Clin. Cardiol. Vol. 18 (Suppl.
11), 11-26-11-33 (1995)
The Effects of ACE Inhibition on Ischemic Cardiac Events: Pump Failure,
Reinfarction, Hospitalization for Angina, and Ventricular Tachyarrhythmias
CARLJ.&PINE, M.D., F.A.C.C.
Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA
Summary: Angiotensin-converting enzyme (ACE)inhibitors
have been shown to reduce the incidence of mortality follow-
ing myocardial infarction (MI) and to have beneficial effects
on the consequencesof MI. Various studies, including several
large-scaletrials such as ISIS-4, GISSI-3, SAVE, AIRE, and
SOLVD, have demonstratedthe beneficial effects of ACE in-
hibitors on mortality and morbidity after both early (up to 48 h
post-MI) and late (weeks to months post-MI) intervention.
Morbidity benefits includereduced incidencesof heart failure,
unstable angina, and reinfarction, although the latter two ef-
fects may not become evident until 9 and 18 months, respec-
tively, after treatment initiation.These effects are independent
of dose used, and a class effect of ACE inhibitors seems likely.
Finally, a primary advantage of using ACE inhibitors in pa-
tients with cardiac disease is shown by the substantial savings
which can be achieved, particularly in terms of reduced need
for hospitalization for reinfarction, unstable angina and heart
failure. In addition to their proven mortality benefits in acute
MI, ACE inhibitorsreduce heart failure and/or left ventricular
dysfunction. Benefit accrues whether treatment is initiated
early or late.
Key words: angiotensin-converting enzyme inhibitors, my-
ocardial infarction,mortality, morbidity
Introduction
Atherosclerosisis a principal contributor to the pathogene-
sis of myocardial infarction (MI), while hypertensionis impli-
cated in left ventricular hypertrophy (LVH),congestive heart
Address for reprints:
Professor Carl J . Pepine
Division of Cardiovascular Medicine
University of Florida
1600 Archer Road
PO Box 100277
Gainesville, FL 32610-0277, USA
failure (CHF), and cardiac dysrhythmias.' The consequences
of hypertensive heart disease involve increased myocardial
oxygen demand associated with reduced coronary blood flow
and flow reserve. These are, in part, related to LVH and its as-
sociated microvascular disease. '
The risk of coronary heart disease is intimately associated
with high blood pressure; however, there is limited evidence to
date that antihypertensiveagents prevent or even reduce the
incidence of MI, with the exception of beta blockers. What-
ever the effects of antihypertensivetreatment on variables im-
plicated in coronary pathology, such as lipid metabolism, glu-
cose, and insulin resistance, the most important factor is the
overall effect on prognosis for coronary events.'
Although angiotensin-convertingenzyme (ACE) inhibitors
have been shown to reduce mortality in patients with severe
CHF, no data are available as yet which clearly demonstrate a
reduction in sudden death,*but they do seem to reduce the in-
cidence of subsequent acute coronary events such as late car-
diac death, MI, and unstable a n g i ~ ~ a . ~ - ~
In animal models of myocardial infmtion, ACE inhibitors
prevented progressive ventricular enlargement and also pro-
longed survival compared with controls. Such experimental
data suggest that ACE inhibitor therapy alters ventricular re-
modeling after MI and may, therefore, influence heart failure
and survival?
Clinical Evidence for the Anti-Ischemic Actions of
ACE Inhibitors
The clinical benefits of administeringACE inhibitors dur-
ing evolving MI and following MI are reviewed below. A
summary of the trials used to provide data for this review is
shown in Table I.
Mortality Benefits of Early Intervention with ACE
Inhibitors in Myocardial Infarction
The renin-angiotensin system is activated early during
acute MI, leading to stimulation of cardiac contraction and in-
creased systemic and coronary vascular re~istance.~ Increases
in systemic vascular resistance may increase myocardial wall
 C. J. Pepine: Effects of ACE inhibition on ischemic cardiac events
TABLE1 Summary of trials using ACE inhibitors in the manage-
ment of MI
Timing of
Patient ACE Follow-up
TriaVACE inhibitor population inhibitor (months)
GISSI-3flisinopril AMIAJAP 524h 1.4
ISIS-4/captopril AMWAP 524h 1.2
AIWramipril AMVCHF 5 days 15
SAVWcaptopril EF <40%IAMI 11 days 42
SOLVD/enalapril EFI 35%/MI/IHD > 30 days 48
Abbreviations:ACE = angiotensin-convertingenzyme, AM1 = acute
myocardial infarction,UAP =unstable angina pectoris, CHF = con-
gestive heart failure,EF = ejection fraction,MD = ischemicheart dis-
ease.
stress, leading to further unwanted effects, such as infarct ex-
pansion and an increase in ventricular arrhythmia^.^^^
The potential benefits of early or late interventionwith ACE
inhibitorsafter MI are clearly of value, but are not limited to ef-
fects on left ventricularsize and shape. The extent of infarct ex-
pansion and left ventricular dilatation, which is also an early
pathophysiologic event, has an important bearing on clinical
progno$s.'O It has been established that left ventricular dilata-
tion can be improved if ACE inhibitors are started more than 1
week afterMI, producing a subsequent reduction in the occur-
rence of heart failure.ll9 However, as the potential for pro-
gressive ventricular dilatation exists from the time of the in-
farction, and severe left ventricular dysfunction is present in
many patients by the time CHF is clinically evident, it follows
that earlier interventionwould confer even greater benefit.
S e v d small-scalestudies have shown that ACE inhibitors
given alone or in combination with other agents ( e g , nitro-
glycerin, tissue-typeplasminogen activator) within 24 to 48 h
of onset of MI symptoms can lower the incidence of ventricu-
lar dilatation,decreaseleft ventricular volumes, and favorably
influence early left ventricularremodeling.13-17
Three large-scale studies have investigated mortality bene-
fits of early intervention with ACE inhibitors after MI. The
InternationalStudy of Infarct Survival4 (IS1S-4)l8compared
addition of oral captopril(1month), oral controlled-releaseni-
trates (1 month), or intravenous magnesium (24 h) to about
58,000 patients presenting within 24 h of onset of suspected
acute MI. At the end of 35 days of treatment,there was a statis-
tically significant mortality benefit in the captoprilg r 0 ~ p . l ~
The Gruppo Italian0 per lo Studio della Sopravvivenza
nell'Infarto Miocardico-3 (GISSI-3)*Otrial involved approxi-
mately 19,000 patients who were treated within 24 h of MI
with lisinopril alone, nitrates alone, lisinoprilplus nitrates, or
no trial therapy; 95% of patients had a documented acute MI.
There was an 11% reduction in 6-week mortality for oral
lisinopril alone or in combination with glyceryl trinitrate
(6.3%)compared with controls (7.1%), and a reduction in the
incidence of severe left ventricular dysfunction or death. This
study includedhigher-risk groups such as the elderly.
11-27
The second Cooperative New Scandinavian Enalapril
Survival Study (CONSENSUS II)? which examined the ad-
dition of intravenous enalapril to conventional therapy withm
24 h of the onset of chest pain in 6,090 patients, showed con-
flicting results. No survival advantage was found for the group
receiving enalapril at 6 months compared with placebo, and
the study was terminated earlier than planned. The results may
have been due to the aggressive intravenous treatment regi-
men used which may have given rise to clinically important
hypotension in susceptible patient groups. Other suggested
reasons include inadequatedosing, suppression of angiotensin
11-mediated compensatory mechanisms during early healing,
the antihypertensiveeffect of intravenous enalaprilat, or too
short a follow-upperiod.
Preliminary results from the Chinese ACE-AM1 trial, in
which over 10,000patients with acute MI received either cap-
topril or placebo within 36 h of the event, support the results
from GISSI-3 and ISIS-4.22
Morbidity Benefits of Early Interventionwith ACE
Inhibitors in Myocardial Infarction
In response to ventricular dysfunction, ventricular dilata-
tion (increased left ventricular diastolic and systolic volume
indices) develops progressively,to an extent dependent on the
amount of primary damage induced by the infarction, and
global contractile performance declines. This parameter, as-
sessed by ejection fraction, is reduced in direct relation to the
extent of the histologic However, stroke volume
does not decline consistently after infarction, as acute and
long-termcompensatory responses help to maintain it, provid-
ing the noncontractileregion involves less than approximately
20% ofthe left ventricular circumference.2426
kj?ventricularfinction: The effect of lisinopril treatment
on ventricular function in approximately 19,000patients with
early MI was investigated as part of the GISSI-3trial?O Exten-
sive left ventricular damage, identifiedby an ejection fraction
of <35%, was present in a greater percentage of control pa-
tients (5.3%) than in those receiving lisinopril(4.8%) after 6
weeks of treatment. The combined end point of mortality,
heart failure, and left ventricular dysfunction was significantly
lower in the lisinopril group (15.6%) compared with patients
not receiving lisinopril(17.0%; 2p = 0.009).
Data from GISSI-3 also suggest that Killip class may be a
more reliable indicator of clinical heart failure; 27.5% of pa-
tients presented with a Killip classificationgreater than I, and
lisinoprilwas associatedwith a greaterbenefit in these patients
compared with those in Killip class I.
In a study involving 10patients with heart failure following
MI, treatment with captopril significantly improved cardiac
hemodynamics, reducing left ventricular filling pressure, sys-
temic vascular resistance and pulmonary arterial pressure, and
increasing cardiac output. These beneficial effects were main-
tained for up to 3 ~ears.2~
In the CONSENSUS 11trial?l although enalapril treatment
did not have a beneficial effect on mortality from heart failure,
significantlyfewer patients had their therapy changed because
11-28 Clin. Cardiol. Vol. 18 (Suppl II), April 1995
of worsening heart failure (27%) compared with placebo
(30%; p < 0.006).Similar results were obtained in the smaller
Captopril After Thrombolysis Study (CATS) in which capto-
pril treatment was given to 298 patients receiving streptoki-
nase within the first 24 h of MI; the reported incidence of heart
failure fell from 24 to 1.5% (p < 0.05).?8The Survival of Myo-
cardial Infarction Long-Term Evaluation (SMILE) pilot study,
in which 204 patients who were not receiving concomitant
thrombolytic therapy were investigated, reported that acute
left ventricular failure was decreased by 63% in patients re-
ceiving xofenopril treatment; ejection fraction improvements
were also observed after 4 weeks.2y
Angina: In the SMILE pilot study, the incidence of unstable
angina during the in-hospitalphase was significantly reduced in
the ACE inhibitor-treated arm compared with placebo-treated
patients (8.9 vs. 27%). Recurrence of angina was significantly
prevented: anginal episodes in zofenopril-treated patients were
reduced by 68% in the short term and by 56% in the long term.29
However,zofenopril had no effect on stable angina.
Arrhyihmius: Two studies of small sample size have sug-
gested suppression effects of early administration of oral ACE
inhibitors on the frequency of ventricular arrhythmias. In 20
patients with CHF, 14 of whom were post-MI, enalapril
treatment significantly reduced the incidence of ventricular
complexes, ventricular couplets, and ventricular tachycardia
compared over 3 months with placebo; there was also a non-
significant reduction in atrial premature complexes.30In the
GISSI-3 study, sustained ventricular tachycardia was signifi-
cantly reduced during the in-hospital phase in patients treated
with lisinopril compared with those not receiving lisinopril
( 183 events vs. 226 events; 2p < 0.05). However, this effect
was not seen in the following 6 weeks, although a trend in
favor of lisinopril was noted (1 96 events vs. 234 events) (un-
published data).
In another study, however, oral captopril treatment did not
significantly reduce the incidence of ventricular arrhythmias
in theearlyphase(48 h)ofacuteMIin lOOpatient~.~’
In the CATS study, the frequency of ventricular arrhythmia
in the acute phase was 18% lower in ACE inhibitor-treatedpa-
tients compared with placebo.28Similarly, ventriculararrhyth-
mias were reduced by 39%in zofenopril-treatedpatients in the
SMILE study.29
Mortality Benefits of Late Intervention with ACE Inhibitors
Multiple large-scale studies have shown significant reduc-
tions in mortality following use of ACE inhibitors in MI. In the
Survival and Ventricular Enlargement trial (SAVE): captopril
or placebo were administered within about 11 days after MI to
patients withejectionfractionsof140% (1,115 and 1,116pa-
tients, recpectively), for an average of 42 months. Mortality
from all causes was significantly lower in the ACE inhibitor
group compared with placebo (20 vs. 25%, respectively); the
reduction in risk was 19% (p = 0.019).4Furthermore, cardiac
death, development of severe heart failure, hospitalization for
heart failure, and recurrence of MI were all substantially re-
duced in the active treatment group.
In the Acute Infarction Ramipril Efficacy (AIRE) study,5
patients received either placebo (n = 982) or ramipril (n =
1,004)from approximately 5 days after acute MI for an aver-
age of 15 months. Mortality in the placebo group was signifi-
cantly higher (23%) than in the ramipril group ( I 7%); the
overall reduction in risk was 27% (p = 0.002).The study con-
cluded that oral administration of an ACE inhibitor to patients
with clinical evidence of either transient or ongoing heart fail-
ure, initiated between the second and ninth day after MI, re-
sulted in a substantial reduction in premature death from all
causes.
Morbidity Benefits of Late Intervention with ACE
Inhibitors
The benefits of ACE inhibitors administered 48 or more
hours after the first onset of symptoms are even greater than
the reduction in mortality. Infarct expansion, beginning within
a few days of MI, reaches a plateau at 1 week and continues
over a period of 6 to 30 months, and is accompanied by a sig-
nificant increase in left ventricular cavity size.32-3sAlthough
early cavity enlargement tends to restore normal systemic he-
modynamic function, as previously discussed, long-term con-
sequences are potentially deleterious?
In the Study of Left Ventricular Dysfunction (SOLVD)
combinedtrials,” the majority of patients were not in heart Fail-
ure and did not require heart failure treatment, whereas 80%
had definite ischemic heart disease and 76% had a document-
ed MI. In these trials, involving 6,797 patients with left ven-
triculardysfunction (ejection fraction 5 35%) mostly due to re-
mote MI (e.g., > 30 days), enalapril reduced death, hospitali-
zation for unstable angina, and MI on average 2(h300/0.Fol-
low-up was for as long as 6 years (average 4 years).
In 27 patients with left ventricular dysfunction following
MI (mean ejection fraction 33%), treatment with an ACE in-
hibitor, initiated during the second year, resulted in reduced
ventricular volumes and increased stroke volume index and
ejection fraction (Fig. l).37These data demonstrate that pro-
gressive left ventricular dysfunction following MI can be par-
tially reversed with late ACE inhibitor.
Heurtfailure: Various large-scale placebo-controlled stud-
ies have shown the long-term benefits of ACE inhibitor inter-
vention (Fig. 2). Two of these (SAVE4 and AIRES) have
reported reductions in the incidence of heart failure when
treatment was initiated within 3 to 16 days of MI, and in
SOLVD3when initiated well after 30 days post-MI.
In the SAVE trial: in which patients did not have overt
heart failure or symptoms of myocardial ischemia but did have
ejection fractions of 540% the incidences of both fatal and
nonfatal major cardiovascular events were consistently re-
duced in the captopril group. The reduction in risk was 37%
for development of severe heart failure4 (which was virtually
identical to that seen in SOLVD) and 22% for congestive hem
failure.
In the SOLVD 39 significantly fewer patients treat-
ed with an ACE inhibitor died or were hospitalized for heart
failure compared with placebo [434 vs. 5 18 in the prevention
 C. J. Pepine: Effects of ACE inhibition on ischemic cardiac events
121
0 1 3 6 9 1 2 1 8 2
Months
FIG.I Serial changes in end-diastolic volume index and end-sys-
tolic volume index following myocardial infarction during the first
year with placebo or furosemide treatment and the second year with
open captopril treatment (from Ref. 37). -= end-diastolic volume
index, .......= end-systolic volume index.
arm (p<O.OOI) and 613 vs. 736 in the treatment arm (p <
0.OOo 1 ), respectively].
While all patients enrolled into the AIRE trials had clinical
evidence of heart failure, fewer patients in the ACE inhibitor-
treated gmup were classified as having severehesistant heart
failure ( 14%) compared with placebo-treated patients (1 8%)
at end point; risk reduction for severehesistant heart failure
was approximately 28%.
Uti.v/ahleAngina: The effect of ACE inhibitor treatment on
the incidence of post-MI angina has been investigated in the
two SOLVD trials’ which involved patients with low ejection
fractions, mostly due to ischemic heart disease with old MI.
Patients with overt heart failure (n = 2,569) were entered into
the treatment trial and those with asymptomatic left ventricu-
lar dysfunction into the prevention trial (n = 4,228). Over a
mean follow-up period of 40 months, combined data showed
that significantly fewer patients in the enalapril group were
hospitalixd for unstable angina compared with placebo-treat-
ed patients (Table 11), although this effect on unstable angina
AIRE *
SAVE **
(prevention)
SOLVD *** ~-~p<o.Ool
, 1 , I
0 10 20 30
YORisk reduction
FIG.2 Development of heart failure in three major intervention tri-
als. *Severe/resistantheart failure, **severe heart failure, ***con-
gestive heart failure.
11-29
I1 Number of patients hospitalized for unstable angina in the
TABLE
SOLVD treatment and prevention trials
Enalapril Placebo p-Value
SOLVD (prevention) 312 355 < 0.05
SOLVD (treatment) 187 240 < 0.00 I
was not seen until about 9 months after treatment initiation.
However, the effect of ACE inhibitor treatment on the inci-
I
dence of new or worsening stable angina was not significantly
4 different to that of placebo.
Myocardial infarction: Three of the large-scale trials have
also documented a significantly reduced incidence of MI
(Fig. 3). In the two SOLVD studies,3the risk reduction in non-
fatal MI appeared to be larger than the reduction in fatal MI
(29 vs. 14%), although confidence intervals do not suggest
heterogeneity; the average reduction in MI was 24%. Pre-
vention of reinfarction took at least 18 months of treatment,
from which time progressive improvement was seen. In the
SAVEtrial: the reduction in reinfarction was 25% in ACE in-
hibitor-treated patients, virtually identical to the results of the
~0~~~triais.3
It has been postulated that reduction in MI after ACE-in-
hibitor treatment is probably due to a combination of mecha-
nisms, including blood-pressure reduction, coronary vasodi-
latation, antiproliferative effects, prevention of atherosclerosis
progression, and inhibition of the adverse effects of angio-
tensin II on the balance between increased myocardial oxygen
demand and supply.4O,41 The fact that in the SOLVD trials
there was no difference in outcome between patients having
above average or below average oxygen demand suggests that
the long-term effect of ACE inhibitors is not due solely to re-
duction in blood pressure.
Arrhythmias: ACE inhibitor treatment ha? been found to re-
duce the number of arrhythmic episodes in patients with
symptomatic heart failure who had exercise-induced ventricu-
lar arrhythmias after previous Q-wave MI. After 3 months of
treatment with benazepril, ventricular tachycardia was reduc-
ed by 66% and premature Ventricular complexes by 61 %.42
SOLVD pc0.02
(treatment)
SOLVD * p<o.o1
(prevention)
SAVE ** p=0.015
I
40
0 5 10 15 20 25
% Risk reduction of MI
FIG.3 Risk reduction of myocardial infarction (MI) in three major
intervention trials. *Fatal and nonfatal MI, **recurrentMI.
11-30 Clin. Cardiol. Vol. 18 (Suppl II), April 1995
TAf3I.E Ill Doses of ACE inhibitors used in large-scale studies
Study (drug) Dose
ISIS-4 (captopril)18 100mg/day
CONSENSUSI1 (enalapril)21 20 mg/day
SAVE (~aptopril)~ 75 mg/day ( m a . 150mglday)
AIRE (ramipril)’ up to 10mg/day
SOLVD (enala~ril)~ up to 20 mg/day (average 17.5mg)
None of the patients had sustained arrhythrmas. Enalapril
treatment also produced a significant decrease in premature
ventricular complexes, ventricular couplets, and ventricular
tachycardia in patients with CHF due to MI, whereas the
placebo group had no change in arrhythmia frequency. How-
ever, in the SOLVD trials, no significant effect on ventricular
arrhythmias was found in a subgroup of 365 patients random-
ized to enalapril compared with 369 patients randomized to
pla~ebo.~’
Since ACE inhibitors do not have a direct antiarrhythmic
action, the beneficial effect has been attributed to improved
hemodynamics and changes in ventricular loading which in-
fluence repolarization.‘“‘
Doses of ACE Inhibitors
As shown in Table 111,the doses of ACE inhibitors used so
far in clinicaltrials have tended to be high.
However, where dose analysiswas performed,there was no
apparent gradient effect across 2.5 to 5 to 10 mg of enalapril.
Nevertheless, it must be borne in mind that more severely ill
patients (who benefit most from treatment) probably will be
taking lower doses as they are unable to tolerate the higher
dose le~els.4~ Consequently,it is not necessary to discontinue
treatment in patients who are unable to tolerate the full ACE
inhibitor dose.
Because of the paucity of data on doses, there is an ongoing
trial which is assessing the effect of high and low doses of
lisinoprilon morbidity and survival in patients with moderate
to severe heart failure (ATLAS)?6
Class Effects of ACE Inhibitors
ACE inhibition is associated with the prevention of
ischemia-related events in patients with coronary heart dis-
ease. In both animal and human studies, the effects of ACE
inhibitors extend across all agents regardless of whether they
are CNS active (e.g., enalapril), contain a sulphydryl group
(e.g., captopril),or are tissue active (e.g., ramipril).
This class effect of ACE inhibitors is best illustrated by
comparing results from major studies which have utilized dif-
ferent agents. Mortality following MI was reduced following
interventionwith enalapril (SOLVD),3lisinopril (GISSI-3),2O
captopril (ISIS-4;SAVE)!. l 8 and ramipril
Beneficial effects, where specifically studied, were noted
with respect to ventricularfunction [lisinopril(GISSI-3)20and
~aptopril~~],heart failure [enalapril (CONSENSUS 11):’
ramipril (AIRE)? and captopril (SAVE)4],arrhythmias (enal-
apriL30~aptopril,~’and benazepri14*)and reinfarction [enal-
april (SOLVD)3andcaptopril(SAVE)4].
Cost Effectiveness
At a time of limited financial resources and unlimited de-
mand for health care, cost savings within health services are
becoming ever more important to hospital administrators.The
search for methods of cost reduction in health-care provision,
which include promotion of preventive measures, effective
drug treatments, and the preventiodreduction of hospital
stays, are therefore being sought.
Data from the SOLVD trial3demonstratedthat addition of
an ACE inhibitor to conventional therapy significantly re-
duced hospitalizationsdue to heart failure (by 30%) in patients
with chronic CHF and low ejection fractions mostly due to old
MI (75% had documented MI). Reduced hospitalizations
were also reported in the A R E study.5Furthermore, a study
designed to assess the economic impact of enalapril on the
health-carebudget in Canada showed a 30% reduction in hos-
pitalizationsfor unstable angina and heart failure over a 4-year
period, which represented a saving of approximately $600 per
~atient.4~ Similarly, a Dutch study of ACE inhibitor treatment
of heart failure estimated net savings in total health-care costs
of 12million Dutch Guilders (approximately& I
million) in the
first year, increasing to 30 million DG (El 1 million) per year
from the third year onward if all heart failure patients were
treated with ACE While neither of these calcula-
tions specifically involved patients with acute MI, the data are
still relevant as many post-MI patients go on to develop heart
failure.
The consistent beneficial effects seen in the ACE inhibitor
trials in MI patients (GISSI-3,ISIS-4, SAVE, and AIRE) indi-
cate that a class effect of ACE inhibitom is re~ponsible.4”~‘
To calculate the cost benefit of the various ACE inhibitors,
misleading conclusions will be drawn if the costs for manag-
ing a patient using a particular ACE inhibitor are based on the
costs of that agent in the trial in which it was used. Such cost
comparisons would not take into account the different trial de-
signs and patient populations. Currently, the only valid cost
comparison is the cost of the daily effective dose of each ACE
inhibitor based on the doses employed. The costs given in
Table IV have been calculated using United Kingdom prices
and show lisinopril to be the cheapest ACE inhibitor over 28
days of treatment.51
The GISSI-3 trial used early ACE inhibition with lisinopril
in a relatively unselected patient population.This “all-comers’’
approach, with the decision about long-term continuation
made during subsequent weeks, would mean that all patients
who could benefit would receive treatment. Furthermore, this
approach was easy to introduce a d cost effective:the cost was
lessthanE12perpatient.50
It is suggested that effective treatment with ACE inhibitors,
although relatively more expensive than cardiovascular medi-
cation, may offer substantial savings in terms of future
 C. J. Pepine: Effects of ACE inhibition on ischemic cardiac events
TABLE 1V Cost of 28 days of treatment with effectivedoses of ACE
inhibitors used in myocardial infarction and left ventricular dysfunc-
tion clinical trials
~
Drug Dose (mg) Cost (ESterling)
Captopril 50” 30.75
5ob 20.50
Enalapril‘ 10 22.06
Ramiprild 5 19.10
LisinoprilC 10 1 1.83
Based on: *SAVE (thrice daily); bISIS-4 (twice daily); 3OLVD
(twicedaily); dAIRE (twice daily); eGISSI-3(oncedaily).
morbidity following MI with a large proportion of savings as a
direct result of reduced hospitalizationfor heart failure.
Discussion
MI is a significanthealth-careproblem, not only because of
its mortality, but also its associated morbidity. The prognosis
of survivors of acute MI is related to complex interactions in-
volving a number of characteristics, such as age, coexisting
conditions, the extent of coronary artery disease, propensity
toward arrhythmias, and degree of left ventricular dysfunc-
ti01-1.~~ACE inhibition is associated with the prevention of is-
chemia-relatedevents in patients with coronary heart disease,
particularly following acute MI.
A reduction in the mortality of MI following early and late
intervention has been suggested with a pooled analysis of the
early intervention trials (ISIS-4,18GISSI-3,2O and Chinese22)
showing a statistically significant reduction in mortality fol-
lowing ACE inhibitortreatment.These studiesalso confirmed
that it was acceptableto administerACE idubitors, from a tol-
erability point of view, within 24 h of the onset of symptoms of
acute MI.I8Significantreductions in mortality compared with
placebo were also evident in the late intervention trials
[SAVE4(1 1 days), ARE5 (5 days), and even SOLVD (> 30
days)’]).The greater mortality benefit seen in SAVE and ARE
compared with GISSI-3 probably reflects differences in the
patient types studied and duration of treatment; for example,
GISSI-3 population was unselected and the treatment period
was only 6 weeks while SAVE was restricted to patients with
left ventricular dysfunction and ARE! to those with clinical
heart failure, with both studies continuing treatment for many
months.
The beneficial effects of ACE inhibitors on morbidity fol-
lowing MI are diverse and include improvements in reinfarc-
tion, anginal episodes, and heart failure. In the SAVE trial?
greater increases in chamber size occurred in patiepts who
subsequently died or in whom heart failure developed during
the follow-up period.53It would appear that ischemia-related
heart failure in left ventricular dysfunction can be prevented
over a spectrum of risk reductionsby both early and late inter-
vention with ACE inhibitors.
11-3I
Activation of the renin-angiotensin system is a powerful
determinant of survival in patients with severe chronic heart
fail~re.5~3 55 Although the mechanisms for the prevention of
ischemic-related events remain unclear, the balance between
left ventricularoxygen supply and demand is restored early af-
ter initiationof treatment with ACE idubitors. Possible expla-
nations for this include inhibition of angiotensin 11-mediated
vasoconstriction, increased arterial compliance, reduced left
ventricular dilatation, inhibition of angiotensin II-mediated
inotropy, and prevention of some deleterious neurohormonal
effects. ACE inhibition may also have antiatherosclerotic
effectswhich are independentof the beneficial effectsassociat-
ed with their hypotensive action. Possible mechanisms for this
include a decrease in smooth muscle cell growth, decrease in
migration and proliferation, and potentiation of arterial brady-
kinin activity.
There are, however, many remaining questions appertain-
ing to the mode of action of ACE inhibitors in preventing is-
chemic events. For example, in the SOLVD trial,3reductions
in unstable angina and reinfarction were not apparent until at
least 6 months after the initiation of ACE inhibitor treatment,
suggesting that beneficial effects of ACE inhibitors on is-
chemic events were unlikely to be due to an immediate effect
such as reduction in myocardial oxygen demand and may only
partly be explained by reductions in blood pressure. Theories
that angiotensin I1 adversely affects the balance between in-
creased cardiac oxygen demand and supply by either a direct
coronary vasoconstrictor effect or by increased inotropy have
still to be investigated.m,41
Nevertheless, the obvious benefits of treatment, together
with the GISSI-320results and the ISIS-418results, provide
strong supportfor treating all hemodynamicallystablepatients
who have had an MI within the previous 24 h.
Finally, a particularly important benefit associated with
ACE inhibitor use, which will become even more vital, is the
reduction in hospitalizationrates reported in SOLVD3and oth-
er studies. This has implications both in terms of substantial
cost reductions and improved quality of life for the patient.
Conclusions
In addition to their proven mortality benefits in acute MI,
ACE inhibitorsreduce heart failure and/or left ventriculardys-
function as well as reducing the risk of arrhythmias and future
reinfarction. Benefit accrues whether treatment is initiated
early or late, so treatment should not be withheld in either situ-
ation. Another advantageis the possible reduction in hospital-
ization which will become even more important as health-care
costs escalate.
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