Why to use digoxin in heart failure? Yves Juillire, Cardiology, - - PowerPoint PPT Presentation

Why to use digoxin in heart failure?

From HEENAN SM et al, J Mol Graph Model 2005; 23: 465-75

Binding orientation of digoxin

Representation of the extracellular loops and the transmembrane domain regions

• f the sheep α1-subunit of Na+,K+-ATPase

Digitalis purpurea Yves Juillière, Cardiology, ILCV, CHU Nancy-Brabois, France

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

Hemodynamic Model

Reduced contractility Pump dysfunction Treatment: Positive inotropic drugs to stimulate contractility Vasodilators to « unload » the heart Conventional drugs Diuretics Digitalis 1980s - 2000

Neurohormonal Model

Progressive remodeling with impaired myocardial performance Treatment: Prevention of progression with neurohormone blockers Conventional drugs Diuretics Digitalis Emerging therapies Endothelin blockers Neutralendopeptidase inhibitors Chimeric atrial peptides Cytokine inhibitors Matrix metalloproteinase inhibitors

Heart Failure: a changing paradigm

Francis GS, Am J Med 2001; 110(7A): 37S-46S

Long-term digitalis therapy improves LV function in HF

ARNOLD SB et al, N Engl J Med 1980; 303: 1443-1448

Discontinuation Acute readministration

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 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

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

• utcomes in patients with heart failure (DIG trial)

RATHORE SS et al, JAMA 2003; 289: 871-878

Association of serum digoxin concentration and

• utcomes 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 first hospitalization due to WHF HR for all-cause mortality

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

43% HF-Action ??% 75% 28% 58% 45% ??% 67% 50% ANDROMEDA CORONA GESICA CARE-HF COMPANION SCD-HeFT AVID MADIT-II MADIT 31% 99% PRAISE 59% A-HeFT 75% 55% 61% 93% 39% ??% 67% 63% 53% EPHESUS RALES CHARM-P CHARM-I CHARM-A VALIANT Val-HeFT ELITE II 34% V-HeFT III 59% OVERTURE 77% RECOVER ??% ATLAS 26% TRACE COMET 12% AIRE 43% BEST 25% SAVE ??% SENIORS 12% SOLVD P 63% CAPRICORN 66% SOLVD T 46% COPERNICUS 100% V-HeFT- II 57% MERIT-HF 100% V-HeFT- I 58% CIBIS II 92% CONSENSUS

Between 11% and 100%, mean: 55%

CIBIS III 33% PEP-CHF 13% 91% US Carv Trial I-Preserve 11% RENAISSANCE 83% EMPHASIS 27% SHIFT 22%

Should we SHIFT

• ur 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%

• nly 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

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 »

« After all, in spite of opinion, prejudice or

error, time will fix the real value upon this discovery »