1. health and fitness
2. disease

Chapter 10
Drug differences between ACE-inhibitors in
experimental settings and clinical practice.
Adriaan A. Voors1,2, J.Herre Kingma1,2, and Wiek H. van Gilst1
1. Department of Clinical Pharmacology, University of Groningen, the Netherlands.
2.Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
:
J Cardiovasc Risk 1995;2:413-22.
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Summary
In recent years years, growing evidence has suggested a beneficial effect from the use of
ACE-inhibitors after myocardial infarction. Since important differences between
structure and effects of the various ACE-inhitors exist, differences in outcome can be
expected. This review discusses the structural, pharmacodynamic and pharmacokinetic
differences between ACE-inhibitors administered after myocardial ischemia, both in
experimental settings and in clinical practice.
Introduction
In the first days after acute myocardial infarction, the renin-angiotensin system (RAS) is
activated.1 In some patients, this activation continues, which may cause harmful effects.
Angiotensin-converting enzyme (ACE)-inhibitors have been described to influence this
activation beneficially. Therefore, administration of ACE-inhibitors after acute
myocardial infarction could lead to a reduction in morbidity and fatal events. Indeed,
experimental studies have revealed protective effects of ACE-inhibitors after myocardial
ischemia.2,3 However, there has been considerable variability in the type, structure and
dose of the ACE-inhibitor used. Studies comparing the effects of different ACEinhibitors after myocardial ischemia have consequently resulted in controversial
outcomes. In the experimental setting, some studies showed equally beneficial effects
for all drugs tested,4-7 other studies did not find any beneficial effects of ACE-inhibitors
after myocardial infarction,8,9 and some studies reported only beneficial effects for ACEinhibitors containing a sulphydryl-group.10
The majority of clinical studies on the effects of ACE-inhibitors after acute myocardial
infarction have resulted in decreased morbidity and mortality. However, when ACEinhibitors were started early after acute myocardial infarction in a non-selected patient
group, the results remained controversial.11
ACE-inhibitors after acute myocardial infarction have been postulated to act through
different mechanisms. Most of their effects contribute substantially to the risk of
subsequent clinical events.12 Because of this heterogeneity, the overall clinical outcome
may be a result of both beneficial and harmful aspects.
Besides the use of different ACE-inhibitors and the heterogeneous effects of these
drugs, there may be other explanations for the contradictory results: for example,
differences in experimental settings. In clinical studies, the selection of patients and the
time at which the therapy was started could have seriously affected the outcome. This
review discusses structural, pharmacodynamic and pharmacokinetic differences between
various ACE-inhibitors in view of the contradictory results of ACE-inhibitors
administered after myocardial infarction.
differences between ACE-inhibitors
Local vs. Circulating RAS
It was initially thought that the RAS was an enzymatic cascade that acted only as a
circulating endocrine system. Circulating renin is formed by the juxta-glomerular cells of
the kidney and converts angiotensinogen to angiotensin I. Finally, in the plasma, ACE
cleaves off two aminopeptides, rendering the effector angiotensin II. However, studies
have demonstrated that chronic administration of ACE-inhibitors lowers blood pressure
when plasma renin activity is not elevated,13 or even low, as in anephric subjects.14 Also,
in asymptomatic cardiac dysfunction, increased plasma renin activity was either not
associated with clinical outcome,15 or not related to the beneficial effects of the ACEinhibitor captopril.16 Thus, the clinical effects of ACE-inhibitors might not be related to
the activity of the plasma renin.
Meanwhile, renin-like enzymes were found in the heart, the blood vessels and many
other tissues.17 These findings led to the hypothesis that ACE inhibition may additionally
act through inhibition of tissue RAS, rather than just inhibition of the circulating RAS.
Cohen and Kurz18 were the first to describe how, in spontaneously hypertensive rats,
administration of an ACE-inhibitor could inhibit ACE in various tissues, including the
vascular wall. They also demonstrated that the antihypertensive action was associated
with persistent ACE inhibition in the kidney and the vascular wall, whereas it was not
related to ACE inhibition in the plasma. Additionally, Johnston et al.19 and Hirsch et al.20
reported an increased activation of tissue cardiac ACE after experimental myocardial
infarction, suggesting that some of the harmful effects might originate from local
activation of the RAS. Therefore, based on these data, it seems reasonable to conclude
that, after myocardial infarction, the effects of ACE-inhibitors on the local RAS may be
more important than the effects on the circulating RAS. Consequently, tissue
penetration of different ACE-inhibitors is probably a crucial determinant of each drug's
ability to inhibit ACE in the tissue, and could be more important than their kinetic
properties in the plasma.
Structural differences between ACE-inhibitors
The ACE-inhibitors can be divided in three groups21-23: (1) ACE-inhibitors that contain a
sulphydryl-group, such as captopril, zofenopril and alacepril; (2) carboxyl containing
compounds such as enalapril, ramipril, perindopril, cilazapril and quinapril; and (3) the
phosphorus containing inhibitors, such as fosinopril and ceranapril.
In general, carboxyl containing inhibitors are more potent than captopril, but may
have a limited bioavailability.24 This problem has been largely overcome by developing
prodrugs, which have to be converted into the active form. The potencies of the
relatively new class of phosphorus containing ACE-inhibitors are comparable with
captopril but they have a longer duration of action. Independent of their ACE inhibiting
property, the sulphydryl-containing inhibitors may exert cardiac effects due to the
presence of the thiol moiety. It has been suggested that the sulphydryl group acts as a
scavenger of free radicals and/or as antioxidant agent. These actions may play an
important role after myocardial infarction because of their beneficial effects on
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reperfusion-induced depression of contractility and reperfusion arrhythmias.25,26 Another
effect of the sulphydryl group is vasodilatation, either by a direct effect or by
potentiation of nitrovasodilatators.27,28 The variation in lipophilicity between ACEinhibitors might affect their ability to inhibit tissue ACE. Single oral doses of captopril,
fosinopril and particularly zofenopril were found to produce striking and long-lasting
inhibition of cardiac ACE, whereas equivalent doses of ramipril and enalapril only
induced minimal inhibition.29 This selective inhibition was confirmed by Frohlich and
Horinaka,30 when they compared effects of six ACE-inhibitors on cardiovascular
structure and function and systemic hemodynamics in rats. Although all ACE-inhibitors
(except quinapril) reduced ventricular mass, pumping ability remained unchanged at the
reduced pressure loads with both quinapril and captopril. Pumping ability was
diminished with CGS-16617, enalapril, and utibapril, whereas the performance curve
improved with cilazapril. Whether these dissociated responses were due to
pharmacodynamic (e.g., enzyme binding) or pharmacokinetic differences (e.g.,
lipophilicity), remains uncertain. Differences in tissue penetration between ACEinhibitors will mainly depend on molecular size and lipophilicity. However, differences
between ACE-inhibitors in tissue ACE inhibition are also due to different enzyme
binding properties. Other pharmacokinetic characteristics of different ACE-inhibitors
might also be important, such as the route and half-life elimination time.31 Relative
potencies measured in vitro by Cushman et al.32 of the active forms of seven ACEinhibitory drugs are: SQ29852, 1; captopril, 3.5; enalapril, 12; fosinopril, 13; zofenopril,
20; lisinopril, 24; and ramipril, 51. Further kinetic properties of the active forms of
several ACE-inhibitors from the three different groups are presented in table 1.
Effects of ACE-inhibitors after myocardial infarction
The effects of ACE-inhibitors after myocardial infarction have been postulated to be due
to several mechanisms (Figure 1). An important function of ACE-inhibitors is their
inhibition of the conversion of angiotensin I to angiotensin II. Angiotensin II causes
vasoconstriction as a direct effect, but also through stimulation of the synthesis and
secretion of aldosterone from the adrenal cortex, renal sodium reabsorption and volume
expansion of extracellular fluid. Another effect of angiotensin II is an increase of
sympathic activity by facilitation of noradrenaline release from presynaptic nerve
endings. This stimulation of the sympathic nerve system by angiotensin II may also be
mediated by other mechanisms, such as inhibition of noradrenaline re-uptake,
stimulation of adrenergic ganglia, increases in catecholamine biosynthesis and
sensitization of postsynaptic structures.33,34 Sympathic $-adrenergic stimulation during
acute ischemia is known to be arrhytmogenic.35 Finally, angiotensin II causes
proliferation of human vascular smooth muscle cells both directly and indirectly via its
adrenergic and catecholaminergic effects.
Another mechanism of action of ACE-inhibitors is the reduction of bradykinin
breakdown. During myocardial ischemia and reperfusion, bradykinin is stimulated, and
this effect can be potentiated by captopril.36 Bradykinin has vasodilatory properties by
release of prostaglandins37 and endothelium derived relaxing factor (EDRF).38 EDRF
Table 1. Kinetic properties of ACE-inhibitors
group
Sulfhydryl
generic name
Captopril
Enalapril
Ramipril
Perindopril
Cilazapril
Quinapril
Fosinopril
-
enalaprilat
ramiprilat
perindoprilat
cilazaprilat
quinaprilat
-
70%
40%
54-65%
19%
45-47%
?
25-29%
0.5-1.5 hours
4 hours
1.5-3 hours
2-6 hours
1.3-3.2
hours
1.5-2.1 hours
3 hours
renal
renal
metabolites
mainly renal
70% renal
80-99%
renal
renal
<50% renal
23-35 nM
1.0-5.2 nM
1.5-4.2 nM
2.4 nM
1.93 nM
3 nM
11 nM
1-2 hours
1 hour
5 min
?
active metabolite
Bioavailability
Effective plasma half life
time
Route of elimination
In Vitro IC50 for ACE*
Carboxyl
time to onset of action
0.5 hours
2-4 hours
1-2 hours
after oral dose
*IC50=concentration required for 50% inhibition of the ACE enzyme activity from rabbit lung
Phosphorus
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also has antigrowth properties. Other effects of bradykinin are the reduction of
reperfusion arrhythmias39 and inducibility of ventricular tachycardia 2 weeks after
myocardial infarction.40
Thus, ACE-inhibitors exert their effects through both the angiotensin II and the
bradykinin pathway, as well as having additional effects of the sulphydryl group of some
compounds. Therefore, ACE-inhibitors may have beneficial effects on myocardial
ischemia by several mechanisms. An example of the combined effects of ACE-inhibitors
is the reduction in myocardial oxygen demand: after myocardial infarction, ACEinhibitors reduce myocardial oxygen demand by decreasing afterload (angiotensin II9,
noradrenaline9, bradykinin8, prostacyclin8, EDRF8) without increasing heart rate
(angiotensin II9, noradrenaline9), and by causing regression of cardiac hypertrophy
(angiotensin II9, EDRF8).
Figure 1. Scheme explaining the mechanisms of action of ACE-inhibitors in ischemic heart disease.
EDRF=endothelium-derived relaxing factor; SH=sulfhydryl group.
Another mechanism by which ACE-inhibitors may exert anti-ischemic effects is
vasodilatation of the coronary vessels. To what extent this property is due to the
prevention of angiotensin II formation or to the inhibition of bradykinin breakdown
remains to be established. In our laboratory, we found that an Ang II-AT1-receptor
blocker completely abolished the vasoconstrictory effects to Ang I in human arteries,
differences between ACE-inhibitors
103
while ACE-inhibition only resulted in a small reduction of Ang II induced
vasoconstriction. These results indicated that effects other than the inhibition
angiotensin II formation may explain the clinical effects of ACE-inhibitors.41 The antiarrhythmic properties of ACE-inhibitors after myocardial ischemia are the result of
reduced angiotensin II formation, the inhibition of bradykinin breakdown and additional
effects of the sulphydryl group of some inhibitors.
Experimental setting
In experimental models, myocardial ischemia is mainly induced by ligation of a coronary
artery or by inflation of a balloon catheter. This causes an abrubt discontinuation of the
blood supply to a proportion of the myocardium, including the left ventricle. In some
models, this closure is discontinued, which causes reperfusion. Although there is a
marked resemblance with clinical myocardial infarction, some differences remain. The
most important concerns the abrubt nature of the experimental setting, which contrasts
with the gradual progression of coronary artery disease in the clinical setting, and which
may lead to formation of collateral circulation. Furthermore, in the experimental
situation, the non-infarcted regions of the heart are unaffected, whereas when
multivessel disease is present in the clinical situation, this will not be the case. These
differences should be considered when the results of experimental studies are compared
to the clinical situation.
In experimental studies, various beneficial effects of ACE-inhibitors after myocardial
infarction have been descibed. It needs to be emphasized that the effects of ACEinhibitors, administered early after the onset of myocardial ischemia, may be mediated
by acute intervention of a deleterious process, while the beneficial effects of ACEinhibitors, started after the healing process has completed, are probably due to
secondary prevention.
Amount of myocardial damage and infarct size
Animal studies in vivo have shown that ACE-inhibitors may reduce infarct size
during myocardial ischemia and reperfusion. Ertl et al.42 showed that captopril reduced
infarct size in dogs, although these results could not be confirmed by others.5,8 With a
closed chest pig model, we found that in vivo administration of captopril reduced
myocardial damage upon reperfusion after 1 h of ischemia in a dose-dependent way.43
In-vivo studies in cat and rat showed that enalapril may also reduce infarct size after
myocardial ischemia with and without reperfusion,44-46 while Martorana et al.47 found a
similar effect with ramiprilat in dogs. In isolated rat hearts, Grover et al.48 showed that
cell death was reduced only by the sulphydryl-containing ACE-inhibitors captopril and
zofenopril, compared with fosinopril, ceranapril, lisinopril, enalapril and ramipril,
although all compounds almost completely inhibited cardiac ACE activity. They
concluded that cardiac ACE inhibition alone was not sufficient to explain the antiischemic effects of ACE-inhibitors, and that the sulphydryl group might play an
important role. In an open-chest rabbit model, Hartman et al.49 compared the effects of
ramiprilat with the angiotensin II receptor antagonist losartan on myocardial infarct size
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and area at risk. They concluded that the reduction of myocardial infarct size was
independent of angiotensin II synthesis inhibition. Noda et al.50 compared the effects of
captopril with two other inhibitors of angiotensin II forming enzymes, nafamostat and
chymostatin. They found that the increase in Ang II release was inhibited by nafamostat
and chymostatin, but not by captopril, whereas bradykinin release was augmented only
by captopril. Since only captopril could reduce infarct size, the authors pointed out the
importance of bradykinin accumulation on the beneficial effects of ACE-inhibitors on
myocardial infarct size.
Thus, a reduction in myocardial damage could be demonstrated ACE-inhibitors
containing a sulphydryl group, with carboxyl containing compounds, and with
phosphorus containing inhibitors. Several investigators pointed out that these beneficial
effects were due not only to inhibition of angiotensin II formation, but also to
bradykinin accumulation and independent effects of the sulphydryl group.
Attenuation of the remodelling process
After myocardial infarction, the left ventricle can change its shape and size as a
response to loss of viable myocytes. This may lead to early infarct expansion,
accompanied by compensatory hypertrophy in the non-infarcted region and progressive
global dilatation, the major stimulus being wall stress. In selective patients, progressive
ventricular remodeling has an important impact upon survival.51,52 In rats with chronic
myocardial ischemia, it has been shown that ACE-inhibitors attenuated remodeling after
myocardial infarction, and this may result in a reduction of mortality.53,54 These findings
were supported by studies in canine, which demonstrated that captopril, started 2 days
after myocardial infarction, may have beneficial effects on the process of remodeling.55
The beneficial effects of ACE-inhibitors on the remodeling process after myocardial
infarction might be attributed to the reduction in preload or the combination of the
reduction of both preload and afterload.56 However, other factors that may alter the
remodeling process, including adrenergic stimulation, circulating hormones and
neuroendocrinologic factors, have not been well studied.57
Maintainance or even increase in ventricular performance/function
The reduction of preload and afterload by ACE-inhibitors is probably also the main
mechanism of maintainance or even increase in ventricular function after myocardial
infarction. It has been shown repeatedly in intact animals with acute left-ventricular
failure following coronary occlusion that several ACE-inhibitors improved ventricular
performance.58-60 In a study in isolated rat hearts, Grover et 48al. showed that ACEinhibitors containing a sulphydryl group improved post-ischemic contractile function,
whereas compounds without a sulphydyl group did not.
The influence of captopril on cardiac function after myocardial infarction was also
studied by Schoemaker et al. in conscious rats.61 They concluded that when captopril
therapy was started more than 3 weeks after infarction, cardiac function was improved
in a dose-dependent manner by increasing stroke volume. However, captopril treatment
started from 1 to 21 days after infarction not only failed to improve ventricular function
but also might have caused deterioration. These findings, and many other results, led to
differences between ACE-inhibitors
105
the important question about the optimal timing of the treatment with ACE-inhibitors
after myocardial infarction. Gay adressed this question in a study in rats subjected to
coronary ligation.62 He demonstrated that when rats were studied for 4 months,
initiation of captopril at 2 h after ischemia did not appear to produce a greater effect on
left ventricular volume and hemodynamic function than when it was started after 21
days.
Thus, treatment with ACE-inhibitors after myocardial ischemia might improve
cardiac function, especially after completion of the healing process. However, early
ventricular dilatation and hypertrophy may be an adaptive process, necessary to
maintain cardiac performance. Blocking these compensatory mechanisms could lead to a
decreased performance of the infarcted ventricle.63 This implies that ACE inhibition
early after onset of myocardial ischemia may act as a delicate balance between beneficial
and possible adverse effects. The ACE-inhibitors containing a sulphydryl group may
have additional effects on ventricular performance.
Anti-arrhythmic properties
Ventricular arrhythmias contribute significantly to the early mortality after acute
myocardial infarction. Clinical evidence suggests that sudden restoration of coronary
blood flow after myocardial infarction can result in serious structural and functional
derangements, leading to ventricular fibrillation.64-67 These reperfusion arrhythmias are
quite distinct from those associated with ischemia.68 Several authors suggested that
ACE-inhibitors have anti-arrhytmic properties.69,70 Studies in isolated rat hearts
consistently showed a reduction in ventricular arrhythmias after reperfusion.6,46,71-73
These findings were further supported by the results of in vivo studies.10,72,74,75 In a
direct comparison of the effects of captopril, enalapril and ramipril on the reduction of
reperfusion arrhythmias, we showed that captopril and ramipril protected against
reperfusion arrhythmias, where enalapril did not.76
We concluded that this effect was independent of inhibition of the formation of
angiotensin II, and was associated with an abolition of noradrenaline overflow upon
reperfusion, in which stimulation of prostacyclin synthesis appeared to play an important
role. However, since beneficial effects on reperfusion arrhythmias were also found with
ACE-inhibitors without a sulphydryl group, it remains uncertain whether these effects
could be ascribed to the sulphydryl group. An antiarrhythmic effect of bradykinin on
ischemia-induced arrhythmias and on reperfusion-induced ventricle fibrillation has also
been reported.40,77 Other mechanisms by which ACE-inhibitors could have
antiarrhythmic effects are the increase in sympathic tone, the increase in serum and total
body potassium, the reduction of ventricular damage and ventricular remodeling and the
increase in cardiac parasympathic activity.78
Thus, reduction of reperfusion arrhythmias after myocardial infarction with several
ACE-inhibitors have been clearly described in experimental models. However, because
of the multiplicity of mechanism, it remains uncertain whether these effects are more
pronounced in one group of ACE-inhibitors than in another.
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Reduction in mortality
Hypothetically as a result of all above described mechanisms, ACE inhibition during
or after myocardial ischemia should reduce mortality. Indeed, several experimental
studies described a prolonged survival with different ACE-inhibitors.53,54,79-81 Effects of
ACE-inhibitors on morbidity and mortality after acute myocardial infarction will be
further described in clinical studies.
ACE-inhibitions started after 48 h: clincial studies
In the previous part of this report, we described how the effects of ACE-inhibitors on
morbidity and mortality after acute myocardial infarction in the clinical situation can be
expressed by several ways. In addition, differences between the type of ACE-inhibitor
and its dose may influence clinical outcome. Another major determinant may be the time
at which ACE-inhibitor therapy is started. The effects of ACE-inhibitors administered
early after the onset of symptoms are due to intervention in a possible deleterious
process, while the aim of chronic administration, after the termination of the healing
process, is secondary prevention of complications. Clinical studies are now described in
which ACE-inhibition was started more than 48 h after the onset of ischemia.
Pfeffer et al.80 showed that the administration of captopril (maximum 3x50mg),
started 20 (range 12 to 31) days after myocardial infarction in patients with left
ventricular impairment, might attenuate the process of progressive left ventricular
dilatation. The beneficial effects on left ventricular dilatation of captopril (maximum
3x25mg) started late after myocardial infarction were also found by others.81
The Survival and Ventricular Enlargement (SAVE)82,83 study assessed long-term effects
of delayed (3-16 days) captopril therapy (maximum 3x50mg) in selected patients who
had symptomless left ventricular dysfunction. The authors concluded that long-term
administration of captopril was associated with an improvement in survival and reduced
morbidity and mortality due to major cardiovascular events. The same beneficial effects
were found with ramipril by the AIRE investigators.84,85 Patients with clinical evidence
of either transient or on-going haert failure, received ramipril (maximum 2x5mg)
between the second and ninth day after myocardial infarction, which resulted in a
substantial reduction in premature death from all causes.
After a follow-up period of 4 years, the TRAndolapril Cardiac Evaluation (TRACE)
study showed a significant (22%) reduction of mortality in patients with reduced left
ventricle function given trandolapril (4mg), 3 to 7 days after acute myocardial
infarction.(unpublished data)
Thus, clinical strudies with several ACE-inhibitors started after the acute phase of the
myocardial infarction in patients with reduced left ventricle function showed consistent
beneficial effects on cardiac morbidity and mortality. It should be noted that at the time
of administration of the ACE inhibitor, the remodelling process and infarct expansion
had already started. In addition, most of the reperfusion-induced arrhythmias should
have occurred within that time. It can be concluded therefore, either that there are other
mechanisms by which ACE-inhibitors exert their effects after acute myocardial
infarction or that the effects of ACE-inhibitors on remodelling, ventricular performance
differences between ACE-inhibitors
107
and infarct expansion are still present and important when therapy is started after the
healing process is completed.
ACE-inhibitors started within 48 h
The promising effects of the previous described clinical studies led to the question
whether earlier administration of ACe-inhibitors in patients with both impaired and
normal left ventricle function would provide additional beneficial effects.
This question was adressed by Sharpe and co-authors,86 who concluded that early
treatment with captopril (24-48 h after onset, maximum 2x50mg) effectively prevented
ventricular dilatation after acute myocardial infarction in patients with Q-wave
infarction but without clinical heart failure. These findings were supported by the results
of Vannan et al.,87 who reported that very early administration (within 24 h after onset)
of enalapril had beneficial effects on the ventricular remodeling after acute myocardial
infarction. However, theyt found no differences with administration of enalapril, started
at the third day after onset.
In the Cooperative New Scandinavian ENalapril SUrvival Study (CONSENSUS II)
study,88,89 intravenous administration of enalaprilat was started within 24 h after onset of
acute myocardial infarction, followed by oral administration (20mg), in a non selected
patient group. Compared with the placebo group, no significant difference was found in
mortality in the treatment group during the 180 days after infarction. Administration of
zofenopril (maximum 2x30mg) within 24 h after the onset of an anterior infarction in
the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study90,91 yielded
a mortality reduction of 29% after 1 year follow-up. In the Cats study,92-94 only patients
who were eligible to receive thrombolitic therapy were randomized within 6 h after the
onset of a first acute myocardial infarct to either captopril 3dd 6.25 mg orally or
placebo, within 30 minutes of the start of the streptokinase infusion. After 1 year of
follow-up, no significant reduction in mortality was found. However, patients
administered to captopril had a reduced incidence of heart failure and a reduction in
infarct size.
Two large clinical trials were performed to study the effects on mortality of ACEinhibitors started within 24 hours after the onset of myocardial infarction. Patients in the
Gruppo Italiano per lo Studio della Sopreavvivenza nell'Infarto miocardico (GISSI-3)
trial95,96 were randomly assigned to either receive lisinopril (10mg) or placebo. After 6
weeks, lisinopril produced significant reductions in overall mortality (11%) and in the
combined outcome measure of mortality and severe ventricular dysfunction.
A small but significant reduction in mortality of 6% after 5 weeks was also found
with captopril (maximum 2x50mg) by the Fourth International Study of Infarct Survival
(ISIS-4) investigators.97 No significant reduction in mortality was observed in the
Chinese Cardiology study, where 11345 patients received either captopril (3x12.5mg)
or placebo within 36 hours after the onset of myocardial infarction, and were followed
up for 4 weeks.98
The only clinical study in which a direct comparison was made between
administration of two types of ACE-inhibitors given within 24 hours after infarction, is
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the PRACTICAL study.99 The authors showed that enalapril (maximum 3x5mg) and
captopril (maximum 3x25mg) had a comparable effect on left ventricular function.
However, survival at 90 days and 12 months was significantly improved in the enalapril
group.
Compared to the consistently positive results of the studies in which ACE-inhibitors
were started after 48 h only in patients with left ventricular impairment, earlier
administration in an unselected patient group yielded less uniform results. Although in
most patients after acute myocardial infarction, the elevation of te RAS has returned to
normal by the 10th day, Rouleau et al.1 pointed out that clinical evidence of heart failure
was correlated with a continued activated RAS. Together with previous described
studies, it can be hypothesized that especially the modification of a prolonged activation
of the RAS by ACE-inhibitors results in a decreased mortality and morbidity.
Reduction of mortality by ACE-inhibitors are probably an overall result of different
actions, some of which can be beneficial and others harmful. Hence, conclusions about
the effects of one class of drugs compared to the other are difficult to make. Positive
effects of one drug on the one hand may be compensated by negative effects on the
other. For example, in the CONSENSUS II study, enalapril seemed to result into a
negative effects, yet in the PRACTICAL study, it proved more effective than captopril
in reducing mortality. However, the negative effects seen in the CONSENSUS II study
could have been caused by the intravenous administration, which frequently resulted in
hypotensive episodes. Such findings emphasize the possible importance of kinetic
properties of ACE-inhibitors on clinical outcome. Another comparison could be made
between the GISSI-3 and the ISIS-4; although there seems to be a small benefit of
lisinopril over captopril, the 20% longer duration of follow-up in the GISSI-3 study
should be taken into consideration.
Conclusions
It is now well accepted that the actions of ACE-inhibitors are strongly related to the
local inhibition of ACE in the vascular wall, the heart and other tissues. Therefore, the
tissue-kinetics of various ACE-inhibitors seem to be important. At present, ACEinhibitors are divided into three groups: (1) sulphydryl-containing compounds, (2)
carboxyl-containing compounds; and (3) phosphorus- containing compounds. As a
result of their different structure, different ACE-inhibitors have different abilities to
inhibit tissue ACE. An important effect of ACE-inhibitors is the inhibition of the
formation of angiotensin II, which exerts various effects on different organ systems.
However, several authors have suggested that other effects of these drugs are even
more important than the reduction of angiotensin II formation. The inhibition of
bradykinin breakdown may also contribute significantly to the effects of ACE-inhibitors;
moreover, independent effects of the sulphydryl group have also been demonstrated.
Thus, the effects of ACE-inhibitors may result from a wide variety of mechanisms.
Consequently, it is also conceivable that different ACE-inhibitors have different effects
on each of these pathways. Some ACE-inhibitors may have positive effects on one
aspect, and simultaneous negative effects on another. For this reason, it may be difficult
differences between ACE-inhibitors
109
to correlate structural differences of ACE-inhibitors with outcome of both experimental
and clinical studies.
Experimental models showed that ACE-inhibitors administered during or after acute
myocardial ischemia, can reduce myocardial infarct size, attenuate the adverse
remodelling process, increases cardiac performance, limit reperfusion arrhythmias and
may reduce mortality. Although in some experimental studies, the ACE-inhibitors
containing a sulphydryl group were more effective than those without a sulphydryl
group, those differences were not confirmed by other studies. Notably, some additional
benefits of the sulphydryl group on ventricular performance were reported.
Although different effects between ACE-inhibitors are difficult to detect in
experimental studies, conclusions about differences between ACE-inhibitors in clinical
studies are even more difficult, mainly because other factors also appeared to be
important. Administration of ACE-inhibitors in patients with left ventricular impairment,
more than 48 h after the onset of acute myocardial infarction resulted in a decreased
mortality. However, when administered during the acute phase, albeit in a non selected
patient group, studies provide contradictory results. The inclusion of patients with a
normal left ventricle function may have counteracted the benefits seen in patients with a
deteriorated function. Moreover, early administration may have had a negative effect on
the results, possibly because of adverse mechanisms. For example, reduction of blood
flow is usually tolerated without problems, but in an ischemic myocardium, this may not
be the case. Also, a large body of evidence suggests that a prolonged activation of the
RAS after acute myocardial infarction is harmful, whereas an acute stimulation could be
less hazardous. Especially in clinical trials, both beneficial and adverse effects of ACEinhibitors administered early after acute myocardial infarction, may have resulted into a
neutral effect. The positive effects on the ischemic event of longterm administration of
ACE-inhibitors after acute myocardial infarction further suggests anti-ischemic effects
of ACE-inhibitors. Consequently, a large, randomized, double-blind, placebo-controlled
studie has been started to establish the anti-ischemic events of longterm administration
of quinapril.100
Thus, as a result of the wide variety of mechanisms by which ACE-inhibitors may act,
and of the wide variety in settings of both experimental and clinical studies, no
preference can currently be made for one type of ACE-inhibitor over the other.
Additional experimental and clinical studies should be performed to correlate more
specifically the adverse and beneficial effects of ACE-inhibitors on clinical events with
the drugs' properties at the tissue level. Such a study is QUO VADIS (The effects of
QUinapril On Vascular Ace and Determinants of ISchemia) study, which we recently
started. The aim of this randomized, double-blind, placebo-controlled trial is to
determine the effects of quinapril on ischemic events during coronary bypass surgery
and at 1 year follow-up, and to correlate these results with in-vitro measurements of the
activity of the ACE-inhibitor at tissue level. These and other studies will, we hope,
result in a better understanding of how ACE-inhibitors contribute to the beneficial
outcome in clinical events, which in turn should lead to a more selective approach to the
type of ACE-inhibitor to be used.
110
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