum digoxin concentration and outcomes in patients with heart failure (DIG trial) RATHORE SS et al, JAMA 2003; 289:

9 Association of serum digoxin concentration and outcomes in patients with heart failure (DIG trial) RATHORE SS et al, JAMA 2003; 289:

10 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:

11 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: HR for all-cause mortality HR for all-cause mortality or first hospitalization due to WHF

12 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:

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15 Percentage of Digoxin in HF studies CONSENSUS V-HeFT- I V-HeFT- II SOLVD T SOLVD P SAVE AIRE TRACE ATLAS OVERTURE PEP-CHF 92% 100% 100% 66% 12% CIBIS II 53% CIBIS III 33% MERIT-HF US Carv Trial COPERNICUS 63% 91% 67% 25% CAPRICORN??% 12% SENIORS 39% 26% BEST 93%??% COMET 61% 59% RECOVER 55% 11% RENAISSANCE 83% V-HeFT III 75% PRAISE 99% ELITE II Val-HeFT VALIANT CHARM-A CHARM-I CHARM-P I-Preserve RALES EPHESUS 50% 67%??% 45% 58% 28% 13% 75%??% EMPHASIS 27% MADIT MADIT-II AVID SCD-HeFT COMPANION CARE-HF A-HeFT GESICA CORONA ANDROMEDA HF-Action 58% 57% 46% 63%??% 43% SHIFT 22% 59% 77% 34% 31% 43% Between 11% and 100%, mean: 55%

16 Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction CASTAGNO D et al. Eur Heart J 2012; 33:

17 Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction CASTAGNO D et al. Eur Heart J 2012; 33:

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19 Mortality and morbidity of HF treated with digoxin. A propensity-matched study ANDREY JL et al. Int J Clin Pract 2011; 65: All-cause survival Mean F/U: 46.1±11.2 mths

20 Cardiovascular mortality Mortality and morbidity of HF treated with digoxin. A propensity-matched study ANDREY JL et al. Int J Clin Pract 2011; 65:

21 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

22 What is the economic value of digoxin therapy in CHF patients? (DIG trial) EISENSTEIN EL et al, J Card Fail 2006; 12:

23 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: /mo for 25 pts/yr Cost for Digoxin: - Total French price: 2.75 /mo 825 for 25 pts/yr

24 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

25 «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»