2. 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)
3. 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…
4. 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!
5. 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
7. 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
8. ACE-Inhibitors:ACE-Inhibitors:
The clinical evidenceThe 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
9. 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?
10. The effect of ACEIs on morbidity & mortalityThe 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 at
6 months
Mortality at
1 year
Mortality at
end of trial
Percentageofpatients
Placebo
Enalapril
0%
10%
20%
30%
40%
50%
60%
70%
80%
All-cause mortality
during follow-up
(p<0.0036)
Hospitalised at
least once for HF
during follow-up
period (p=0.006)
Hospitalisation for
HF or death
during follow-up
period (p<0.0001)
Percentageofpateints
Placebo
Enalapril
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!
11. The use of ACEIs post-MIThe use of ACEIs post-MI
12. 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
13. 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 ACEIs
1.
2.
• Hard to identify candidates with asymptomatic HF
(Packer, 1996)
14. 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…
15. 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: 2202-2212
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
Jong 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. The Lancet; 2003; 361: 1843-1848
Kober, L., Torp-Pedersen, C., Carlsen, J.E., Bagger, H., Eliasen, P., Lyngborg, K., Videbaek, J., Cole, D.S., Auclert, L., Pauly, N.C., Aliot, E., Persson, S., Camm, A.J. for the
Trandolapril Cardiac Evaluation (TRACE) Study Group: A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med; 1995; 333: 1670- 1676.
Konstam, M.A., Rousseau, M.F., Kronenberg, M.W., Udelson, J.E., Melin, J., Stewart, D., Dolan, N., Edens, T.R., Ahn, S., & Kinan, D. (The SOLVD Investigators): Effects of
the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation; 1992; 86:
431-438
Konstam, M.A., Kronenberg, M.W., Rousseau, M.F., Udelson, J.E., Melin, J., Stewart, D., Dolan, N., Edens, T.R., Ahn, S., & Kinan, D. (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: 2277-2283
MacFadyen, 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:
1-13
Mann, D.L., Kent, R.L., Parsons, B. & Cooper, G.: Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation; 1992; 85: 790-804
Moreau, 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: 1593-1597
Mosterd A. & Hoes A.W.: Clinical epidemiology of heart failure. Heart; 2007; 93: 1137-46
Nguyen, 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: 115-119
Packer 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? Journal of the American College of
Cardiology. 1996 28: 1323-1327
Pfeffer, M.A., Braunwald, E., Moye, L.A., Basta, L., Brown, E.J., Cuddy, T.E., Davis, B.R., Geltman, E.M., Goldman, S., Flaker, G.C. for the SAVE group: Effect of captopril
on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J
Med; 1992; 327: 669-677. Abstract.
Sadoshima, J. & Izumo, S.: Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role
of the AT1 receptor subtype. Circ. Res.; 1993; 73: 413-423
Tan, L.B., Jalil, J.E., Pick, R., Janicki, J.S. & Weber, K.T.: Cardiac myocyte necrosis induced by angiotensin II. Circ. Res.; 1991; 69: 1185-1195
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical
evidence of heart failure. The Lancet; 1993; 342: 821-828. Abstract.
The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril
Survival Study (CONSENSUS). N Engl J Med; 1987; 316: 1429-1435
The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med; 1991;
325: 293-300
Weber, K.T. & Brilla, C.G.: Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation; 1991; 83: 1849-1865
Weber, K.T., Sun, Y., & Guarda, E.: Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension; 1994; 23: 869-877
Yusuf, S., Pfeffer, M.A., Swedberg, K., Granger, C.B., Held, P., McMurray, J.J.V., Michelson, E.L., Olofsson, B. & Östergren, J.: Effects of candesartan in patients with
chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet; 2003; 362: 777-781
Zile, M.R. & Brutsaert, D.L.: New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II: Causal Mechanisms and Treatment. Circulation; 2002; 105:
1503-1508
