The History and Future of Heart Failure WCN Peter Dunselman Lecture 28 november 2018 Dirk J. van Veldhuisen, cardioloog Universitair Medisch Centrum Groningen University Medical Center Groningen
Conflict of Interest Statement • No relevant conflicts, other than Principal Investigator of DECISION trial (Digoxin survival study, supported by ZonMW and Hartstichting, #848090001) University Medical Center Groningen
Heart Failure: A Public Health Crisis Hospitalizations x 3 in last 25 Years Hospitalizations/100,000 Population 250 200 65+ years 150 100 45-64 years 50 0 1970 1975 1980 1985 1990 1995 Year NHLBI. Morbidity and Mortality: 2000 Chartbook on Cardiovascular, Lung, and Blood Diseases . Geneva: World Health Organization; 1996. University Medical Center Groningen
Improved Survival after MI: Increased Incidence of Heart Failure Lenfant NEJM 2003
Population of the Netherlands Changes from 1900-2050 1900 1950 2000 2050 (?) Source: CBS/NRC Handelsblad
Doelen bij de behandeling van chronisch hartfalen 1-vermindering van morbiditeit: betere kwaliteit van leven minder ziekenhuisopnames betere inspanningstolerantie 2-vermindering van mortaliteit: ofwel: verbetering van overleving University Medical Center Groningen
Doelen bij de behandeling van chronisch hartfalen 1-vermindering van morbiditeit: betere kwaliteit van leven minder ziekenhuisopnames betere inspanningstolerantie 2-vermindering van mortaliteit: ofwel: verbetering van overleving University Medical Center Groningen
ACE-remmers verminderen mortaliteit bij ernstig CHF: CONSENSUS N Engl J Med 1987; 316: 1420
Double-blind randomised ◼ controlled study 3991 patients CHF ◼ NYHA II – IV ◼ LVEF ≤40% ◼ optimum standard therapy ◼ randomly assigned to target ◼ of 200 mg metoprolol CR/XL or placebo The study was stopped early ◼ on the recommendation of the independent safety committee. M Lancet 1999
CIBIS II – mode of death CIBIS II – mode of death Patients 100 p=0.00 11 83 80 6% Biso pro lol (n = 1327) 60 Placebo (n = 1320) p=0.00 12 p=0.17 49 48 47 4% 4% 4% 40 p=0.58 36 3% p=0.41 28 2% 23 23 20 2% 2% p=0.75 18 1% 14 1% 8 7 1% 1% 0 Sudden Pump M yo cardial Other car dio - Non-car dio - Unk no wn caus e death failure infarction vascular deaths vascular deaths of death Hazar d r atio : 0.56 0.74 0.85 1.17 0.75 0.45 (95% CI ) (0.39 – 0.80) (0.48 – 1.14) (0.31 – 2.34) (0.67 – 2.03) (0.37 – 1.50) (0.27 – 0.74) Lancet 1999 University Medical Center Groningen
SOLVD- Treatment 16% reduction University Medical Center Groningen
RALES: All-Cause Mortality 1.00 Risk Reduction 30% 0.95 95% CI 18 – 40% 0.90 p <0.001 0.85 0.80 Spironolactone + standard therapy 0.75 Probability 0.70 of survival 0.65 Standard therapy 0.60 (ACE inhibitor + loop diuretic ± digoxin) 0.55 0.50 0.45 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Pitt et al, N Engl J Med, 1999.
University Medical Center Groningen
EMPHASIS: primary outcome Zannad et al. NEJM 2011
Treatment of HFrEF
CHARM C andesartan in H eart failure A ssessment of R eduction in M ortality and morbidity On behalf of the CHARM Programme Investigators and Committees
CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARM CHARM CHARM Alternative Added Preserved n=2028 n=2548 n=3025 LVEF £ 40% LVEF £ 40% LVEF >40% ACE inhibitor ACE inhibitor ACE inhibitor intolerant treated treated/not treated Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death 5
CHARM Programme Mortality and morbidity CV Death or All Cause Mortality CHF Hospitalisation 0.77 Alternative p=0.0004 0.85 Added p=0.011 0.89 Preserved p=0.118 0.91 0.84 Overall p=0.055 p<0.0001 0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Hazard ratio Hazard ratio p heterogeneity=0.37 p heterogeneity=0.43 57
Recommendation MRA and ARB
Statins in HF: CORONA University Medical Center Groningen
Mortality by Intention-to-Treat 0.4 HR 97.5% Cl P-Value Amiodarone vs. Placebo 1.06 0.86, 1.30 0.529 ICD Therapy vs. Placebo 0.77 0.62, 0.96 0.007 0.3 Mortality 0.2 Amiodarone 0.1 ICD Therapy Placebo 0 0 6 12 18 24 30 36 42 48 54 60 Months of follow-up Bardy et al. NEJM 2005;352:225
The effect of cardiac resynchronization on morbidity and mortality in heart failure Cleland et al; NEJM 2005
CV Death or HF Hospitalization (Primary Endpoint PARADIGM) 40 Enalapril 1117 Kaplan-Meier Estimate of 32 (n=4212) Cumulative Rates (%) 914 24 LCZ696 (n=4187) 16 HR = 0.80 (0.73-0.87) P = 0.0000002 8 Number needed to treat = 21 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236
HFREF vs HFPEF University Medical Center Groningen
Reduced left Preserved left ventricular systolic ventricular systolic function function
HFPEF-recommendations University Medical Center Groningen
University Medical Center Groningen
ESC HF Guidelines 2016 University Medical Center Groningen
University Medical Center Groningen
Digoxine-DIMT Exercise time Norepinephrine JACC 1993 University Medical Center Groningen
Digoxin-DIG Study All-cause mortality NEJM 1997 Death or worsening HF University Medical Center Groningen
Digoxin-DIG Low-dose Rathore JAMA 2003 University Medical Center Groningen
University Medical Center Groningen
DECISION-trial Digoxin Evaluation in Chronic heart failure: Investigational Study In • Outpatients in the Netherlands Patients (n=950) with heart failure and Sinus Rhythm or Atrial Fibrillation • Low-dose digoxin (serum levels 0.5-0.9 ng/ml) • Primary endpoint: Cv Mortality and (repeat) HF hospitalizations • Starting in 2019; 38 sites, 34 WCN / 4 UMCs • Funded by ZonMW and Heart Foundation • University Medical Center Groningen
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