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(Circulation. 1997;95:2643-2651.)
© 1997 American Heart Association, Inc.
Articles |
Early Versus Delayed Angiotensin-Converting Enzyme Inhibition Therapy in Acute Myocardial Infarction
The Healing and Early Afterload Reducing Therapy Trial
From the Brigham and Women's Hospital (M.A.P., S.C.G., R.J.G., F.S.L., R.T.L., P.M.R., S.D.S., C.H.H.), Boston, Mass; Victoria Hospital (J.M.O.A.), London, Ontario, Canada; Geisinger Medical Center (F.J.M.), Danville, Pa; University of California, San Francisco (E.R.); and Montréal Heart Institute (J.L.R)., Montréal, Québec, Canada.
Correspondence to Marc A. Pfeffer, MD, PhD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail MAPFEFFER{at}BICS.BWH.HARVARD.EDU.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix OFReferences |
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Background Although ACE inhibitor therapy has been shown to reduce mortality in patients with acute myocardial infarction (MI), the optimal dose and the timing of its initiation have not been determined.
Methods and Results In a double-blind trial of 352 patients
with anterior MI, we compared the safety and effectiveness of early
(day 1) versus delayed (day 14) initiation of the ACE
inhibitor ramipril (10 mg) on
echocardiographic measures of left
ventricular (LV) area and ejection fraction (EF). An early,
low-dose ramipril (0.625 mg) arm was also evaluated. Clinical events
did not differ. During the first 14 days, the risk of manifesting a
systolic arterial pressure of 
90 mm Hg was
increased in both ramipril groups. LVEF increased in all groups during
this period, but the early, full-dose ramipril group had the greatest
improvement in EF (increase: full, 4.9±10.0; low, 3.9±8.2%; delayed,
2.4±8.8%; P for trend <.05) and was the only group that
did not demonstrate a significant increase in LV diastolic
area.
Conclusions The results of the present study demonstrated that in patients with anterior MI, the early use of ramipril (titrated to 10 mg) attenuated LV remodeling and was associated with a prompter recovery of LVEF. The use of low-dose regimen did not prevent hypotension and had only intermediate benefits on LV size and function. The more favorable effects on LV topography of the early use of full-dose ramipril support the results of the major clinical trials, which have demonstrated an early survival benefit of ACE inhibition.
Key Words: ventricular remodeling • echocardiography • angiotensin-converting enzyme inhibitor • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix OFReferences |
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The use of ACE inhibitors in MI has advanced rapidly from experiments in animals1 2 to a clinically proven therapy that reduces cardiovascular morbidity and mortality.3 4 5 6 7 8 9 In post-MI patients, increased relative and absolute benefits of ACE inhibitors have been obtained in studies in which those at higher risk were selected and either objective or subjective criteria for LV dysfunction were used while the ACE inhibitor was sustained on a long-term basis.10 11 The results of the Survival and Ventricular Enlargement (SAVE),3 Acute Infarction Ramipril Efficacy (AIRE),4 and Trandolapril Cardiac Evaluation (TRACE)9 studies consistently demonstrated a
20% reduction in all-cause
mortality. By design, in these three trials, the ACE
inhibitor was not administered during the first day of MI.
It was presumed that this delay would reduce the potential for
provoking symptomatic hypotension and aggravating
ischemia in patients with marginal coronary
perfusion. Despite this inherent risk with the early use of an ACE inhibitor, an equally compelling rationale for its early initiation was the potential benefit of minimized infarct expansion and early ventricular remodeling. The CONSENSUS II was the first to report data on the early use of ACE inhibition in MI.12 In this trial, the initial dose of the ACE inhibitor was administered intravenously within the first day of the MI. Although CONSENSUS II was designed to enroll 9000 patients, the Data Safety Monitoring Committee recommended early termination after 6050 patients were entered into the trial, mainly due to an inability to detect a benefit of the drug and the increased incidence of worrisome hypotension.13 Concurrent and even larger studies such as Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio (GISSI-3)5 and the Fourth International Study of Infarct Survival (ISIS-4),7 which used orally administered ACE inhibitors starting within the first day of a MI, continued for several years until their scheduled completion.
Based on the existing totality of evidence, the HEART study was designed to compare the safety and efficacy of immediate versus delayed administration of the ACE inhibitor ramipril on echocardiographic evidence of ventricular dilatation in patients with anterior MI. In addition, this study was designed to evaluate whether a low, "nonhemodynamic" dose of this ACE inhibitor would avoid the risk of symptomatic hypotension yet still be effective in attenuating early LV remodeling.
During the conduct of the HEART trial, data from the GISSI-3 and ISIS-4 investigators14 were made available to the HEART Study Executive Committee that demonstrated that a substantial proportion of the lives saved by ACE inhibition occurred within the first several days of the acute MI. This information led to a HEART Study Executive Committee decision to terminate enrollment before randomization of the planned 600 patients.15 This report summarizes the HEART study experience of the 352 patients who were randomized to (1) compare the safety and echocardiographic effectiveness of a full-dose titration of ramipril commencing on the first versus the 14th day of MI and (2) evaluate the possible benefits of the early use of a low dose of ramipril in acute MI.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix OFReferences |
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HEART was a randomized, double-blind, placebo-controlled trial that enrolled 352 patients with acute MI from 36 centers in the United States and Canada (see "Appendix"). Men and women over the age of 21 years who had experienced an MI within 24 hours were considered to be eligible. Exclusion criteria were relative contraindications to the use of an ACE inhibitor, need of an ACE inhibitor for treatment of congestive heart failure, serum creatinine level of
2.5 mg/dL, presence of a major
complication of infarction that was not stabilized before randomization
(eg, cardiogenic shock, persistent ischemia, or unstable
rhythm), systolic blood pressure of <100 mm Hg, or
failure to complete all prerandomization evaluations within 24 hours
from the onset of chest pain. Institutional review board approval was
obtained, and all patients provided signed informed consent before
randomization. Drug therapies—mainly aspirin, thrombolytic therapy or other reperfusion strategies, ß-blockers, heparin, and magnesium—were used at the discretion of the responsible physician. Nitroglycerin preparations, if used, had to be discontinued 1 hour before the prerandomization baseline echocardiogram. The use of calcium channel antagonists and antiarrhythmic agents, although not recommended, was not prohibited.
A baseline prerandomization echocardiogram was obtained on all patients within 3 hours before randomization. The study had two distinct treatment phases: I (early, 1 to 14 days) and II (late, 14 to 90 days). Therapy assignment for both phases was accomplished through random assignment from the Data Coordinating Center with equal probability of being entered into one of three study groups: group I (early placebo, late full-dose [10 mg] ramipril), group II (early low-dose, late low-dose [0.625 mg] ramipril), and group III (early full-dose and late full-dose [10 mg] ramipril). The randomization process was stratified by center and use of reperfusion therapy.
Blood pressure and heart rate were determined before and 6 hours after each of the first four doses. The initial dose was 0, 0.625, or 1.25 mg ramipril for the placebo, low-dose, and full-dose groups, respectively. Thereafter, those in the full-dose group received 2.5 mg ramipril at 12 hours and were subsequently titrated in 24-hour intervals to a maximal dose of 10 mg/d. Those in the placebo and low-dose groups remained at 0 mg and 0.625 mg, respectively, throughout the double-blinded titration period. Patients who did not tolerate a specific dose could be returned to a prior dose level. Reinitiation was permitted in patients who were unable to tolerate even the initial dose level.
The highest achievable dose in the early phase was maintained for the first 14 days, after which a repeat quantitative echocardiogram was obtained. The second, blinded titration initiated the late phase (14 to 90 days), when active therapy was given to all patients. With the blind maintained, those previously assigned to full-dose ramipril or placebo were titrated to 10 mg ramipril, whereas the early-phase low-dose group were maintained on 0.625 mg ramipril. Therapies were continued through 90 days, at which time a clinical assessment and repeat echocardiogram were obtained. Thereafter, the use of ACE inhibitors was at the discretion of the treating physician and no longer under the control of a protocol.
Echocardiographic Studies
An echocardiographic core laboratory was
established to maximize the quality of the studies and generate the
centrally determined quantitative echocardiographic
endpoints. Before the trial, ultrasonographers from all participating
centers underwent training and submitted preliminary echocardiograms to
ensure standardization of views. Parasternal short-axis views were
obtained at three levels of the LV: mitral valve level (mitral valve
leaflets visible), high papillary muscle level (chordal attachments
visible), and low papillary muscle level (papillary muscle body visible
without chordal attachments). Long-axis views were obtained from the
apex in the four- and two-chamber views. A technically acceptable
two-dimensional echocardiogram included a minimum of three of these
five possible views with adequate endocardial definition and included
both short- and long-axis views.
Quantitative Analysis of LV Size and Function
End-diastolic (onset of the QRS complex) and
end-systolic (smallest LV cavity dimension) frames of the LV
were digitally acquired on a Nova Microsonics computer system for
off-line analysis. For all measurements, three separate
high-quality cardiac cycles were traced. LV endocardium was digitized
in end diastole and end systole, and LV cavity areas and
cavity perimeters were calculated.
Major echocardiographic end points were LV area in end diastole and systole as the sum of their respective short- and long-axis views.16 LV end-diastolic and end-systolic volumes (LVEDV and LVESV, respectively) were calculated with the use of a modified Simpson's rule from long-axis views to obtain LVEF=[(LVEDV-LVESV)/LVEDV]x100.16
The extent of LV wall motion abnormality was assessed through visual determination of akinetic or dyskinetic segments evaluating systolic thickening with repeated real-time video playback. The total akinetic and dyskinetic segment length was expressed as the percentage of the sum of all views that were assessed as noncontractile relative to the sum of the perimeters. Quantitative echocardiographic determinations were made without knowledge of treatment group or, for the most part, temporal sequence. Intraobserver reproducibility was assessed by recycling 50 study tapes for blinded quantitative review. Intraclass correlation coefficients quantifying the agreement between these 50 repeated measurements and the original grades were as follows: EF, .89; total akinetic and dyskinetic segment length, .96; summed diastolic cavity area, .98; and summed systolic cavity area, .98. An additional 50 echocardiograms of nonstudy patients without prior infarction or valvular heart disease were obtained for noninfarction reference values.
Clinical Assessment
Vital status, recurrent nonfatal MI, development of heart
failure requiring open-label ACE inhibitor therapy, stroke,
unstable angina requiring urgent percutaneous
coronary angioplasty or coronary artery bypass graft
surgery were prespecified clinical end points. Tolerability of the
blinded therapy was evaluated, and the reasons for discontinuation of
study medication were determined.
Statistical Analysis
All data were centrally processed and analyzed at the
Data Coordinating Center. Initial analyses compared the
distributions of baseline characteristics across the three treatment
groups. For discrete characteristics, comparisons were based on
Fisher's exact test, and for continuous variables, comparisons
across the three groups were made with the Kruskal-Wallis test. In
addition, we compared the distributions of baseline characteristics
between each pair of treatment groups by using Fisher's exact test for
discrete characteristics and the Wilcoxon rank sum test for
continuous variables.
Student's t tests were used to compare mean systolic and diastolic arterial blood pressure measures between each pair of treatment groups 6 hours after the first administration of a new treatment dose. We used repeated-measures ANOVA to examine treatment group differences and interactions with time in these repeated blood pressure measurements. These repeated-measures analyses were made with BMDP statistical software and the assumption of an unstructured covariance matrix.17 Student's t tests were also used to compare mean changes in echocardiographic measures between treatment groups from baseline to 14 days and from 14 to 90 days after randomization. Fisher's exact test was used to compare rates of clinical events between treatment groups. Multiple linear regression models were used to control for baseline echocardiographic measures in additional comparisons of change between groups. We tested for linear trends in echocardiographic effects during the first 14 days by assigning the scores 0, 1, and 2 to the early placebo/late full-dose, early low/late low-dose, and early full/late full-dose groups, respectively.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix OFReferences |
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Prerandomization
Patient Characteristics
The 352 patients were randomized into three groups: 117 in the early placebo/late full-dose ramipril group, 116 in the early low/late low-dose ramipril group, and 119 in the early full/late full-dose ramipril group. The patient demographics were comparable in these groups. Overall, 78% were men, mean age was 60.6 years, 35% were smokers, 21% had a history of diabetes, and 42% had hypertension (Table 1
). The randomization occurred an average of
18±5 hours from onset of chest pain. Before randomization, 78% of the
patients were Killip class I, 72% had thrombolytic
therapy, and 22% had coronary angioplasty performed.
Prerandomization medication use was also similar between groups:
aspirin, 91%; heparin, 92%; ß-blockers, 69%;
nitroglycerin, 85%; and calcium channel blockers, 12%
(Table 1).
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Echocardiogram
An acceptable quantitative baseline echocardiogram was obtained in
90.1% of patients (317 of 352). The baseline characteristics of
patients with and without quantitative echocardiograms were similar. As
anticipated, EF was reduced, and by design, the percentage of the
circumference that was either akinetic or dyskinetic was distinctly
different from the noninfarcted reference group (Table 2). Prerandomization end-diastolic and
-systolic cavity areas were already greater than the non-MI
reference group. At baseline, groups randomized to receive placebo, low
dose, or full dose during the early phase had comparable
diastolic and systolic cavity areas as well as EF.
Although not significantly different across the three groups, the
akinesis/dyskinesis percentage of the group randomized to receive early
full-dose ramipril tended to be slightly less than the placebo group
(Table 2).
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Early Phase
Blood Pressure and Tolerability
Blood pressure at randomization was 121±16/72±11 mm Hg and
declined progressively over the first 2 days in all groups. At 6 hours
after the fourth dose, the systolic blood pressures of the
full- and low-dose ramipril groups were significantly lower than that
of the placebo group (Fig 1). For all groups, blood
pressure rose between the fourth dose and the 14th day after MI.
However, the pressures of both active treatment groups at the end of
the early phase remained lower than that of the placebo group (Fig 1).
Repeated-measures ANOVA revealed a highly significant effect of time on
blood pressure during the titration period (P<.001) but no
significant interaction between treatment group and time. Compared with
the placebo group, the average systolic pressure during this
period was 3.5 mm Hg lower (P=.03) in the high-dose
group and 3.0 mm Hg (P=.07) lower in the low-dose
group; comparable differences in diastolic pressure were
4.1 mm Hg (P<.001) and 2.3 mm Hg
(P=.02) lower in the actively treated groups, respectively.
The blinded titration reached target dose level in 91.5% (107 of 117)
of placebo, 88.8% (103 of 116) of low-dose, and 88.2% (105 of 119) of
full-dose patients (P=NS). Hypotension was more frequent in
both ramipril groups; 31.1% (37 of 119) of patients assigned to
high-dose ramipril were found to have at least one systolic
blood pressure measurement of 90 mm Hg during this early phase
compared with 22.4% (26 of 116) of patients assigned to low-dose
ramipril and 14.7% (17 of 116) assigned to placebo
(P=.01).
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Clinical Events
During the early phase, there were eight deaths (2.3%), 12
patients (3.4%) who developed congestive failure, and 7 (2.0%)
patients had recurrent MIs. One stroke occurred in the low-dose group.
Thirty-one patients (8.8%) underwent a coronary
revascularization procedure during the first 14
days. As expected, there were no significant differences in the
frequency of these events across therapy groups (Table 3).
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Echocardiography
Of the 317 patients with acceptable baseline echocardiograms, 299
(94.3%) had acceptable echocardiograms at 14 days. During this early
phase, there was a marked reduction in the extent of akinesis and
dyskinesis (percentage of LV that was noncontractile) in all groups
(placebo, 27.9±9.7% to 19.9±14.2%; low dose, 26.0±10.9% to
18.6±12.5%; full dose, 24.8±12.2% to 16.7±12.7%;
P<.01 each group). LVEF increased in all groups during the
early phase (Fig 2, top). This improvement in EF during
the first 14 days was greatest in the full-dose ramipril group.
Specifically, improvements occurred of 2.4±8.8 units in the placebo,
3.9±8.2 units in the low-dose, and 4.9±10.0 units in the full-dose
groups, respectively (P for trend, .047) (Fig 2, bottom).
The regression model of the early change in EF demonstrated a
significant (P=.011) improvement with the use of ramipril. A
significant interaction (P=.039) between ramipril use and
baseline EF indicated that patients with the lowest baseline EFs had
the greatest ramipril effect. Despite this improvement in indices of
regional and global LV function, LV diastolic area
increased in all groups. However, this change (LV enlargement) during
the first 14 days was significant only in the placebo and low-dose
groups (not in the full-dose ramipril group) (Fig 3).
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Based on the known importance of infarct size on the extent of LV
remodeling, a prespecified subgroup of patients with baseline akinesis
and dyskinesis above and below the median value of this
parameter (27.2%) were examined. As expected, patients
(n=158) with a greater wall motion abnormality had a greater increase
in diastolic cavity area from day 1 to 14 (median,
52.0±9.8 to 52.7±10.2 cm2; P=NS; >median,
52.2±10.7 to 54.9±11.9 cm2; P<.001). During
this early phase, patients with baseline akinesis/dyskinesis above the
median who did not receive ramipril had the greatest
ventricular enlargement, whereas those who received
full-dose ramipril had the least enlargement (Fig 4A).
Patients with the higher prerandomization percentage of
akinesis/dyskinesis who were assigned to full-dose ramipril also had
the greatest improvement in global LVEF (Fig 4B).
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Late Phase
Blood Pressure and Tolerability
By design, all patients were on active therapy from day 14 to 90.
Those randomly assigned in the early phase to either placebo or full
dose were retitrated in the late phase to receive 10 mg ramipril,
whereas those assigned to the low dose in the early phase continued on
0.625 mg. Both dose levels were equally well tolerated as 90.4% (94 of
104) of patients who were maintained on the low dose reached their
target compared with 88.2% (186 of 211) of the two groups who were
assigned to receive full-dose ramipril for the second titration
(P=NS). Although the blood pressures of the groups during
the second phase were not significantly different, the group on low
dose tended to have a higher arterial pressure than the two
groups receiving full dose (systolic, 127±18 versus
123±19 mm Hg, P=.09; diastolic, 76±10
versus 74±10 mm Hg, P=.12, low versus the two
full-dose groups at the 90-day visit).
Clinical Events
During this late phase, all patients were on active therapy, and
the clinical events were comparable between groups. There were six
(1.8%) additional deaths after the second titration. The overall
mortality for the 352 patients from randomization (18 hours) to 90 days
was 14 (4.0%). During the late phase, 9 (2.6%) of the patients
developed heart failure, and 7 (2.0%) patients experienced a recurrent
MI (Table 3
). Two patients had a stroke, and 12 (4 each group) had a
coronary revascularization procedure (Table 3).
Echocardiography
Of the 288 patients with paired
echocardiographic studies during the late phase, there
was a continued reduction in the proportion of the LV that was assessed
as either akinetic or dyskinetic (placebo to full dose, 19.9±14.2% to
16.9±13.9%; low dose to low dose, 18.6±12.5% to 16.8±13.6%; and
full dose to full dose, 16.7±12.7% to 15.4±13.6%). However,
only the group who received ramipril for the first time (placebo to
full dose) during the late period showed a statistically significant
(P=.02) improvement in wall motion. During this late phase
when all groups were on active therapy, diastolic areas did
not increase further. However, only the group who was previously on
placebo and subsequently received full-dose ramipril (delayed therapy)
had a trend toward a decrease in LV end-systolic area
(33.5±11.0 to 32.3±10.6 cm2, n=91; P=.16) and
an improvement in EF (54.0±10.5% to 55.9±9.5%, n=91;
P=.14) during the late phase.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix OFReferences |
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Randomized clinical trials3 4 5 6 7 8 9 led to the clinical recommendation now endorsed by major professional societies that ACE inhibitors should be used as standard therapy in most patients experiencing a MI infarction to reduce mortality and the development of congestive heart failure.18 19 20 21 22 However, in trials that initiated ACE inhibition within the first day of MI, there was an increased incidence of worrisome hypotension.5 6 7 8 11 12 One aim of the present trial was to determine whether modification of the timing of initiation or the dose of the ACE inhibitor ramipril could be optimized to avoid some of the adverse consequences of this therapy without loss of the benefits.
The attenuation of late LV enlargement by therapy with ACE inhibition after MI23 24 25 was established before and served as the major rationale for the larger long-term clinical outcomes trials.3 4 9 Similarly, recent serial echocardiographic studies of the early use of ACE inhibition in acute MI26 27 28 provided mechanistic support for the newer observations of the prompt survival benefit observed in the shorter-term megatrials.5 7 It is now clear that a substantial degree of ventricular enlargement can occur within the first week of an MI and that ACE inhibitor therapy during this critical period can reduce this deleterious consequence.26 27 28 29 30 31 The GISSI-3 investigators reported that a prominent component of the early lives saved with prompt ACE inhibitor therapy in MI is a 45% reduction in the deaths attributed to cardiac rupture and pump failure.32 Cardiac rupture has been considered an extreme form of infarct expansion,33 and the favorable effects of early ACE inhibition on LV topography demonstrated by these early echocardiographic studies is supportive of this early life-saving mechanism. The present trial data indicate that a strategy of delaying therapy does reduce worrisome hypotension but at the unacceptable cost of a less prompt improvement in LV function and early enlargement. The major mortality and echocardiographic studies therefore would support early initiation of ACE inhibition in acute MI, especially in higher-risk individuals in whom this therapy should be maintained on a long-term basis.
The HEART study also addressed whether the strategy of using a lower
dose of the ACE inhibitor could reduce adverse consequences
yet sustain the beneficial effects on LV remodeling. The impetus for
the low-dose concept was based on observations from experimental animal
studies in which an extremely low, nonhemodynamically
detectable dose of ramipril was effective in preventing LV
hypertrophy produced by aortic banding.34 This
trial raised the question of whether this tissue-selective ACE
inhibitor would have favorable effects on LV remodeling at
a dose that avoided hemodynamic consequences. The 0.625
mg ramipril dose was specially formulated for this trial and is one
half of the lowest clinically approved and available dose. Our data do,
however, suggest that even this low dose of ramipril was associated
with a reduction in arterial pressure and an increase in
the proportion of patients manifesting systolic
arterial pressures of 90 mm Hg. Although not
definitive, the echocardiographic outcomes of the
low-dose group were consistently intermediate between those of
the placebo and full-dose ramipril groups. Based on these observations,
we do not recommend the low-dose strategy and would titrate the ACE
inhibitor to the full dose used successfully in large-scale
trials demonstrating benefits on mortality, which for ramipril, was 10
mg daily based on the AIRE trial.4 The present trial
extends the AIRE experience in which ramipril was initiated between
days 3 and 10 of the MI and indicated that early titration to full-dose
ramipril starting within 24 hours is safe and effective in improving LV
function.
A particularly striking finding from this quantitative echocardiographic study was the marked recovery of regional wall motion during the first 14 days of an acute anterior MI. The process of myocardial stunning has been well defined in experimental animal studies as an initially noncontractile, although viable, region that slowly recovers function after the restoration of coronary perfusion.35 Numerous, often striking individual clinical examples have confirmed this experimental observation.36 37 The HEART study provided an opportunity to quantify this recovery of function in an anterior MI population treated in the modern era of thrombolytics, aspirin, and ß-blockers. Indeed, 87% of our patients received either thrombolytic therapy or angioplasty before randomization. Although within this trial there were several individual examples of outstanding recovery of LV function, from marked wall motion abnormalities to no detectable akinesis or dyskinesis, the overall group changes provide a better perspective of the magnitude of recovery that can be anticipated. In this cohort in whom quantitative echocardiography determined that 27% of the left ventricle was either akinetic or dyskinetic on the initial day of the MI, substantial recovery of wall motion was apparent (akinesis or dyskinesis reduced by approximately one third) by 14 days. It is of interest that despite this recovery of regional function, global ventricular enlargement did occur.38 As anticipated, this post-MI ventricular remodeling was most marked in those with greater baseline wall motion abnormalities.23 25 39 40
The HEART study was terminated because new data indicated a clear and conclusive benefit on mortality with the early use of ACE inhibitors in acute MI.15 For this reason, it may represent one of the last placebo-controlled evaluations (even if only 14 days) of ACE inhibitors in a high-risk MI population. The trial does demonstrate that even in the modern reperfusion era, in anterior MI, particularly in those with the greater wall motion abnormalities, early ventricular enlargement does occur despite recovery of wall motion abnormalities. The quantitative echocardiographic studies, including the present one, indicate that the early use of an ACE inhibitor attenuates LV remodeling and is associated with a prompter recovery of LVEF. In perspective, it now appears that delay in therapy to avoid the risks of hypotension also delays benefits regarding mortality. The total weight of the evidence from large-scale trials as well as echocardiographic studies supports the early judicious use of an ACE inhibitor in acute MI with continued long-term therapy in those with depressed ventricular function, clinical symptoms, anterior MI, or any other indication of higher risk. Whether after MI all patients will benefit from ACE inhibitor therapy requires additional data from randomized trials.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by an investigator-initiated grant from Hoechst Marion Roussel (formerly Hoechst Roussel Pharmaceuticals, Inc) and The Upjohn Company. We are indebted to the study patients for their cooperation and to all study personnel. Donald Verrecchia facilitated study implementation. Cristina Godinho skillfully served as the project coordinator, and the efforts of Christine Clemente, Ellie Danielson, Kimberley Shaw, Myles Cassidy, and Jean MacFadyen at the data coordination center were greatly appreciated, as were the secretarial efforts of Angela Moscaritolo and Pamela Hsieh.
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Footnotes |
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1 List of participants is given in "Appendix."
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Appendix OF |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix OFReferences |
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J. Malcolm O. Arnold, MD; Ruth Miles, RN; Julie Occhipinti, RN; Victoria Hospital and St Joseph's Hospital, London, Ontario; Elliot Rapaport, MD; Carolyn Somelofski, RN; University of California, San Francisco Affiliated Hospitals, San Francisco General Hospital, and Alameda Hospital, Calif; Francis J. Menapace, Jr, MD; Marie Kleman, RN; Geisinger Medical Center, Danville, Pa; Jean-Lucien Rouleau, MD; Lucette Whittom, RN; Montréal Heart Institute, Montréal, Québec; Gerald C. Timmis, MD; Denise Mason, RN; William Beaumont Hospital, Royal Oak, Mich; J. Wayne Warnica, MD; Brenda L. Smith, RN; Foothills Provincial Hospital, Calgary, Alberta; Jonathan F. Plehn, MD; Susan J. Kennedy, RN; Dartmouth-Hitchcock Medical Center, The Cheshire Medical Center, Keene, NH; Klaus Lindpaintner, MD; Tina Godinho; Brigham and Women's Hospital, Boston, Mass; Claude Lauzon, MD; Francine Ouimet, RN; Centre Hôpital de la Région de l'Amiante, Thetford-Mines, Québec; Peter H. Ackell, MD; Marcia Noble, RN; Appleton Medical Center and Theda Clark Regional Medical Center, Appleton, Wisc; Gary Marais, MD; Patricia Eakes, MA; Redlands Community, St Bernadine's Hospital, Redlands, Calif; Marc Klein, MD; Ginette Gaudette, RN; Hôpital du Sacré-Coeur de Montréal, Montréal, Québec; Steven Goldman, MD; Ray Holcombe, LPN; Tucson VA Medical Center, Tucson, Ariz; Bruce A. Sussex, MD; Marlene Tobin, RN; The General Hospital Cooperation, Health Sciences Centre, Memorial Hospital Clinical Offices, St John's, Newfoundland; Sandra J. Lewis, MD; Mindy Gramberg, RN; Good Samaritan Hospital and Medical Center, Portland, Ore; Robert Beanlands, MD; Sharon Ann Kearns, RN; University of Ottawa Heart Institute, Ottawa, Ontario; Ralph Gianelly, MD; Debra Tomaszewski, RN; Baystate Medical Center, Springfield, Mass; Richard C. Conti, MD; Kay Worley, ARNP; University of Florida, College of Medicine, Gainesville, Fla; Paul A. Sobotka, MD; Eric Louie, MD; Rosita Picchi-Szocka, RN; Loyola University Medical Center, Maywood, Ill; Arnold Conrad, MD; Lisa Blanz, RN; Nassau County Medical Center, East Meadow, NY; David Korn, MD; Kimberly Vitale, RN; Mount Sinai Medical Center, Miami Beach, Fla; Vicki Bernstein, MD; Susan Mooney, RN; Vancouver Hospital of Health Sciences Center, Vancouver, British Columbia; Barry F. Uretsky, MD; Srinivas Murali, MD; Susan Loftus, RN; Presbyterian University Hospital, Pittsburgh, Pa; John D. Rutherford, MB, ChB; Linda Morgan, RN, BSN; Parkland Memorial Hospital, Dallas, Tex; Ha Dinh, MD; Nancy Patterson, BSN; University of Arkansas and John L. McClellan Memorial VA Hospital, Little Rock, Ark; Richard M. Steingart, MD; Suzanne Bilodeau, RN; Winthrop University Hospital, Mineola, NY; Normand Racine, MD; Hôpital Notre-Dame, Montréal, Quebec; Park W. Willis III, MD; Eileen Worden, RN; Michigan State University, East Lansing, Mich; Stanley Rubin, MD; VA Medical Center, Long Beach, Calif; David F. Gordon, MD; Mark Polich, RN; Iowa Heart Institute, Des Moines, Iowa; Lawrence Gimple, MD; Charlotte Beagle, RN; University of Virginia (Charlottesville); Cara East, MD; Syed M. Nawab, MD; Baylor University Medical Center, Dallas, Tex; Robert Bryg, MD; Lynn Semenza, RN; Mary Bryant, RN; University of Nevada and Washoe Medical Center, Sparks, Nev; Richard Haichin, MD; Connie Muldoon, RN; Royal Victoria Hospital, Montréal, Quebec; Patrick T. O'Gara, MD; Coral Haggan, RN; Massachusetts General Hospital, Boston, Mass; Marc D. Tischler, MD; MichaelAnn Rowan, RN; Medical Center Hospital of Vermont (Burlington); Michael Pasquale, MD; Christiana Hospital, Newark, Dela; Douglas E. Vaughan, MD; Vanderbilt University Medical Center, Nashville, Tenn.
Clinical Coordinating Center, Brigham and Women's Hospital: Marc A. Pfeffer, MD, PhD (Principal Investigator); Cristina Godinho, BA (Project Coordinator); Scott D. Solomon, MD; Klaus Lindpaintner, MD; Paul M. Ridker, MD.
Myocardial Infarction Data Core Laboratory, University of Texas Southwestern at Dallas: John D. Rutherford, MB, ChB.
Echocardiography Core Laboratory, Brigham and Women's Hospital: Sally Greaves, MD; Richard T. Lee, MD; Scott D. Solomon, MD.
Data Coordinating Center, Brigham and Women's Hospital: Christine Clemente; Robert Glynn, DSc; Charles H. Hennekens, MD, DrPH; Fran S. LaMotte, BS; Jean G. MacFadyen; Paul M. Ridker, MD.
Received September 5, 1996; revision received November 25, 1996; accepted December 16, 1996.
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