Download Comparison of Enalapril Versus Captopril on Left Ventricular

Comparison of Enalapril Versus Captopril
on Left Ventricular Function and Survival
Three Months After Acute Myocardial Infarction
(the "PRACTICAL" Study)
Stephan G, Foy, MB, ChB, Ian G. Crozier, MD, John G. Turner, MD, A. Mark Richards, MD,
Christopher M. Frampton, PhD, M. Gary Nicholls, MD, and Hamid Ikram, PhD
Left ventricular (LV) function and survival can be
improved with captopril when initiated later than 24
hours after acute myocardial infarction. Animal
studies suggest additional benefits may be
obtained with earlier initiation of angiotensinconverting enzyme (ACE) inhibitors. The effects on
LV function of captopril and enalapril initiated within
24 hours of myocardial infarction were studied. Two
hundred twenty-five patients with acute myocardial
infarction were enrolled within 24 hours of the
onset of chest pain. They were randomized to
receive either captopril 25 mg three times daily,
enalapril 5 mg three times daily, or placebo. LV
ejection fraction (EF) and volumes were measured
by radionuclide ven-triculography at baseline during
treatment and at 3 months after a 3-day withdrawal
from therapy. The ACE inhibitor group had a
significant increase in EF (45 ± 1 to 47 ± 1%; p =
0.005) and significantly attenuated LV dilatation
compared with results in the placebo group (175 ±
6 to 189 ± 7 ml in the placebo group vs 168 ± 4 to
172 ± 4 ml in the ACE inhibitor group; p = 0.051 for
LV end-diastolic volume; and 99 ± 6 to 108 ± 7 ml
in the placebo group vs 94 ± 3 to 94 ± 4 ml; p s
0.026 for LV end-systolic volume). The beneficial
effects of ACE inhibitor therapy on LV function
were observed irrespective of the degree of initial
LV dysfunction and were comparable in both the
captopril and enalapril groups. Survival at 90 days
and 12 months was significantly improved in the
enalapril group (7 placebo, 9 captopril, 1 enalapril
[p = 0.038] and 12 placebo, 10 captopril, 2 enalapril
[p = 0.022]; deaths at 90 days and 12 months,
respectively). Immediate administration of captopril
and enalapril improved LV function and prevented LV
dilatation after acute myocardial infarction. The
benefit was similar with both ACE inhibitors and
was in excess of the benefits of optimal conventional therapy.
(Am J Cardiol 1994;73:1180-1186)
left ventricular (LV) dilatation is an imProgressive
portant determinant of prognosis after acute myocardial infarction. 1 Captopril administered later than
24 hours after the onset of acute myocardial infarction has been demonstrated to attenuate LV dilatation in patients with impaired LV function.2-5 That earlier administration of angiotensin-converting enzyme
(ACE) inhibitor therapy could result in additional clinical benefit is suggested by experimental work on myocardial infarction.6-8 ACE inhibition soon after sustained
coronary occlusion in anesthetized dogs reduced
infarct size and improved regional myocardial blood
flow.6 In the isolated rat heart both the addition of
ACE inhibitor to the perfusate and oral pretreatment
with an ACE inhibitor increased coronary blood flow7,8
and improved left ventricular mechanics during
ischemia,7 while pro-tecting against reperfusion
arrhythmias.7 However, to date, early administration of
ACE inhibitor therapy af-ter acute myocardial
infarction has had no beneficial ef-feet9-11 or has had
beneficial effects on LV function in only some
categories of patients.12
Several important practical issues concerning the
ad-ministration of ACE inhibitor therapy in acute
myocar-dial infarction remain unresolved: (1) whether
beneficial effects occur with earlier administration, (2)
whether benefits are confined to patients with reduced
LV ejection fraction (EF), (3) whether all ACE
inhibitors are equally efficacious, and (4) whether
alternative dosing regimens can improve drug
tolerability yet maintain ef-ficacy. We examined these
issues in a placebo-controlled, randomized, ACE
inhibitor, comparative trial in cardiac infarction and
LV function (PRACTICAL), conducted in a single
center. This study presents the results of a comparison
of the effects of immediate postinfarction treatment
with either captopril or enalapril with placebo on LV
function, the primary end point, after 90 days of
treatment, and survival after 12 months treatment.
METHODS
Patient selection: The study was approved by the
From the Departments of Cardiology and Nuclear Medicine, The
Canterbury
Area Health Board Ethics Committee and
Princess Margaret Hospital and Christchurch Hospital, Christchurch, New
Zealand. Manuscript received June 23, 1993; revised manuscript received all patients gave written informed consent. Patients
November 4, 1993, and accepted November 6.
were el-igible for enrollment if they presented within
Address tor reprints: Humid Ikram, PhD. The Princess Margaret
24 hours of the onset of chest pain considered to be the
Hospital, Private Bag, Christchurch, New Zealand.
initial-symptom of acute myocardial infarction, and if
the pain was associated with at least 1 of the following
features: elevation of the ST segment in 2 contiguous
electro-cardiographic leads, new pathologic Q waves,
or eleva-tion of plasma creatine phosphokinase.
1180 THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 73
JUNE 15, 1994
TABLEI Clinical Characteristics of Treatment Groups at Baseline
Characteristic
Mean age (years)
Age >70 years (%)
Men/women (%)
Thrombolytic therapy (%)
Prior clinical history (%)
Myocardial infarction
CHF
CABG
PTCA
Medications at entry (%)
blocker
Calcium antagonist
Digoxin
Diuretic
NSAID
Infarct location and type (%)
Anterior
Inferior
Q-wave
Non-Q-wave
Mean ST elevation (mm)
Mean time to entry (min)
Mean peak creatine
kinase(U/L)
Mean systolic blood
pressure (mm Hg)
Mean serum sodium
(mmol/L)
Mean serum potassium
(mmol/L)
Placebo
(n = 75)
Captopril
(n = 75)
Enalapril
(n = 75)
64
20 (27)
58 (77)/7(23)
55 (73)
64
17(23)
48 (75)/ 16(25)
51 (68)
63
21 (28)
59(79)/16(21)
56 (75)
8(11)
4(5)
0
1(1)
13(17)
2 (3)
5(7)
2(3)
10(13)
0
5(7)
1(1)
11(15)
11(15)
3(4)
10(13)
3(4)
19 (25)*
16 (21)
2(3)
7(9)
8(11)
8(11)
11(15)
3(4)
3(4)
9(12)
37 (49)
38 (51)
55 (73)
19 (25)
2
746
1979
34(45)
40 (53)
52 (69)
23 (31)
37 (49)
33 (44)
52 (69)
22 (29)
2
650
1762
2
569
1949
129
133
139
140
140
139
4
4
4
*p = 0.046.
CABG = coronary artery bypass grafting; CHF = congestive heart failure; NSAID = nonsteroidal antiinflammatory drug;
PTCA = percutaneous transluminal coronary angioplasty.
Patients were excluded if they had any of the following: persistent hypotension with systolic blood pressure <90 mm Hg, a history of sensitivity to ACE inhibitors or the use of ACE inhibitors within 1 week of
the infarction, hemodynamically significant valvular
stenosis, clinically severe renal or hepatic disorders, or
a clear indication for treatment with an ACE inhibitor.
Those who did not give informed consent or those who
were expected to comply poorly with treatment were also
excluded.
Study design: Patients were randomized, in a double-blind manner, to 1 of 3 parallel treatment groups.
One group received oral captopril 6.25 mg at 2-hour intervals for 3 doses, followed by 25 mg 3 times daily begun 6 hours after initial dose; the second group received
oral enalapril 1.25 mg at 2 hourly intervals for 3 doses,
followed by 5 mg 3 times daily begun 6 hours after initial dose; the third group received placebo at matching
times with groups 1 and 2. Blood pressure was recorded
before each scheduled dose in the first 48 hours. Doses
were withheld if systolic blood pressure was <90 mm
Hg at the scheduled dose time. Randomized therapy was
continued for a total of 12 months. All patients otherwise received conventional therapy as clinically indicated including thrombolytic agents and  blockers.
Open ACE inhibitor therapy was used if, after randomization, a clear indication for ACE inhibitor treatment
developed. Patients were reviewed at 1 and 3 months,
and then at 3-month intervals.
Methods of assessment: The primary end points
of the study were EF and LV volumes as measured by
radionuclide ventriculography. The baseline study was
performed during randomized treatment within 10 days
of infarction or as soon thereafter as practicable. Followup study was scheduled at 3 months after infarction following a 3-day withdrawal of randomized treatment.
Each study was performed using a General Electric 400T
gamma camera interfaced to a General Electric STAR
II computer system after in-vivo technetium-99m red
blood cell labeling. General Electric PAGE software was
used for analysis of EF based on a count-generated
method, and an area-length method was used to measure LV end-diastolic volume. The method developed at
our institution uses the PAGE edge-detection algorithm
and radial vectors defining the ventricular edge at enddiastole. The volume was generated from data acquired
from the left anterior oblique view. LV end-systolic volume was calculated from EF and end-diastolic volume.
The effect of the 2 ACE inhibitor regimens on blockade of the circulating renin-angiotensin axis was tested
in a subgroup of 36 patients. Plasma angiotensin II was
measured before the first dose of randomized treatment
and 2 and 12 hours after the first dose. Patients entered
the trial within 6 hours of acute myocardial infarction,
but were otherwise unselected. Plasma angiotensin II
was measured by radioimmunoassay. 13,14
Statistical analysis: Power analysis based on data
from a previous study2 indicated that 50 patients were
ACE INHIBITION AFTER MYOCARDIAL INFARCTION 1181
required in each treatment group in order to detect a 3%
difference in the EF from baseline between the combined
ACE inhibitor group and placebo, with  = 0.05 and
= 0.20. This would also allow detection of a difference
in the change in EF of 4% between the active and
placebo groups ( = 0.05 and  = 0.20). The enrollment
target was therefore set at 75 per treatment group to allow for attrition. All end points were evaluated by the
intention-to-treat principle. Characteristics were compared by the-chi-square test for categorical variables, and
continuous variables were tested by analysis of variance,
and analysis of variance with repeated measures as appropriate. Survival analysis with the Kaplan-Meier estimate was used to estimate survival curves. Comparison
of survival curves was obtained by the Mantel-Cox
statistic. Statistical significance (2-tailed tests) was set at
5%. Data are presented as mean ± SEM.
RESULTS
Patient population: The study group was taken from
523 consecutive patients with acute myocardial infarction admitted to The Princess Margaret Hospital Coronary Care Unit. Two hundred twenty-five patients (43%)
were randomized, 75 patients to each treatment group.
Patients were excluded for the following reasons: consent declined (n = 101), administrative reasons (n = 80),
current ACE inhibitor therapy (n = 46), pain onset >24
hours after admission (n = 41), persistent hypotension
(n = 27), malignancy (n = 2), and known adverse effects with an ACE inhibitor (n = 1). Baseline characteristics (Table I) were similar except there were significantly more patients using  blockers in the captopril
group (p = 0.046).
Patient withdrawals and drug tolerabitity: Fortytwo patients were withdrawn from randomized treatment; 12 (16%) taking placebo, 18 (24%) taking captopril, and 12 (16%) taking enalapril. The most frequent
reasons for withdrawal were hypotension (2 placebo, 5
captopril, 5 enalapril), rash (1 placebo, 3 captopril, 4
enalapril) and withdrawal of consent (3 placebo, 1 captopril, 4 enalapril). A further 12 patients underwent dose
reduction because of intolerable adverse effects at the
target dose (8 captopril and 4 enalapril). The target dose
level was achieved in 75% of patients (80% placebo,
65% captopril, 79% enalapril) and was not significantly
different between groups (chi-square = 5.2, degrees of
freedom [df] = 2, p = 0.074). Other adverse effects not
requiring withdrawal of randomized treatment or dose
reduction included: dizziness (6 placebo, 15 captopril,
14 enalapril); rash (6 captopril, 4 enalapril); cough (2
placebo, 6 captopril, 4 enalapril); loss of taste (5 captopril, 1 enalapril); gastrointestinal upset (1 placebo, 2 captopril); and headache (1 placebo, 1 enalapril).
Reproducibility of radioniiclide ejection fraction
and end-diastolic volume: The precision of the radionuclide method was determined by repeating studies
on the same day in 29 patients. The coefficient of vari
ation (10% at end-diastolic volume [125 ml] to 4% at
end-diastolic volume [250 ml]) followed an essentially
linear pattern. The coefficient of variation for EF was
4% over the EF range 35% to 75%.
Effects of angiotensin-converting enzyme
inhibi-tion on left ventricular function: Paired
baseline and 3-month assessments of LV function were
not available in 43 patients; 17 because of death, 21
for administrative reasons, and 5 patients withdrew
consent Mean times from infarction to baseline and 3month assessment were 7 ± 0.3 days and 13 ± 0.1
weeks, respectively.
EF was not significantly changed in the placebo
group (n = 62; 45 ± 2 to 45 ± 2%; p = 0.68), but
increased 2% in patients receiving an ACE inhibitor (n
= 120; 45 ± 1 to 47 ± 1%; p = 0.005); however, the
difference in the changes was not significant when
compared with the placebo group; p = 0.15 (Figure 1).
The placebo group had a significant increase in enddiastolic volume (175 ± 6 to 189 ± 7 ml; p = 0.004),
whereas in the ACE inhibitor group the increase in enddiastolic volume was attenuated (168 ± 4 to 172 ± 4 ml;
p = 0.30). The difference in the change between placebo
and ACE inhibitor groups did not quite achieve statistical significance; p = 0.051 (Figure I).
After 3 months of treatment, the placebo group had
a significant increase in end-systolic volume (99 ± 6 to
108 ± 7 ml; p = 0.007), but this did not change in pa-
FIGURE 1. Changes in left ventricular (LV) function and volume from baseline (B) to 3 months (Mo) in patients re ceiving an angiotensin-converting enzyme inhibitor or placebo after acute myocardial infarction. Closed circles represent the angiotensin-converting enzyme inhibitor group; open circles represent the placebo group.
1182 THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 73
JUNE 15, 1994
tients receiving an ACE inhibitor (94 ± 3 to 94 ± 4 ml;
p = 0.94). The difference in the changes in end-systolic
volume was statistically significant; p=0.026 (Figure 1).
Effect of individual angfotensin-converting enzyme inhibitors on left ventricular function: Captopril (n = 55) significantly increased EF by 2% (45 ± 6
to 47 ± 6%; p = 0.023), whereas in the enalapril group
(n = 65) EF increased by 2% (46 ± 6 to 48 ± 6%) and
the change almost achieved statistical significance (p =
0.08). There was no significant difference in these
changes between groups (p = 0.66) (Figure 2).
End-diastolic volume did not change significantly in
either the captopril (171 ± 23 to 176 ± 24 ml; p = 0.23)
or the enalapril (167 ± 21 to 168 ± 21 ml; p = 0.65)
groups, nor was there a statistically significant difference
between groups (p = 0.51).
End-systolic volume showed little change in either
the captopril (97 ± 5 to 98 ± 7 ml; p = 0.78) or the
enalapril (92 ± 5 to 91 ± 5 ml; p = 0.88) groups, nor was
there a significant difference between groups (p = 0.75).
Benefits in patients with ejection fraction >40%:
Sixty-five percent of patients had a baseline EF >40%.
In these patients, EF did not change in the placebo group
(n = 44; 51 ± 1 to 51 ± 1%), but tended to increase with
ACE inhibition (n = 84; 52 ± 1 to 53 ± 1%; p = 0.28).
The placebo group had a 7% increase in end-diastolic volume (160 ± 5 to 171 ± 6 ml; p = 0.066), whereas
in the ACE inhibitor group there was a 1% decrease in
end-diastolic volume (158 ± 4 to 156 ± 4 ml; p = 0.61).
The difference in these changes between placebo and
ACE inhibitor almost achieved statistical significance
(p = 0.056) (Figure 3).
End-systolic volume increased by 8% in the placebo
group (78 ± 3 to 84 ± 4 ml; p = 0.096), whereas there
was a 4% decline in the ACE inhibitor group (77 ± 3
to 74 ± 3 ml: p = 0.19). There was a significant difference in these changes between placebo and ACE inhibitor groups (p = 0.026) (Figure 3).
Comparability of angiotensin-converting enzyme
inhibitor regimens on circulating angiotensin II:
There was no significant change in plasma angiotensin
II level from baseline to 12 hours in patients receiving
placebo (n = 11; 37 ± 6 to 36 ± 13 pmol/liter, p = 0.96),
but was significantly reduced both in the captopril (n =
13; 43 ± 9 to 18 ± 5 pmol/liter, p = 0.001) and in the
enalapril (n = 12; 69 ± 18 to 16 ± 8 pmol/liter, p = 0.01)
groups.
The difference in the change in angiotensin II levels
from baseline to 12 hours was not significantly different
between the captopril and enalapril groups (p = 0.13).
Blood pressure: In the placebo group (n = 58) there
was a significant decrease in systolic blood pressure from
FIGURE 2. Change in left ventricular (LV) ejection fraction from baseline (B) to 3 months (Mo) in patients receiving captopril or enalapril after acute myocardial infarction. Diamonds represent the enalapril group;
squares represent the captopril group.
FIGURE 3. Changes in left ventricular (LV) end-diastolic and end-systolic volume from baseline (B) to 3 months
(Mo) in patients with an initial ejection fraction >40% receiving an angiotensin-converting enzyme inhibitor or
placebo after acute myocardial infarction. Closed circles represent the angiotensin-converting enzyme inhibitor
group; open circles represent the placebo group.
ACE INHIBITION AFTER MYOCARDIAL INFARCTION 1183
baseline to 48 hours (129 ± 3 to 113 ± 3 mm Hg; p
<0.001). A similar decline in systolic blood pressure was
observed in both the captopril (n = 55;130 ± 3 to 116 ±
3 mm Hg; p <0.001) and the enalapril (n = 54; 132 ± 3
to 109 ± 2 mm Hg; p <0.001) groups.
The difference in the change from baseline to 48
hours in systolic blood pressure between the captopril
and enalapril groups was almost statistically significant
(p = 0.052), but there was a significantly greater decrease
in blood pressure with captopril at 2 hours (p = 0.004)
(Figure 4).
Mortality: Seventeen deaths (8%) from all causes occurred during the first 90-day study period (7 placebo, 9
captopril, and 1 enalapril). There were 16 deaths (7%)
from cardiac causes, the majority being mechanical (i.e.,
LV failure and cardiac rupture; 6 placebo, 4 captopril).
Six deaths were presumably due to ventricular arrhythmias; 5 were sudden undocumented deaths with no premonitory symptoms (1 placebo, 3 captopril, 1 enalapril)
and 1 was from documented ventricular fibrillation.
Twenty-four deaths (11%) from all causes occurred
in the 12-month follow-up period (12 placebo, 10 captopril, 2 enalapril). There were 21 deaths from cardiac
causes (12 placebo, 8 captopril, 1 enalapril) of which 12
(8 placebo, 4 captopril) were due to either LV failure or
cardiac rupture and 9 were sudden, due to either documented or presumed ventricular arrhythmias (4 placebo,
4 captopril, 1 enalapril). There were 3 non-cardiac-re
lated deaths, 1 due to cerebrovascular accident (capto
pril), 1 resulting from acute gastrointestinal bleeding
(captopril), and 1 from metastatic carcinoma of the
bronchus (enalapril).
Kaplan-Meier estimates of survival curves showed a
significantly improved survival at 90 days (Mantel-Cox
chi-square = 6.52, df = 2; p = 0.038) and at 12 months
(Mantel-Cox chi-square = 7.67, df = 2; p = 0.022) in patients treated with enalapril (Figure 5).
DISCUSSION
Progressive LV dilatation occurs after acute myocardial infarction, leads to heart failure, and is an important
predictor of mortality.1,15 Previous studies have shown
that captopril initiated late after myocardial infarction attenuated progressive LV dilatation, reduced heart failure, and improved survival.2-5 Data from animal studies
suggest that very early ACE inhibition may have addi
tional benefits by decreasing infarct size and reducing
arrhythmias.6-8 The role of early initiation of ACE in
hibitors in humans after myocardial infarction remains
unclear.
The primary objective of the present study was to
evaluate the effects of ACE inhibition on LV function
when initiated immediately within 24 hours of the on
set of acute myocardial infarction in a relatively unselected group of patients entering a single coronary care
unit. We demonstrated that LV enlargement is reduced
by both captopril and enalapril, and that these benefits
are comparable with results of studies using captopril
given later in the course of cardiac infarction.2-4 Enalapril
has not previously been documented to improve LV
function after myocardial infarction. Our data show that
enalapril and captopril had a comparable effect on LV
function, and therefore it is likely this was a class effect
of ACE inhibition.
Because this was a study of immediate administration of ACE inhibitor therapy after the onset of acute
myocardial infarction, we elected not to assess LV function before initiation of randomized therapy. LV func-
FIGURE 4. Change in systolic blood pressure from baseline to 48 hours in patients receiving captopril or enalapril
after acute myocardial infarction. Diamonds represent the enalapril group; squares represent the captopril group;
*p = 0.004.
1184 THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 73
JUNE 15, 1994
tion in the first few hours after the onset of acute infarction is highly unstable because it is affected by the
evolution of the infarction as well as acute treatment, especially thrombolytic therapy. Because >80% of patients
had not experienced a previous myocardial infarction, it
is likely that LV function was normal and similar in all
treatment groups before initiation of randomized therapy. The absence of any discernable drug effect on infarct size and early remodeling is indicated by the absence of significanr differences between groups in LV
function and volume at the initial measurement 7 days
after infarction.
Our trial design almost certainly minimized the magnitude of benefit by excluding the acute effects of afterload reduction because the initial measurement of LV
function was performed during randomized treatment,
and the subsequent assessment was performed after 3
days without treatment. This is in contrast to previous
studies in which assessment was performed during treatment, and thus the changes observed would have been
magnified by the effect of afterload reduction in addition
to any effects on remodeling.
In this study we observed that LV dilatation occurred
even in patients with EF >40%. ACE inhibitor therapy
attenuated this dilatation and this benefit was comparable to those with EF <40%. These observations extend
the conclusions of previous studies in which only patients with EF <40% were considered, by demonstrating
beneficial effects on LV function irrespective of initial
EF.
Concern has been expressed as to the risk of excessive hypotension from the addition of an ACE inhibitor
to conventional optimal therapy because the multiple hypotensive drugs may cause deleterious hypotension.11
However, in the present study, despite the inclusion of
all patients in an unstable phase of acute infarction, the
target dose was reached in 72% treated with active ther-
apy without development of a significant excess of patient withdrawals because of early hypotension or other
drug side effects. These tolerability data suggest that frequent smaller oral doses of captopril and enalapril may
be better tolerated in patients with acute myocardial infarction than larger, less frequent and intravenous regimens.11 This study demonstrated that these lower doses
have comparable therapeutic benefit to previous studies
of higher doses of captopril after myocardial infarction.2-5
This study was not designed to assess the effects of
acute ACE inhibitor therapy on mortality. However, mortality was carefully monitored because of concerns regarding the potential adverse mortality effect of early
ACE inhibitor treatment. There was no excess mortality
in either ACE inhibitor group and, indeed, in the
enalapril group mortality was significantly reduced. This
study contrasts with the Cooperative New Scandanavian
Enalapril Survival Study II (CONSENSUS II) which
failed to demonstrate any mortality benefit over a period
of 180 days.11 The reason for the lack of benefit in CONSENSUS II is uncertain, but a major concern that led to
premature termination of the study was the high incidence of early hypotension, which may have had an adverse effect. This may have been due to the intravenous
regimen that, by inducing hypotension and compromising myocardium with marginal viability, may have adversely affected prognosis. In our study, oral enalapril resulted in a gradual, well-tolerated decrease in blood
pressure.
The conclusions from the PRACTICAL study are
that immediate administration of captopril and enalapril
improved LV function and prevented progression of ventricular dilatation after myocardial infarction. This benefit was similar with both ACE inhibitors and occurred
in patients with impaired LV function and in those with
relatively preserved LV function. These benefits were in
FIGURE 5. Kaplan-Meler survival curves for 12-month total mortality in patients receiving placebo, captopril, or
enalapril after acute myocardial infarction.
ACE INHIBITION AFTER MYOCARDIAL INFARCTION 1185
addition to those of optimal conventional therapy. The
doses resulted in comparable reduction of circulating angiotensin II and were well tolerated. There was a significant reduction in mortality with enalapril.
Acknowledgment: We thank Margaret J. Milne for
her administrative assistance, and the nursing, medical,
and technical staff of the Coronary Care Unit and the
Departments of Cardiology and Nuclear Medicine for
their assistance. We are grateful to Merck Sharp &
Dohme (NZ) Ltd and Bristol-Myers Squibb (NZ) Ltd
for the supply of active drug and placebo.
1. White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Left
ventricular end-systolic volume as the major determinant of survival after recovery
from myocardial infarction. Circulation 1987;76:44-51.
2. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988;1:
255-259.
3. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N
EnglJ Med 1988:319:80-86.
4. Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention
of left ventricular dysfunction following myocardial infarction with angiotensinconverting-enzyme inhibition. Lancet 1991;337:872-876.
5. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR,
Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J,
Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM. Effect of captopril on
1186 THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 73
mortality and morbidity in patients with left ventricular dysfunction after
myocar dial infarction: results of the Survivial and Ventricular Enlargement
Trial N Engl J Med 1992;327:669-677.
6. Erfl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental
infarct size by an angiotensin-converting enzyme inhibitor. Circulation 1982;65
40-48.
7. Linz W, Scholkens BA, Han Y-F. Beneficial effects of the converting enzyme
inhibitor, ramipril, in ischemic rat hearts. J Cardiovasc. Pharmacol 1986;8(suppl.
10):S91-S99.
8. van Gilst WH, Scholtens E, de Graaf PA, de Langen CD, Wesseling H. Differ
ential influences of angiotensin converting-enzyme inhibitors on the coronary circulation Circulation 1988;77(suppl I):I-24-I-29.
9. Nabel EG, Topol EJ, Galaena A, Ellis SG, Bates ER, Werns SW, Walton JA
Muller DW, Schwaiger M, Pitt B. A placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator in acute
myocardial infarction. J Am Coll Cardial 1991; 17:467-473.
10. Hargreaves AD, Kolettis T, Jacob AJ, Flint LL, Turnbull LW, Muir AL, BoonNA. Early vasodilator treatment in myocardial infarction: appropriate for the majority or minority? Br Heart J 1992;68:369-373.
11. Swedberg K, Held P, Kjekhus J, Rasmussen K, Ryden L, Wedel H. Effects of
early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study I
(CONSENSUS II). N Engl J Med 1992:327:678-684.
12. Oldroyd KG, Pye MP, Ray SG, Christie J, Ford I, Cobbe SM, Dargie HJ. Ef
fects of early captopril administration on infarct expansion, left ventricular remod
elling and exercise capacity after acute myocardial infarction. Am J Cardiol 1991;68
713-718.
13. Nicholls MG, Espiner EA. A sensitive rapid radio-immunoasssay for angiotensin II .N Z Med J 1976:83:399-403.
14. Richards AM, Wittert GA, Espiner EA, Yandle TG, Ikram H, Frampton C. Ef
fect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human
volunteers. Circ Res 1992:71:1501-1507.
15. Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial in
farction: the Framingham Study. Am J Cardiol 1979;44:53-59.
JUNE 15, 1994