1. Heart Failure: Why is it important?1. Heart Failure: Why is it important?

• Heart failure is the end-point of many cardiac disorders

• Heart failure affects 1-2% of the population in the western world at any given time (mainly >50yrs)

• Big impact on quality of life:

• The Rotterdam study showed 1 year survival to be only 63%

(Mosterd & Hoes 2007)

ACE-InhibitorsACE-Inhibitors: : The theory behind their use in heart failureThe theory behind their use in heart failure

ACE (also known as kinase 2), also catalyses the breakdown of a substance called bradykinin

• ACEIs act on the RAS

• By inhibiting ACE, they attenuate the effects of angiotensin II

• The RAS plays an important role in HF…

The short-term response to heart failureThe short-term response to heart failure

1. The body detects a decrease in cardiac output

2. The body triggers compensatory mechanisms:

• SNS

• RAS

3. This results in

• Faster, stronger contraction (SNS)

• Vasoconstriction (SNS & RAS)

• Fluid retention (RAS)

TISSUES ARE PERFUSED AGAIN!TISSUES ARE PERFUSED AGAIN!

So why is heart failure progressive?So why is heart failure progressive?

Chronic heart failure is associated with ventricular remodelling

Why does remodelling occur?• Prolonged abnormal forces on the myocardium?

• Prolonged exposure of the myocardium to certain substances?

• Tissue RAS?

Systolic heart failure Diastolic heart failure

Worsening function

Remodelling

The long-term response to heart failureThe long-term response to heart failure

Angiotensin II promotes growth!

Diastolic heart failure

• Increased myocardial mass

• Fibrosis

Overall Concentric hypertrophy

Systolic heart failure

• Eccentric myocyte hypertrophy

• Interstitial fibrosis

Overall Dilated ventricle

Decreased blood supply

Functional regurgitation(Eichhorn & Bristow, 1996)

So…So…

ACEIs may attenuate the short-term response to heart failure

ACEIs may attenuate the long-term response to heart failure

• Prevent increases in preload and afterload

• Dampen sympathetic response

• Reduce vasoconstriction

• Attenuate the ‘growth-response’ to heart failure

ACE-Inhibitors:ACE-Inhibitors: The clinical evidence The clinical evidence

• Many trials on ACEIs over last 20 years

• Outcome measures:

• Symptomatic relief (e.g. NYHA functional class)

• Disease progression (e.g. radionucleotide ventriculography)

• Morbidity (e.g. rates of hospitalisation)

• Mortality

ACEIs for symptomatic reliefACEIs for symptomatic relief

CONSENSUS (1987)

• Bigger improvement in NYHA score in those treated with enalapril vs placebo

• Those that have show equivocal results

• Few subsequent studies have looked at symptomatic benefits

• Circulating angiotensin II decreases with prolonged treatment

• ACEIs may have their main action on the tissue RAS

Why?

The effect of ACEIs on morbidity & mortality The effect of ACEIs on morbidity & mortality

CONSENSUS (1987)

• First trial to show that ACEIs decreased mortality rates in severe HF

• Reduction in deaths due to preventing the progression of HF 0%

10%

20%

30%

40%

50%

60%

Mortality at6 months

Mortality at1 year

Mortality atend of trial

Per

cent

age

of p

atie

nts

Placebo

Enalapril

0%

10%

20%

30%

40%

50%

60%

70%

80%

All-cause mortalityduring follow-up

(p<0.0036)

Hospitalised atleast once for HFduring follow-upperiod (p=0.006)

Hospitalisation forHF or death

during follow-upperiod (p<0.0001)

Per

cent

age

of p

atei

nts

PlaceboEnalapril

SOLVD (1991)

• ACEIs decrease both morbidity & mortality in less severe HF

SOLVD (1992,3)

• ACEIs EF & ventricular dilation

• ACEs have this effect in both symptomatic & asymptomatic patients!

The use of ACEIs post-MI The use of ACEIs post-MI

Limitations to the use of ACEIsLimitations to the use of ACEIs

• The majority of trials use heart failure with left systolic dysfunction

due to: Ischaemic heart disease Dilated cardiomyopathy

• The typical trial subject is a middle aged white male

• The majority of patients:

• In hospital:

Men with left systolic dysfunction due to IHD

• In the community: Elderly women with diastolic dysfunction secondary to hypertension

In trials high doses of ACEIs are used, e.g. 150-300mg Captopril

In clinical practice, lower doses are used, e.g. 25-30mg Captopril

Prescribing issues:

Why?

• Physicians believe these doses to effective (no symptomatic measure of effectiveness)

ATLAS study:‘High dose lisinopril was more effective than low dose for reducing combined mortality and cardiovascular events in congestive heart failure’

• Worry about side effects

Not all eligible patients receive ACEIs1.

2.

• Hard to identify candidates with asymptomatic HF

(Packer, 1996)

SummarySummary

• ACEIs have mortality benefits• ACEIs have morbidity benefits

• ACEIs have these benefits in both symptomatic & asymptomatic patients

In white males with with left ventricular systolic dysfunction:

…little is known about their effects in different types of heart failure & in different types of people!

More research required!

BUT…

References:ACE Inhibitor Myocardial Infarction Collaborative Group: Indications for ACE Inhibitors in the Early Treatment of Acute Myocardial Infarction: Systematic Overview of Individual Data From 100 000 Patients in Randomized Trials. Circulation; 1998; 97: 2202-2212Eichhorn, E.J., & Bristow, M.R.: Medical Therapy Can Improve the Biological Properties of the Chronically Failing Heart A New Era in the Treatment of Heart Failure. Circulation; 1996; 94: 2285-2296Jong P., Yusuf, S., Rousseau, M.., Ahn, S.A. & Bangdiwala S.I.: Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. 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(The SOLVD Investigators): Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation; 1993; 88: 2277-2283MacFadyen, R.J., Lees, K.R. & Reid, J.L.: Tissue and plasma angiotensin converting enzyme and the response to ACE inhibitor drugs. Br J Clin Pharmacol; 1991; 31: 1-13Mann, D.L., Kent, R.L., Parsons, B. & Cooper, G.: Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation; 1992; 85: 790-804Moreau, P. d'Uscio, L.V., Shaw, S., Takase, H., Barton M., and Lüscher, T.F.: Angiotensin II Increases Tissue Endothelin and Induces Vascular Hypertrophy : Reversal by ETA-Receptor Antagonist. Circulation; 1997; 96: 1593-1597Mosterd A. & Hoes A.W.: Clinical epidemiology of heart failure. Heart; 2007; 93: 1137-46Nguyen, K.N., Aursnes, I., & Kjekshus, J: Interaction Between Enalapril and Aspirin on Mortality After Acute Myocardial Infarction: Subgroup Analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). The American Journal of Cardiology; 1997; 79: 115-119Packer M, Poole-Wilson PA, Armstrong PW, et al, on behalf of the ATLAS Study Group. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999 Dec 7;100:2312–8 Packer, M.: Do angiotensin-converting enzyme inhibitors prolong life in patients with heart failure treated in clinical practice? 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Eichhorn, E.J., & Bristow, M.R.: Medical Therapy Can Improve the Biological Properties of the Chronically Failing Heart A New Era in the Treatment of Heart Failure. Circulation; 1996; 94: 2285-2296