From the Cardiovascular Division, Brigham and Women's Hospital,
Harvard Medical School, Boston, Mass.
Correspondence to Dr Pfeffer, 75 Francis St, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Angiotensin-converting
enzyme inhibitors have earned their place along with
aspirin, ß-blockers, and thrombolytic agents as
medical therapies proven to reduce mortality rates in acute myocardial
infarction.1 The results of well-conducted,
randomized, controlled clinical trials have been so consistent
and so conclusive that the emphasis now shifts from research to
implementation. Because the trials demonstrated that the oral use of an
ACE inhibitor can save lives, the pragmatic questions of
who and when to treat are left to the frontline physicians. Unlike the
clinical trial experience with its protocol-directed inclusion and
exclusion criteria, time window for initiation, and the informed
consent process, the practicing physician must make decisions on the
basis of his or her current assessment of the relative merits as well
as the potential for harm by an ACE inhibitor for
individual patients. Because any further major placebo-controlled
trials of ACE inhibitors in acute myocardial infarction are
not likely, physicians must use the sum of the currently available
information to make the best choices for their
patients.2
The leaders of major trials of
antiplatelet3 and
thrombolytic4 therapies in acute
myocardial infarction have formed collaborative groups that pool their
collective data in an attempt to better understand the safety and
efficacy information of their combined experience. This collaborative
approach goes a step beyond routine meta-analysis because the
group not only attempts to develop more uniform definitions but,
importantly, pools their individual data to derive more reliable
life-table experiences and projections. An ACE
Inhibitor Collaborative Group was convened with these same
objectives in the hope of developing a consensus for recommending ACE
inhibitors in patients with acute myocardial infarction.
One of the group's initial decisions was to categorize the ACE
inhibitor trials of myocardial infarction into those that
were early-onset, broad-inclusion and short-term trials or
selective-inclusion, long-term studies for separate analysis.
The first report of the ACE Inhibitor Collaborative Group
in this issue of Circulation summarizes the survival and
safety data from the four major early-onset, broad-inclusion,
short-term studies.5
When therapy started within 36 hours of the onset of chest pain, the
survival benefit attributed to the use of ACE inhibitors in
the broad-inclusion, short-term studies was modest and
consistent. The 7% reduction in 30-day mortality translated
into 5 lives saved per 1000 patients assigned to the ACE
inhibitor. This overall effect was inclusive of a neutral
study that raised an important caution against the
intravenous administration of the first dose of the ACE
inhibitor. Although this modest early survival benefit has
been well known, the power of the present report stems from the
ability to describe the timing of these lives saved and to quantitate
efficacy and risk in specific well-characterized patient
populations.
The extension of the previous report from the ISIS and GISSI groups of
the early survival benefits with this use of an ACE
inhibitor6 is an important feature of
the current systematic overview. In the overview, of the 239 lives
saved that are attributed to the use of an ACE inhibitor,
200 occurred within the first week, most of them in the first 2 days
from randomization. These survival benefits are supported by
mechanistic studies that demonstrated either less enlargement/expansion
or a prompter recovery of left ventricular function with
the early initiation of an ACE
inhibitor.7 8 9 10 The 30-day mortality
data from the combined trials should provide an impetus for the early
initiation of an ACE inhibitor. In this context, it is
equally important to note that an analysis of survival relative
to the time from onset of symptoms to randomization to either control
or ACE inhibitor did not show a time-related trend within
the first 36 hours. Therefore, unlike aspirin and reperfusion
strategies, it is not critical to introduce the ACE
inhibitor in the hyperacute myocardial salvage phase. There
is no therapeutic window in which an ACE inhibitor must be
administered, but the overview suggests that opportunities can be lost
by unnecessary delays of days or weeks. Therefore, the time-dependent
priority decisions are the use of aspirin, reperfusion, and
ß-blockade, followed by reevaluation for ACE inhibitor
therapy. An important aspect of the latter therapy not emphasized in
the overview is that the survival benefit of an ACE
inhibitor is independent of and additive to the use of
these other proven therapies.
The overview recommendations were clearly for early (day 1 to 2)
initiation, but there was less unanimity within the Collaborative Group
concerning patient selection. In general, the proportional reduction in
mortality rates across the major subgroups appeared to be uniform.
Therefore, the overall data set from all 98 496 patients demonstrating
that this early, broad use of an ACE inhibitor probably
will result in a 7% (95% confidence interval, 2% to 11%) reduction
in mortality rates within the first 30 days of the acute myocardial
infarction affords the most valid projection. This leads to the
defensible recommendation for the early treatment of a broad population
of acute myocardial infarction patients who were eligible for the
trials (systolic blood pressure >100 mm Hg and no
contraindications to the use of an ACE inhibitor). The
Collaborative Group appropriately cautioned that with the
nonstatistically significant tests for heterogeneity of
the proportional effect (percent reduction in mortality rate) with the
ACE inhibitor, in most of the subgroup analyses the
overall proportional effect should be considered as the most reliable
estimate.
Despite the potential hazards of overzealous subgroup analyses,
when properly conducted and interpreted, these special patient
population data can generate useful information for clinical decisions.
Even accepting the premise of a similar proportional mortality
reduction across subgroups with ACE inhibitors, the
absolute benefit of therapy would be greater in the subgroups at a
higher risk of death. A strikingly consistent feature from the
systematic overview was that with the exception of advanced age, each
of the clinical or infarct-related descriptors of predefined subgroups
at higher risk for mortality, such as clinical history of prior
infarction, diabetes or hypertension, anterior ECG location, elevated
heart rate, or Killip class above I, identified a group with higher
mortality rates and a greater absolute reduction in death with the use
of an ACE inhibitor. Indeed, for the anterior ECG location
and higher resting heart rate, the statistical test for
heterogeneity was significant, indicating greater
proportional as well as absolute survival benefits with the use of an
ACE inhibitor in these clinically recognizable subgroups.
As described for patients with anterior myocardial infarction, the 14%
reduction in mortality rate corresponds to
Information outside of the trials analyzed in the Collaborative
Group's first systematic overview supports the position of less of a
benefit with the use of an ACE inhibitor in lower-risk
myocardial infarctions. The initial animal
experiments11 and clinical mechanistic
studies12 13 14 targeted myocardial infarctions
with sufficient damage to produce left ventricular
dysfunction and ventricular remodeling as the suitable
subjects for ACE inhibitor therapy. The major clinical
outcome trials that have selected for higher risk patients using either
depressed left ventricular function or clinical signs of
failure such as SAVE,15
AIRE,16 and TRACE,17 each
demonstrated an
A quantitative assessment of the adverse experience that can be
anticipated with this use of an ACE inhibitor is the other
important ingredient in the decision regarding its use. Fortunately,
this is a particularly strong feature of the overview. The incidence of
persistent hypotension almost doubled from 9.3% in the control group
to 17.6% in the ACE inhibitor group. Similarly, the
incidence of reported renal dysfunction increased from 0.6% to 1.3%
with this early use of an ACE inhibitor in acute myocardial
infarction. A pertinent and relatively unique aspect of the overview
was the fact that the absolute risk for experiencing these adverse
events appeared to be uniformly distributed across both the high and
lower risk groups. For example, a twofold increased risk of
experiencing persistent hypotension with the use of an ACE
inhibitor was observed in both anterior and other ECG
locations. Because there was no difference in the rate of hypotension
in their respective control groups, an absolute augmentation in this
medication-induced complication of
Although there was general agreement on the factual aspects from
the overview, the Collaborative Group concluded with two alternate
treatment strategies as recommendations to the practicing physician.
One strategy, supported by the majority, was that all patients with a
systolic blood pressure >100 mm Hg who were without
contraindications to the use of an ACE inhibitor should
receive this therapy, commencing early (within 1 to 2 days of an acute
myocardial infarction). This strategy implies that a reassessment is
made at a later date to either discontinue the ACE
inhibitor in lower-risk patients or continue therapy in
those considered at higher risk. This strategy would maximize the
number of lives saved; however, it would also expose the greatest
number of patients to the adverse consequences of ACE
inhibitor therapy in the early phase of the myocardial
infarction. As previously advocated, a more selective
approach19 20 21 for the use of ACE
inhibitors was also adopted by the Collaborative Group. By
selecting patients at higher risk of death, this approach uses subgroup
analyses with all its limitations and other information to
adopt the position that the vast majority of the lives that can be
saved with the early use of an ACE inhibitor reside in
clinically identifiable populations.
From my admittedly biased perspective as a member of the Steering
Committee, this overview provides a concise compendium of the results
of the broad inclusion, short-term trials of ACE inhibitors
in acute myocardial infarction. The information concerning the
importance of early initiation of therapy and the qualitative safety
data that suggest that the low-risk, potentially low-benefit patients
are as likely to experience an adverse event attributed to therapy with
an ACE-inhibitor are unique, strong features of the
overview. As concluded, both of two treatment strategies, broad or
selective use, can be justified by the data. I believe that the recent
ACC/AHA Task Force guidelines for the management of patients with acute
myocardial infarction have captured the essence of the
issue.22 They designated ACE
inhibitors for a class I recommendation, a condition in
which there is evidence and/or general agreement that a given treatment
is beneficial, useful, and effective for patients within the first 24
hours of myocardial infarction with anterior ST elevation or clinical
heart failure, and a class IIa recommendation, a condition in which
where there is conflicting evidence or divergence of opinion about the
usefulness and/or efficacy of a treatment, but one in which the weight
of evidence and/or opinion is in favor of usefulness and/or efficacy
for all other patients within the first 24 hours of a suspected or
established acute myocardial infarction.22 Both
of these recommendations assume the absence of significant hypotension
or a clear-cut contraindication to the use of an ACE
inhibitor.
In my opinion, ACE inhibitors should be considered in
every patient with acute myocardial infarction soon after the decisions
on the use of aspirin, reperfusion, and ß-blockers have been made.
Patients at augmented risk for early death, such as those with a past
history of hypertension, diabetes, or prior infarcts, or who
present with higher heart rates, anterior ECG involvement, manifest
pulmonary congestion, or left ventricular
dysfunction on an assessment of ventricular
performance have the most to gain from the early initiation of
an ACE inhibitor. These patients are also likely to
continue to benefit from the long-term use of this therapy. ACE
inhibitor use in acute myocardial infarction has shifted
from investigational to standard therapeutics. The implementation of
this therapy to reduce mortality and morbidity rates will now be
determined by the treating physician. The luxury of adopting
alternative strategies applies to committees but not to the frontline
physician, who has to make a decision for a specific patient.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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© 1998 American Heart Association, Inc.
Editorials
ACE Inhibitors in Acute Myocardial Infarction
Patient Selection and Timing
Key Words: Editorials • angiotensin • myocardial infarction
11 lives saved per 1000
treated. Indeed, >85% of the lives saved attributed to ACE
inhibitor therapy in the overview occurred in the anterior
myocardial infarction subgroup that represented 37% of the
overall population.5 It is likely that the
converse analysis, indicating that the majority of patients can
be classified at lower risk with less absolute potential benefit, has
influenced practice patterns of many physicians. 20% reduction in mortality rate with long-term
administration of an ACE inhibitor. In addition to the
select versus broad inclusions, the obvious differences in therapy
duration between the short- and long-term studies make comparisons
difficult. Although we cannot extrapolate beyond study duration in the
broad inclusion, short-term studies, the 30-day survival data are
available from the long-term, selective-use
studies.18 The lives saved per 1000 patients
treated during the first 30 days in each of these selected higher-risk
populations was greater than that in the broad-inclusion studies of the
overview. The TRACE study, which consecutively screened all patients
with enzyme-confirmed myocardial infarctions, probably provides the
best comparative data. The TRACE investigators estimate that their
higher-risk patients who were selected by
echocardiographically detected wall motion
abnormalities represent 25% of the acute myocardial
infarction population. Their finding of 24 lives saved per 1000
patients treated with the ACE inhibitor in the first 30
days is fourfold to fivefold greater than the 5 lives saved per 1000
treated in the broad inclusion population. These numbers become quite
comparable if there is a negligible ACE inhibitor survival
benefit in the remaining 75% of the lower risk patients, the so-called
"dilutional effect."17 80 per 1000 treated was produced
in both the higher and lower fatality risk groups. Similarly, both the
relative and absolute risks of persistent hypotension were similar
between patients with Killip class I and those with class
II.5
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