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ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcıa
(Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France),
Jaap Deckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl
(Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), Joa ~o Morais (Portugal), Ali Oto (Turkey),
Otto A. Smiseth (Norway)
Document Reviewers, Maria Angeles Alonso Garcıa (CPG Review Coordinator) (Spain), Diego Ardissino (Italy),
Cristina Avendano (Spain), Carina Blomstro € m-Lundqvist (Sweden), Denis Cle ment (Belgium), Helmut Drexler
(Germany), Roberto Ferrari (Italy), Keith A. Fox (UK), Desmond Julian (UK), Peter Kearney (Ireland), Werner Klein
€ ber (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo (Poland),
(Austria), Lars Ko
Maarten Simoons (The Netherlands) Kristian Thygesen (Denmark), Gianni Tognoni (Italy), Isabella Tritto (Italy),
Lars Wallentin (Sweden)
0195-668X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ehj.2004.06.003
ESC Expert consensus document 1455
clinical judgement. This consensus document does not, competitively inhibited by ACE-I. The major effects of
however, override the individual responsibility of health angiotensin-II are summarized in Table 1.
professionals to make appropriate decisions in the cir-
cumstances of the individual patient, in consultation
ACE-Inhibitor classification
with that patient, and where appropriate and necessary
the patient’s guardian or carer.
ACE-I are classified in three categories according to the
group that binds the zinc atom of the ACE molecule into
those containing a sulfhydril, a carboxyl or a phosphoryl
Pharmacology group as zinc ligand (Table 2).4
Carboxyl-containing inhibitors
Cilazapril 10 80 1.25–5 daily 0.5–2.5 daily
Enalapril 11 88 2.5–20 b.i.d. 2.5–20 b.i.d.
Lisinopril 12 70 2.5–10 daily 2.5–5 daily
Phosphinyl-containing inhibitors
Fosinopril 12 50 10–40 daily 10–40 daily
CrCl: creatinine clearance.
*
Prodrug.
**
Significant hepatic elimination.
lipophylic and they have a better access to the target Inhibition of plasma ACE appears to be less important
tissue where they are converted to the active compound. during chronic administration. At this time, inhibition of
Most ACE-I and their metabolites are mainly excreted by ACE in different tissues (i.e., vessels, kidney, heart) may
the renal route, whereas fosinopril, zofenopril, trando- be more important in determining their pharmacological
lapril and spirapril display balanced elimination through effects.10
hepatic and renal routes.5 Captopril is eliminated more Since the mechanism of action of ACE-I is the same,
rapidly from the body, which accounts for its brief du- their effects are attributed to the class as a whole.
ration of action (<6 h), whereas ramiprilat (the active Nevertheless, there are important differences in the
metabolite of ramipril) and specially tandrolaprilat are binding affinity to tissue ACE and individual pharmaco-
eliminated more slowly than other ACE-I (Table 2). kinetic properties of individual drugs, which may result in
In patients with congestive heart failure reduced ab- marked differences in tissue concentration and in dif-
sorption and biotransformation may delay the onset of ferential clinical effects. However, the clinical relevance
effect. Due to diminished renal perfusion, renal excre- of such differences has never been demonstrated. In
tion may be reduced, leading to elevated maximum drug fact, all currently available ACE-I can be considered
plasma levels and prolonged duration of action. Thus, equally effective at lowering blood pressure. Therefore,
dose reductions are required in the presence of impaired the choice and dose of the ACE-I should be based on the
renal function (when creatinine clearance falls to 6 30 results of clinical trials where the benefit has been
ml/min).5 Fosinopril, spirapril, trandolapril and zofe- demonstrated.
nopril are excreted in both the urine and bile, so that
their clearance is not significantly altered by renal im- Effects of ACE-inhibitors
pairment (Table 2).
Haemodynamic effects
Mechanism of action ACE-I decrease total peripheral vascular resistances,
promote natriuresis but cause little change in heart
ACE-I competitively block the conversion of angiotensin-I rate.1–4 Local inhibition of ACE and angiotensin-II for-
into angiotensin-II reducing the circulating and local mation in specific target organs, such as the vascular
levels of angiotensin-II. ACE-I also reduce aldosterone and wall, is involved in these responses.
vasopressin secretion and decrease sympathetic nerve In normotensive and hypertensive patients without
activity as well as the trophic effects of angiotensin-II. congestive heart failure, ACE-I have little effect on car-
However, they do not inhibit the actions of angiotensin-II diac output or capillary wedge pressure. In contrast to
mediated via the activation of AT1 and AT2 receptors and other vasodilators, no reflex tachycardia is observed,
they do not interact directly with other components of possibly due to an effect on baroreceptor sensitivity,
the renin–angiotensin system.1–4;6;7 In addition, ACE-I vagal stimulation and/or reduced stimulation of sympa-
may also inhibit kininase II and increase bradykinin levels, thetic nerve activity. Changes in heart rate during ex-
which in turn stimulates the B2 receptors leading to the ercise or postural changes are not impaired.11 ACE-I
release of nitric oxide NO, and vasoactive prostaglandins reverse cardiac hypertrophy in hypertensive patients12
(prostacyclin and prostaglandin E2).8;9 and reduce endothelial dysfunction in normotensive
1458 ESC Expert consensus document
patients with coronary artery disease, hypertension, effect in dilating postglomerular efferent than afferent
non-insulin-dependent diabetes mellitus and heart fail- arterioles, leading to a reduction in glomerular capillary
ure.6;13–15 Improvement in endothelial function is related hydrostatic pressure and GFR.25 Natriuresis is due to the
to attenuation of vasoconstriction and to the increased improvement of renal haemodynamics, a decreased re-
bradykinin-induced production of endothelium-derived lease of aldosterone and bradykinin that exert direct
NO.14;15 tubular effects and inhibition of the direct renal effects
In patients with congestive heart failure ACE-I induce of angiotensin-II. ACE-I prevent progression of microal-
venous and arterial vasodilatation.1–4 Venous vasodilata- buminuria to overt proteinuria,26 attenuate the pro-
tion increases peripheral venous capacitance, reduces gression of renal insufficiency in patients with a variety
right atrial pressure, pulmonary arterial pressure, capil- of non-diabetic nephropathies27 and prevent or delay the
lary wedge pressures and left ventricular filling volumes progression of nephropathy in patients with insulin-
and pressures, producing a rapid relief of pulmonary con- dependent diabetes mellitus.28
Antiproliferative effects
Effects on fibrinolytic balance
ACE-I also exhibit antiproliferative effects (reduction of
ACE-I also modulate vascular fibrinolytic balance by de-
vascular and cardiac hypertrophy and extracellular matrix
creasing angiotensin-II, a potent stimulus for plasmino-
proliferation) and reduce ventricular remodelling after
gen activator inhibitor type 1 (PAI-1) synthesis and by
myocardial infarction.23;24 They reverse ventricular re-
increasing bradykinin levels a potent stimulus for tissue
modelling by reducing ventricular preload/afterload,
plasminogen activator.36 Thus, ACE-I lower plasminogen
preventing the proliferative effects of AII and sympathetic
activator inhibitor type 1 (PAI-1) concentrations and the
nerve activity and by inhibiting the aldosterone-induced
molar ratio of PAI-1 to tissue plasminogen activator.
cardiac hypertrophy and interstitial and perivascular fi-
ACE-I also counteract the platelet aggregation induced
brosis.11;12 In the hypertrophied heart ACE-I reduce car-
by angiotensin-II since they increased the production of
diac hypertrophy and improve diastolic function. ACE-I
NO and prostacyclin.
also prevent apoptosis of cardiac myocytes in pressure-
overloaded hearts.
Side-effects
Renal effects
ACE-I decrease renal vascular resistances and increase In most patients ACE-I are well tolerated, however,
renal blood flow and promote Naþ and water excretion. several adverse reactions may occur.1;2;37
Nevertheless, the Glomerular Filtration Rate (GFR) re- Hypotension. Symptomatic hypotension due to the
mains unchanged or falls slightly, and thus, filtration withdrawal of angiotensin-II mediated vasoconstrictor
fraction is decreased. This is due to the relatively greater tone can occur, especially after the first dose of an ACE-I,
ESC Expert consensus document 1459
particularly in patients with high plasma renin activity foetal abnormalities (i.e., oligohydramnios, pulmonary
(e.g., salt-depleted patients due to high doses of di- hypoplasia, foetal growth retardation, renal dysgenesis
uretics or with congestive heart failure). neonatal anuria and neonatal death).46
Dry cough appears in 5% to 10% of patients38–40 and it Other side-effects, not related to ACE inhibition in-
is not always easy to distinguish that resulting from clude ageusia and other taste disturbances (especially in
pulmonary congestion or concomitant diseases, e.g., the elderly); neutropenia; and maculopapular rash.
respiratory disease.41 The aetiology is unknown, but it Neutropenia is rare and occurs more frequently in pa-
may be related to increased levels of bradykinin and/or tients with renal or collagen vascular disease.
substance P in the lungs. Cough is not dose-dependent, is
more frequent among women and in Asian populations, it Contraindications
usually develop between 1 week and a few months of
treatment and sometimes requires treatment discontin- History of angioneurotic oedema, allergy and bilateral
daily doses of different agents and Table 4 the initial and compared to 35.2% in the active treatment group. This
target doses in patients with chronic heart failure. equates to 45 fewer deaths per 1000 patients treated or a
number needed to treat for one year to save one life
(NNT) of 22 for 3.5 years to prevent or postpone one
Clinical efficacy and practical use
premature death. In the large trials, ACE-I clearly re-
duced hospital admission rates (admissions for all causes
The benefits of and clinical indications to the ACE-I have
but particularly those related to worsening heart fail-
been clearly defined in many cardiovascular conditions
ure). For example, in SOLVD, the NNT was 4.5 for 3.5
and agreement as to their potential usefulness has been
years to prevent one hospitalisation for heart failure and
established in chronic heart failure, asymptomatic left
3.0 for all-cause hospitalisation.
ventricular dysfunction, acute myocardial infarction,
In the second Vasodilator Heart Failure Trial (VheFT-
hypertension and in patients with high risk for cardio-
II)56 the effect of enalapril was compared with that of a
ferent in the two treatment groups, but the combined However, no relationship was found between the dose of
end-point of all-cause death and all-cause hospitalisation enalapril and the clinical outcome during 24 weeks fol-
was significantly less common in patients receiving high low-up. Deaths in each group were 4.2%, 3.3% and 2.9%,
dose treatment, as was the overall number of hospitali- respectively (ns). The combined end-point of death,
sations (24% reduction). For this reason, the higher tar- heart failure related hospitalisation or worsening heart
get doses of ACE-I selected in the key clinical trials are failure was also similar (12.3%, 12.9% and 14.7%, re-
also recommended in clinical practice, although there is spectively; ns) in each group.
probably only a small benefit when comparing interme- It is notable that neither the ACE-I ATLAS or NETWORK
diate and high doses of ACE-I. trials showed differences in end-points between inter-
In the NETWORK trial63 patients with NYHA class II-IV mediate and high dose. In conclusion, clinicians should
heart failure were randomised to receive enalapril 2.5 aim to achieve the targed dose defined in the relevant
mg twice daily, 5 mg twice daily, or 10 mg twice daily. clinical trials, providing the dose is well tolerated.
1462 ESC Expert consensus document
Practical guidance on using ACE-I in heart failure is given failure, to placebo or enalapril. Most patients had coro-
in Table 4.64 nary heart disease and prior MI. After an average of 3.12
years of follow-up, active therapy reduced the risk of
ACE-I compared with angiotensin receptor blockers death or hospitalisation for new or worsening heart
failure from 24.5% to 20.6%. There were approximately
The clinical efficacy of ACE-I has been compared with
70 fewer hospitalisations for worsening heart failure per
that of direct angiotensin-II receptor antagonists in
1000 patients treated (NNT for 3 years ¼ 14). The risk of
several trials. In most of the studies, the angiotensin-II
developing heart failure was reduced from 38.6% to
inhibitors were not superior to the comparator ACE-I. In
29.8% and the median length of time to the development
the second losartan in heart failure survival study
of heart failure increased from 8.3 months in the placebo
(ELITE-2)65 mortality in 3152 patients with chronic heart
group to 22.3 months in the ACE-I group. Neither all
failure was similar in losartan and captopril allocated
cause death nor hospitalisations from any cause were
These data suggest that ACE-I may have a role in early approximately 2.5 years, to prevent or postpone 1 pre-
management as well as in the convalescence phase of mature death). These trials also showed that ACE-I reduce
acute MI but only in high risk groups. If treatment is the risk of developing heart failure and requiring hospi-
initiated early, i.v. enalapril should be avoided; the ini- talisation for heart failure. With ACE-I treatment, the risk
tial dose should be low and increased progressively of reinfarction was reduced from 13.2% to 10.8% and the
within 48 h with monitoring of blood pressure and renal risk of heart failure hospitalisation from 15.5% to 11.9%.
function. As a result of these trials there was debate about how
Late intervention trials. The trials including selected ACE-I should be used in MI. One approach advocated the
high risk patients with treatment initiated later (>48) treatment of all patients initially, with continued treat-
after AMI and continued long term demonstrated a ment only in those with clinical evidence of heart failure
greater benefit obtained from the treatment with ACE-I. or left ventricular systolic dysfunction. Others argued
In the SAVE study31 2230 patients with a LVEF <40% that the small benefit of acute therapy in unselected
heart failure, reduced systolic left ventricular ejection In the Perindopril Protection against Recurrent Stroke
fraction or diabetes, previous myocardial infarction or Study (PROGRESS)99 6,105 hypertensive and non-hyper-
stroke and patients with high coronary disease risk, tensive patients with a history of stroke or transient is-
based on the efficacy of these drugs in these patient chaemic attack, were randomly assigned active
populations91–93 (Table 6). treatment (perindopril, with the addition of indapamide
In the second Swedish Trial in Old Patients with hy- at the discretion of treating physicians) or placebo. The
pertension (STOP-2)94 6,614 patients aged 70–84 years primary outcome was total stroke. After a follow-up of 4
with hypertension were randomly assigned conventional years active treatment reduced the incidence of stroke
antihypertensive drugs (atenolol, metoprolol, pindolol, (10% vs. 14%) and also the risk of total major vascular
or hydrochlorothiazide plus amiloride) or newer drugs events. The reduction of stroke was similar in hyper-
(enalapril or lisinopril, or felodipine or isradipine). Blood tensives and normotensives. Combination therapy with
pressure was decreased similarly in all treatment groups. perindopril and indapamide produced larger blood pres-
33,357 hypertensives with at least one other cardiovas- patients. Enalapril failed to reduce the severity of coro-
cular risk factor. Patients were divided into 3 groups to nary lesions as compared with placebo.
receive chlorthalidone, amlodipine or lisinopril. The Several large multicenter trials were designed to test
primary outcome was cardiovascular death or non-fatal whether an ACE-I reduces major cardiovascular events in
myocardial infarction. Secondary outcomes included all- populations selected for coronary or other vascular dis-
cause mortality, stroke, and different combined cardio- eases, including the Heart Outcomes Prevention Evalua-
vascular outcomes including coronary revascularisation, tion Study (HOPE), the EURopean trial On reduction of
angina with hospitalisation, heart failure and peripheral cardiac events with Perindopril in stable coronary Artery
vascular disease). The follow-up period was 4.9 years. disease (EUROPA), the Prevention of Events with Angio-
Although the primary outcome failed to demonstrate a tensin-Converting Enzyme Inhibition (PEACE) and the
difference between treatments, and all cause mortality telmisartan alone and in combination with ramipril glo-
was also similar for lisinopril vs. chlorthalidone. Lisino- bal endpoint trial (ONTARGET) trials.
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