The History and Future of Heart Failure WCN Peter Dunselman Lecture - - PowerPoint PPT Presentation

University Medical Center Groningen

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

• NHLBI. Morbidity and Mortality: 2000 Chartbook on Cardiovascular, Lung, and Blood
• Diseases. Geneva: World Health Organization; 1996.

Hospitalizations/100,000 Population 1970 50 100 150 200 250 1975 1980 1985 1990 1995

Year 65+ years 45-64 years

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

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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

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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

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%

◼

• ptimum standard therapy

◼

randomly assigned to target

• f 200 mg metoprolol CR/XL
• r placebo

◼

The study was stopped early

• n the recommendation of

the independent safety

• committee. M

Lancet 1999

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CIBIS II – mode of death CIBIS II – mode of death

Patients

Unk no wn caus e

• f death

Non-car dio

• vascular deaths

Other car dio

• vascular deaths

M yo cardial infarction Pump failure Sudden death 0.45 (0.27 – 0.74) 0.75 (0.37 – 1.50) 1.17 (0.67 – 2.03) 0.85 (0.31 – 2.34) 83 6%

p=0.00 11

48 4% 36 3% 0.56 (0.39 – 0.80) 0.74 (0.48 – 1.14) Hazar d r atio : (95% CI )

p=0.17 p=0.75 p=0.58 p=0.41 p=0.00 12

Biso pro lol (n = 1327) Placebo (n = 1320) 20 40 60 80 100 47 4% 7 1% 8 1% 28 2% 23 2% 14 1% 18 1% 23 2% 49 4%

Lancet 1999

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SOLVD- Treatment 16% reduction

RALES: All-Cause Mortality

Pitt et al, N Engl J Med, 1999.

Probability

• f survival

Months

Spironolactone + standard therapy Standard therapy (ACE inhibitor + loop diuretic ± digoxin)

1.00 0.80 0.85 0.90 0.95 0.45 0.50 0.55 0.60 0.65 0.70 0.75 3 6 9 12 15 18 21 24 27 30 33 36 Risk Reduction 30% 95% CI 18–40% p <0.001

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EMPHASIS: primary outcome

Zannad et al. NEJM 2011

Treatment of HFrEF

On behalf of the CHARM Programme Investigators and Committees

Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity

CHARM

5

CHARM Added CHARM Preserved

CHARM Programme

3 component trials comparing candesartan to placebo in patients with symptomatic heart failure

CHARM Alternative

n=2028

LVEF £40% ACE inhibitor intolerant

n=2548

LVEF £40% ACE inhibitor treated

n=3025

LVEF >40% ACE inhibitor treated/not treated

Primary outcome for Overall Programme: All-cause death Primary outcome for each trial: CV death or CHF hospitalisation

57

CHARM Programme

Mortality and morbidity

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

All Cause Mortality CV Death or CHF Hospitalisation

Hazard ratio Hazard ratio

p heterogeneity=0.43

Alternative Added Preserved Overall

p heterogeneity=0.37

p=0.0004 p=0.055 p=0.011 p=0.118 p<0.0001 0.77 0.85 0.89 0.84 0.91

Recommendation MRA and ARB

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Statins in HF: CORONA

Mortality by Intention-to-Treat

0.4 0.3 0.2 0.1 Mortality 6 12 18 24 30 36 42 48 54 60 Months of follow-up Amiodarone ICD Therapy Placebo 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

Bardy et al. NEJM 2005;352:225

The effect of cardiac resynchronization

• n morbidity and mortality in heart failure

Cleland et al; NEJM 2005

16 32 40 24 8

Enalapril

(n=4212)

360 540 720 900 1080 1260

Days After Randomization

180

Patients at Risk

1117

Kaplan-Meier Estimate of Cumulative Rates (%)

914

LCZ696

(n=4187)

HR = 0.80 (0.73-0.87) P = 0.0000002 Number needed to treat = 21

LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236

CV Death or HF Hospitalization (Primary Endpoint PARADIGM)

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HFREF vs HFPEF

Preserved left ventricular systolic function Reduced left ventricular systolic function

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HFPEF-recommendations

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University Medical Center Groningen

ESC HF Guidelines 2016

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Digoxine-DIMT

Exercise time Norepinephrine JACC 1993

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Digoxin-DIG Study

All-cause mortality Death or worsening HF NEJM 1997

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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