From the Istituto di Ricerche Farmacologiche "Mario Negri,"
Milan, Italy.
Correspondence to Dr Maria Grazia Franzosi, ACE Inhibitor Collaborative Group, GISSI Coordinating Centre, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milano, Italy. E-mail depcardio{at}irfmn.mnegri.it
Methods and Results—This overview aimed to include individual
data from all randomized trials involving more than 1000 patients in
which ACE-inhibitor treatment was started in the acute
phase (0 to 36 hours) of myocardial infarction and continued for a
short time (4 to 6 weeks). Data were available for 98 496 patients
from 4 eligible trials, and the results were consistent among
the trials. Thirty-day mortality was 7.1% among patients allocated to
ACE inhibitors and 7.6% among control subjects,
corresponding to a 7% (SD, 2%) proportional reduction (95% CI, 2%
to 11%; 2P<0.004). This represented
avoidance of
Conclusions—These results support the use of ACE
inhibitors early in the treatment of acute MI, either to a
wide range of patients or selectively in patients with anterior MI and
in those at increased risk of death.
Thus, a collaborative group involving the principal investigators
of all the randomized trials was created to collate the individual
patient data from the early and late trials in systematic overviews.
Prespecified end points were analyzed by use of an approach
already successfully applied to evaluate ACE inhibitors in
patients with congestive heart failure,10
antiplatelet therapy in occlusive vascular
diseases,11 or thrombolytic
therapy in acute MI.12
The results of such systematic overviews should help to guide clinical
practice appropriately and thus optimize the benefits attainable with
therapeutic approaches. In this report, we present data from an
overview of the early trials of ACE inhibitors in MI.
In the present overview, only those "early short-term" trials
that randomized more than 1000 patients to ACE-inhibitor
therapy versus control1 2 3 4 5 were to be included,
because patients from these trials represent
Individual Patient Data Collection
Available Data From Different Trials
All randomized patients were to be included in the analyses,
and follow-up for survival to day 30 was almost complete. Only 2% of
patients were lost before day 30 (474 on day 0, 414 on days 1 to 7, and
950 on days 8 to 30), and they were well balanced between the two
groups (920 allocated ACE inhibitors versus 918 allocated
control treatment). No significant differences between baseline
characteristics were found, except for a slight imbalance in history of
hypertension (37.7% ACE inhibitors versus 36.7% control,
2P=0.04).
Statistical Methods
To investigate whether the treatment benefit varied according to the
underlying risk, the effects were evaluated in subgroups according to a
prognostic index derived from logistic regression analysis
among all study patients (irrespective of allocated treatment). The
following variables adjusted by treatment allocation were included
in the model: age (as a continuous variable), sex, systolic
blood pressure (<100, 100 to 120, 121 to 150, and >150 mm Hg),
heart rate (<80, 80 to 99, and
All P values are two-sided; values of 2P<0.05
and 2P<0.01 were considered conventionally significant in
the overall and subgroup analyses, respectively. Similarly,
95% CIs were used for overall analyses and 99% CIs for
subgroup analyses to make some allowance for the effects on
probability values of multiple comparisons. For survival
analyses, the Kaplan-Meier method was used, and the
P value was determined by the log-rank
test.30
There was no specified upper age limit in any of the trials: even so,
the percentage of patients >75 years old varied from 9% in CCS-1 to
23% in CONSENSUS-II (Table 2
Effects on 30-Day Mortality and on 7-Day Mortality
Among patients allocated ACE inhibitors, there were 239
fewer deaths, and subdivision of these deaths by day from initiation of
treatment indicates that 200 (ie, four fifths) were avoided during the
first week (Figure 3
Effects on 30-Day Mortality in Different Subgroups
Systolic Blood Pressure and Heart Rate
Prior MI, Diabetes, Hypertension
Killip Class at Entry
Delay From Symptom Onset and Concomitant Fibrinolytic
Therapy
Site of MI
Subgroups at Different Risk
Effects on Nonfatal Heart Failure
Effect on Other Clinical Events
There was a slight but significant increase with increasing age in the
proportional effect on persistent hypotension after
ACE-inhibitor treatment (test for trend,
2P=0.003) (Table 5
Before these points are discussed in detail, some limitations of this
overview should be underlined: for example, if only the larger trials
(>1000 randomized patients) were considered, information from smaller
trials was lost; also, individual patient data were not available from
the SMILE study.5 However, these trials would
have added only
A second potential limitation concerns heterogeneity
between different studies. Differences in the drug regimens studied
include the study agents (eg, drugs with a short half-life, such as
captopril, and a long half-life, such as lisinopril),
dosages (eg, captopril dose in CCS-1 versus ISIS-4), and routes of
administration (in particular, an initial intravenous
infusion was used in CONSENSUS-II, which was the only trial to report
an adverse trend, albeit nonsignificant, on mortality), and concomitant
nonstudy treatments (Table 3
Benefit of Early ACE-Inhibitor Therapy
In addition, nonfatal heart failure, which was not a primary end point
in any of the studies, was also significantly reduced by early
ACE-inhibitor treatment. This corresponds to 6 additional
events avoided per 1000 patients on top of the survival benefit.
Time Course of the Beneficial Effect of ACE-Inhibitor
Therapy on Survival
Effects of ACE-Inhibitor Therapy on Survival in
Different Patient Subgroups
Safety of ACE-Inhibitor Therapy During Acute
MI
ACE-inhibitor therapy was not generally associated with
proportionally higher risks of hypotension or of renal dysfunction in
specific patient subgroups, except for hypotension with increasing age.
The absolute excesses, however, were greater in certain subgroups at
higher risk (eg, hypotension among those presenting with
systolic blood pressure <100 mm Hg or renal dysfunction
among those
Clinical Implications
In translating these results into clinical practice, two strategies
could be adopted. One strategy involves starting
ACE-inhibitor therapy in acute MI in all patients who do
not have clear contraindications. Such treatment should be reevaluated
at discharge or after a few weeks and should be continued long-term
only in patients considered to be at high risk (such as those with
extensive left ventricular damage or obvious heart
failure). An alternative strategy involves initiating therapy early
only in patients presenting with anterior infarct and in certain
higher-risk individuals, such as those with tachycardia,
heart failure, and perhaps diabetes. By using a number of these risk
markers, we may avoid a high proportion (but not all) of the deaths
potentially prevented by this treatment. Physicians may justifiably
choose either strategy, but irrespective of which they choose, the
present results support the benefits of the use of ACE
inhibitors early in the treatment of acute MI.
Steering Committee (early and late trials): GISSI-3: L. Tavazzi, G.
Tognoni. ISIS-4: R. Collins, C. Baigent, M. Flather, P. Sleight. CCS-1:
L.S. Liu. CONSENSUS II: J. Kjekshus, K. Swedberg. AIRE: S. Ball. TRACE:
L. Køber, C. Torp-Pedersen. SAVE: E. Braunwald, L. Moyé, M.
Pfeffer. SOLVD: S. Yusuf.
Coordinating Centers: Early trials: Gruppo Italiano per lo Studio della
Sopravvivenza nell'Infarto Miocardico (GISSI): M.G. Franzosi, R.
Latini, A.P. Maggioni, E. Santoro, L. Santoro, G. Zuanetti. Late
trials: Canadian Cardiovascular Collaboration (CCC),
McMaster Clinic: M. Flather, J. Pogue, Y. Wang, S. Yusuf.
Received September 25, 1997;
revision received January 15, 1998;
accepted January 30, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Indications for ACE Inhibitors in the Early Treatment of Acute Myocardial Infarction
Systematic Overview of Individual Data From 100 000 Patients in Randomized Trials
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Background—Several large-scale
trials have demonstrated improved survival with
ACE-inhibitor therapy started during acute myocardial
infarction. A systematic overview was conducted to resolve
uncertainties regarding time of initiation, time course of effect, and
identification of patients in whom the benefits or the risks may
be greater. 
5 (SD, 2) deaths per 1000 patients, with most of the
benefit observed within the first week. The proportional benefit was
similar in patients at different underlying risk. The absolute benefit
was particularly large in some high-risk groups (ie, Killip class 2 to
3, heart rate 
100 bpm at entry) and in anterior MI.
ACE-inhibitor therapy also reduced the incidence of
nonfatal cardiac failure (14.6% versus 15.2%, 2P=0.01)
but was associated with an excess of persistent hypotension (17.6%
versus 9.3%, 2P<0.01) and renal dysfunction (1.3%
versus 0.6%, 2P<0.01).
Key Words: ACE inhibitors • myocardial infarction • trials • systematic overview
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
A total of more than
120 000 patients have been randomized in several large-scale
controlled trials to evaluate the effect of ACE inhibitors
during and after acute myocardial infarction
(MI).1 2 3 4 5 6 7 8 In general, mortality and morbidity
were reduced when ACE inhibitors were given during the
acute phase of MI ("early") in a relatively unselected population
of patients,1 2 3 4 5 as well as when they were
started sometime after MI ("late") in patients with evidence of
left ventricular dysfunction.6 7 8
However, uncertainty still exists regarding a number of clinically
relevant questions: for example, whether there are subgroups of
patients in whom the benefits or the risks are
greater.9
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Trials to Be Included
The present overview was to be of the randomized trials in
which ACE-inhibitor treatment begun in the acute phase of
MI (0 to 36 hours from symptom onset) and continued for a short period
of time (generally 4 to 6 weeks) was compared with no routine
ACE-inhibitor treatment. Such trials are
CONSENSUS-II,1 GISSI-3,2
ISIS-4,3 CCS-1,4
SMILE,5 GISSI-3 Pilot,13
ISIS-4 Pilot,14 and several other smaller
studies.15 16 17 18 19 20 21 Long-term trials in which
ACE-inhibitor treatment was started after the acute phase
of MI in selected patients with left ventricular
dysfunction and continued for a longer period (at least 6
months)6 7 8 22 23 24 25 26 will be the subject of a
separate overview. The GISSI Coordinating Center, Milan, Italy, was
responsible for data collection, checking, and analysis of the
present overview, and the Canadian Cardiovascular
Collaboration Project Office at McMaster University, Hamilton,
Ontario, was responsible for the overview of long-term trials. 98% of all
randomized patients, and retrieving reliable individual patient data
from small trials is generally more difficult.12
As a result, several smaller trials were
excluded.13 14 15 16 17 18 19 20 21
Data were collected for individual patients because this allows
more detailed consistency checking, analysis, and
life-table calculations.11 12 27 A common
protocol was developed to provide data to the overview coordinating
centers in a standardized format. These included data recorded
before randomization (such as ECG classification, supplemented by
discharge ECG in the GISSI-3 study; age and sex; systolic blood
pressure and heart rate; history of MI, diabetes, or hypertension;
Killip class; and hours from onset of symptoms), as well as concomitant
medications, clinical events (such as hypotension, renal dysfunction,
cardiogenic shock, second- to third-degree
atrioventricular block, heart failure,
ventricular fibrillation, and stroke), and mortality after
randomization. The last date of follow-up was also collected to allow
survival analyses. The original definitions adopted in each
trial for clinical events were used. Data were checked for completeness
and consistency with the published results; apparent
discrepancies were reviewed with the principal investigators, and any
corrections required were included in the main database.
Individual data were available for 98 496 patients in four of
the eligible trials1 2 3 4 but not for the 1556
patients in SMILE,5 representing
availability of 98% of eligible patients. Mortality data and most
other key clinical outcomes were available from each trial, but some
other data items were not systematically collected in each trial. For
example, history of hypertension or diabetes was not recorded in
ISIS-4; dates of some clinical events were not always collected in
CONSENSUS-II and CCS-1; heart failure at entry, rather than Killip
class, was recorded in ISIS-4 and CONSENSUS-II (and considered
equivalent to Killip class >1 in this overview); and the randomization
date was not available for 13 patients in CCS-1.
The main analyses were of mortality and clinical events
up to day 30 (with special emphasis on days 0 to 7) and of mortality by
subgroup based on baseline characteristics. Statistical
analyses used the modified Mantel-Haenszel
method11 12 28 to calculate stratified estimates
of the proportional treatment effect, which were described as odds
ratios or as percentage reductions in odds. 
2
tests for heterogeneity of the proportional effects
were calculated between different trials or between subgroups.
2 tests for linear trend were also calculated
whenever appropriate. Given the modest size of the overall effect and
the number of subgroups studied, such subgroup analyses need to
be interpreted cautiously; indeed, in many instances, the overall
proportional effect may provide more reliable guidance as to the
proportional effect in some particular subgroup than the effect
observed just within that subgroup.11 12 29 100 bpm), previous MI, Killip class
(1 and >1), and location of MI (anterior and nonanterior). The
patients were divided into four groups that included approximately
equal numbers of deaths: low risk (30-day mortality of 2% to 6%),
medium risk (6% to 10%), high risk (10% to 16%), and very high risk
(16% to 42%). 2 values for
heterogeneity and for linear trend were calculated to
test the treatment effects between these groups.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
Features of Trials and Available Data
The 4 trials of early ACE-inhibitor therapy versus
control treatment, which provided individual patient data for the
overview, recruited a total of 98 496 patients (Table 1
). Captopril was used in 2 of these
trials,3 4 enalapril in 1,1
and lisinopril in 1.2 Three trials
were placebo controlled,1 3 4 and 1 used an open
control2 ; all trials used a 1:1 allocation ratio.
Three trials included patients presenting within 24 hours from the
onset of symptoms,1 2 3 and 1 up to 36
hours.4 Patients with definite or suspected acute
MI were eligible for 2 trials3 4 : 1 included only
patients with ST-segment elevation, new pathological Q waves, or raised
cardiac enzymes1 ; and 1 required two of the
following: typical chest pain, abnormal Q waves with evolutionary ST-T
wave changes on serial ECG, or enzymatic
evidence.2
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Table 1. Characteristics of Trials of ACE
Inhibitors vs Control in Acute MI Involving >1000 Patients ). Patients
presenting with cardiogenic shock (ie, Killip class 4) were
generally excluded from the trials, with a larger proportion of those
patients in CCS-1 in Killip class >1. Antiplatelet and
fibrinolytic therapy were explicitly recommended in GISSI-3 and ISIS-4
(Table 3), and they were used more
commonly in those trials. Nitrates were used commonly in the CCS-1
trial (87% of patients), and oral or transdermal nitrates were given
to approximately half of the patients in the GISSI-3 and ISIS-4 trials,
because such nitrates were also allocated at random in factorial study
designs.
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Table 2. Baseline Characteristics in Relevant Trials
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Table 3. Concomitant Therapies in Hospital
Overall, the cumulative mortality for patients allocated to ACE
inhibitors and to control showed a significant difference
in survival at 30 days (log-rank test, P=0.004). There were
3501 deaths (7.11%) during days 0 to 30 among 49 214 patients
allocated to ACE inhibitor compared with 3740 deaths
(7.59%) among 49 269 control patients (Figure 1). This 7% (SD, 2%) proportional
reduction in 30-day mortality (95% CI, 2% to 11% reduction)
corresponds to the avoidance of 4.8 (SD, 1.7) deaths per 1000 patients.
There was no statistical difference between the effects in the four
trials (2 on 3 df=5.8,
2P=0.1) (Figure 2).
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Figure 1. Effect of ACE-inhibitor therapy on
cumulative mortality during days 0 to 30 in all trials combined.
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Figure 2. Proportional effects of ACE-inhibitor
therapy on 30-day mortality in each trial. "Observed minus
expected" (O-E) number of deaths among ACE
inhibitor–assigned patients (and its variance) is quoted
for each trial. This is used to calculate odds ratio of death among
patients assigned ACE-inhibitor therapy to that among
patients assigned control treatment. Odds ratios (solid squares, with
areas proportional to amount of information contributed by each trial)
are plotted with their 95% CIs (horizontal lines). ). The treatment was
associated with a significant 8% (SD, 3%) proportional reduction
during days 0 to 7 (95% CI, 3% to 14% reduction), with similar
benefit in days 0 to 1 and 2 to 7. This corresponded to avoidance of
4.0 deaths (SD, 1.4) per 1000 patients in the first week (Figure 3).
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Figure 3. Absolute effect of ACE-inhibitor
therapy on deaths in days 0 to 1, 2 to 7, and 8 to 30.
Age and Sex
The mortality reductions at 30 days were separately significant in
the patients 55 to 64 years old (16% [SD, 5%] proportional
reduction; 2P=0.001) and 65 to 74 years (10.8% [SD,
3.7%] proportional reduction; 2P=0.004; Figure 4). There was a trend toward greater
proportional mortality reduction among younger patients
(2 on 1 df=6.2; 2P=0.01)
(Figure 4). The proportional and absolute reductions in death were
similar for both sexes (4.6 [SD, 1.8] lives saved per 1000 in men
versus 5.5 [SD, 3.9] in women) (Figure 4).
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Figure 4. Effects of ACE-inhibitor therapy on
mortality in days 0 to 30 subdivided by presentation
features. Odds of death among patients allocated to
ACE-inhibitor therapy to that among those allocated to
control treatment is derived from "observed minus expected" numbers
of death (and variances) calculated within each subdivision of
presentation features stratified by trial. Odds ratios
within each presentation feature are plotted with their
99% CIs, whereas overall result and 95% CI are
represented by diamond.
The proportional reductions in mortality were not significantly
influenced by systolic blood pressure at entry
(2 for trend=2.2, 2P=0.1). However,
few patients with systolic blood pressure <100 mm Hg
were studied, because such patients were often excluded (Figure 4
). By
contrast, there was a significant trend toward greater proportional
mortality reductions among patients with higher heart rates at entry
(2 for trend=9.9, 2P=0.002). Hence,
the absolute benefits observed among patients with higher heart rates
were larger: 22.7 (SD, 6.7) fewer deaths per 1000 among those with
heart rates 100 bpm and 8.7 (SD, 3.1) fewer deaths per 1000 among
those with heart rates 80 to 99 bpm (Figure 4).
The proportional reductions in mortality in patients with a
history of MI, of diabetes, or of hypertension were nonsignificantly
different from those observed in patients without these conditions
(Figure 4). Because such patients are at higher absolute risk of death
after MI, the absolute benefits of ACE-inhibitor treatment
were greater among patients with prior MI (8.9 [SD, 4.7] versus 4.1
[SD, 1.8] lives saved per 1000), among diabetics (17.3 [SD, 8.9]
versus 3.2 [SD, 2.7] lives saved per 1000), and among hypertensives
(9.0 [SD, 4.7] versus 2.1 [SD, 3.1] lives saved per 1000).
There was no significant difference between the proportional
mortality reduction among patients with heart failure or Killip class
>1 at entry (11% [SD, 4%]) and that among patients in Killip class
1 (5% [SD, 3%]). Because patients with heart failure are at greater
risk of death, the absolute benefit of treatment was greater among
these patients (14.1 [SD, 5.4] versus 2.9 [SD, 1.6] lives saved per
1000) (Figure 4).
The benefits of ACE inhibitors were not significantly
influenced by the delay from onset of symptoms to randomization (within
24 to 36 hours) (Figure 4) or by whether fibrinolytic therapy was used
(7.1% [SD, 3.2%] proportional reduction with ACE
inhibitors in the presence of fibrinolytic therapy and
6.6% [SD, 3.5%] reduction in its absence; data not shown).
Among patients with evidence of anterior MI (ie, anterior
ST-segment elevation with or without other changes), the proportional
reduction of 14% (SD, 3.6%) was greater than that among patients with
other MI locations (2% [SD, 3%]; 2 for
heterogeneity on 1 df=6.3,
2P=0.01). This corresponds to 10.6 (SD, 2.9) deaths avoided
per 1000 patients with anterior MI (Figure 4).
When the effects of ACE-inhibitor treatment were
evaluated in subgroups of patients according to a
multivariate prognostic index (see "Methods"),
there was no evidence of a difference in the proportional benefits in
patients at different underlying risk (Figure 4, bottom). Hence, the
absolute benefits were greater in patients at greater risk of death
(3.8 [SD, 1.5] lives saved per 1000 low-risk patients compared with
13.6 [SD, 9.1] in very-high-risk patients). Mortality after MI
increased steeply with increasing age, whereas the
univariate analyses (above) indicated that the
proportional reductions in mortality with ACE inhibitors
were greater at younger ages. Prognostic scores were therefore also
constructed with age excluded, both for all patients and, separately,
for those <75 years old and those 75 years old. In each case, the
proportional benefits among patients at different absolute risk were
not significantly different from each other (data not shown).
ACE-inhibitor therapy significantly reduced the
incidence of nonfatal cardiac failure: there were 6687 cases of
nonfatal heart failure (14.6%) during days 0 to 30 among patients
allocated to ACE inhibitors compared with 6937 cases
(15.2%) among control subjects. This corresponds to the avoidance of
6.1 (SD, 2.4) cases of nonfatal heart failure per 1000 patients
(2P=0.01), which was distributed throughout the period of
hospitalization (Table 4A).
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Table 4. Clinical Events by Days After AMI by Allocated
Treatment
The incidence rates of reinfarction and stroke were similar in the
two treatment groups (Table 4B). ACE-inhibitor therapy was
associated with a significant excess of 84 (SD, 2) cases of persistent
hypotension per 1000 patients treated (17.6% versus 9.3%). There were
also small but significant increases in cardiogenic shock (4.6 [SD,
1.2] per 1000) and in second- to third-degree
atrioventricular block (5.4 [SD, 1.2] per 1000). Most
of these excesses occurred during days 0 to 7, when most of the
mortality benefit was also observed. There was also a significant
excess of 6.2 (SD, 0.6) cases of renal dysfunction per 1000 (1.3% ACE
inhibitor versus 0.6% control), which was distributed
throughout the period of hospitalization (Table 4B). ).
Otherwise, the proportional effects on hypotension and on renal
dysfunction in the subgroups examined were not clearly different from
those observed overall. In some subgroups, however, the control risks
were much higher, and thus the absolute excesses of complications were
greater. For example, among patients presenting with
systolic blood pressure <100 mm Hg, the absolute excess
of persistent hypotension was 132 per 1000 compared with an overall
excess of 84 per 1000. Similarly, the absolute risks of renal
dysfunction were greater in the elderly, with an absolute excess of 17
per 1000 among those 75 years old compared with 6 per 1000
overall.
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Table 5. Effect on 30 Days Persistent Hypotension and Renal
Dysfunction
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
This systematic overview of trials of early
ACE-inhibitor therapy in acute MI yields four main
messages. First, the benefit on 30-day mortality is consistent
among the trials and, on average, corresponds to 5 lives saved per
1000 patients treated for 1 month. Second, most of the benefit
occurs during the first few days, when mortality is highest. Third, the
proportional benefit is generally consistent among patients
with differing baseline characteristics, so patients at higher risk
generally benefit to a greater absolute extent. Fourth, there is no
subgroup in which the treatment was shown to be definitely harmful,
although hypotension and renal dysfunction with therapy were more
common in patients 75 years old, and there was no direct evidence of
any survival advantage in such patients. It should be remembered that
patients presenting in cardiogenic shock or with persistently low
systolic blood pressure (ie, <100 mm Hg) were generally
excluded from these studies. 5% to the total number of patients, and their
overall results are consistent with the present ones. In
particular, adding the published results for the 1556 patients
randomized within 24 hours of the onset of anterior MI in the SMILE
study (38 deaths at 42 days among 772 patients allocated to
ACE-inhibitor therapy versus 51 among 784 control subjects)
to those for the nearly 100 000 patients included in this overview
would not alter the findings even minimally (data not shown). ). Moreover, there were some differences in
the types of patients studied in the different trials (Table 2) and in
some of the definitions of variables used (such as "site of MI"
or "persistent hypotension"). In assessments of the differences
between subgroups, variations in definitions or baseline
characteristics would tend to decrease the sensitivity of such
analyses to show interactions. However, such differences are
inherent to all overviews and do not introduce any biases into
ascertainment of the average effects observed among the patients
included.
An average 7% proportional reduction in mortality with ACE
inhibitors was observed within 30 days of acute MI,
corresponding to an average absolute benefit of 5 lives saved per
1000 patients treated. In other words, on average,
ACE-inhibitor therapy begun early in acute MI and continued
for only 1 month in 200 patients leads to the saving of 1 life. At
first glance, this beneficial effect may appear modest compared with
that observed in the trials of long-term ACE-inhibitor
therapy among high-risk post-MI patients. But those trials involved a
much longer treatment period (1 to 3 years), so the number of lives
saved per month of treatment per 1000 individuals varied from 1.0 in
SAVE to 3 to 4 in AIRE.9 Thus, the early use of
ACE inhibitors in relatively unselected MI patients leads
to at least comparable absolute survival benefits during the first
month of treatment.
ACE-inhibitor therapy saved lives early after
its initiation, with 40% of the 30-day survival advantage observed in
days 0 to 1, 45% in days 2 to 7, and 15% subsequently (Figure 3). Data from the different studies were consistent in this
respect, strongly supporting the strategy of starting ACE
inhibitors early to maximize their potential benefits. But
because the reduction in mortality was observed irrespective of the
interval between symptom onset and randomization, ACE
inhibitors should not be withheld from patients who
present late.
In general, most of the patient subgroups studied benefited from
ACE inhibition, and there was no subgroup in which the treatment was
clearly shown to be harmful. The CIs for the proportional effects on
30-day mortality in different subgroups overlap each other
substantially and, in general, did not differ significantly from the
overall proportional reduction of 7% (Figure 4). Similarly, when the
results were analyzed in groups subdivided with respect to a
risk score based on multivariate logistic regression
(even with age excluded), the proportional reductions in mortality were
similar at different levels of risk (Figure 4). However, certain
characteristics, such as anterior site of MI and high heart rate, were
clearly associated with a higher benefit. But such patients
represent only a minority of those who present with
suspected acute MI, and the beneficial effects of early
ACE-inhibitor therapy in a lower-risk population may still
have some influence on the impact of the treatment.
Hypotension was anticipated, and this was the reason for titration
of the initial doses of the ACE inhibitors. It was
significantly more common than among control subjects (17.6% versus
9.3%), and although there was an increase in mortality (2.3% versus
1.6%) among patients who became hypotensive, this may well indicate
differences in their baseline risk.31 Moreover,
the excess of hypotension was seen primarily during the first week,
when most of the survival advantage was also seen. A significant
increase in the incidence of renal dysfunction and cardiogenic shock
was also observed in the ACE inhibitor–treated patients,
perhaps reflecting the hypotensive effect of treatment during this
acute phase. The higher incidence of second- to third-degree AV block
might have been a consequence of increased parasympathetic activity and
decreased sympathetic tone induced by the ACE
inhibitor32 or, perhaps, of
hypotension-induced ischemia in some patients. 75 years old), and this should be considered when we
decide whether the likely survival benefit is likely to justify the
treatment of a particular patient.
This overview supports and expands the conclusions of a previous
consensus meeting9 and leads to the following
general considerations. First, ACE-inhibitor treatment may
be started immediately during the acute phase of MI, along with other
routinely recommended treatments (such as
thrombolytics, aspirin, and ß-blockers), in the
absence of clear contraindications. The presence of cardiogenic shock
or systolic blood pressure persistently <100 mm Hg
should generally be considered a contraindication to early treatment
with an ACE inhibitor. Second, the benefit occurs during
the first few days after MI, suggesting that mechanisms other than
benefits on the remodeling process may play a role. These mechanisms
may include an early effect on infarct expansion, a reduction of
neurohormonal activation, or an increase in collateral coronary
flow. Irrespective of the mechanisms, however, these findings strongly
support early initiation of treatment.33 Third,
the proportional benefit is generally larger in higher-risk subgroups,
such as those with anterior site of MI or high heart rate. However,
elderly patients, particularly those 75 years old, are at increased
risk of hypotension with ACE inhibitors, and there is no
evidence of a survival advantage among them. Finally, the data suggest
that the early benefits of 1 month of ACE-inhibitor
therapy started early in acute MI patients is observed largely during
the first week, and it seems likely that this would be complementary to
that observed later in trials of prolonged ACE-inhibitor
therapy initiated several days or weeks after MI in patients with
evidence of heart failure or left ventricular dysfunction
(and the absolute benefits per month of treatment are of similar
size).
Appendix 1
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
The ACE Inhibitor Myocardial Infarction
Collaborative Group
Writing Committee: M.G. Franzosi, E. Santoro, G. Zuanetti, C.
Baigent, R. Collins, M. Flather, J. Kjekshus, R. Latini, L.S.
Liu, A.P. Maggioni, P. Sleight, K. Swedberg, G. Tognoni, S.
Yusuf.
Acknowledgments
This study was supported in part by a Canadian Medical Research
Council joint industry award with Astra, Bristol-Myers Squibb, Hoechst
Marion Roussel, Merck, and Zeneca. The collection, analysis,
and interpretation of the data were performed independently of the
industrial sponsors.
Footnotes
1 A list of the ACE Inhibitor Myocardial Infarction Collaborative Group Members appears in the Appendix. 
References
Top
Abstract
Introduction
Methods
Results
Discussion
Appendix 1
References
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