1. health and fitness
2. disease

ORIGINAL INVESTIGATION
Angiotensin-Converting Enzyme Inhibitors in Patients
With Coronary Artery Disease and Absence of Heart
Failure or Left Ventricular Systolic Dysfunction
An Overview of Long-term Randomized Controlled Trials
Nicolas Danchin, MD, FESC; Michel Cucherat, MD, PhD; Christian Thuillez, MD; Eric Durand, MD;
Zena Kadri, MD; Philippe G. Steg, MD, FESC
Background: Results of randomized trials of angiotensin-
converting enzyme inhibitors in patients with coronary artery disease (CAD) and preserved left ventricular function are conflicting. We undertook this study to determine
whether long-term prescription of angiotensinconverting enzyme inhibitors decreases major cardiovascular events and mortality in patients who have CAD and
no evidence of left ventricular systolic dysfunction.
Methods: We searched MEDLINE, EMBASE, and IPA
databases, the Cochrane Controlled Trials Register (19902004), and reports from scientific meetings (20032004), and we reviewed secondary sources. Search terms
included angiotensin-converting enzyme inhibitors, coronary artery disease, randomi(s)zed controlled trials, clinical trials, and myocardial infarction. Eligible studies included randomized controlled trials in patients who had
CAD and no heart failure or left ventricular dysfunction, with follow-up ␱f 2 years or longer. Of 1146 publications screened, 7 met our selection criteria and included a total of 33 960 patients followed up for a mean
of 4.4 years.
A
Author Affiliations:
Department of Cardiology,
Hôpital Européen Georges
Pompidou (Drs Danchin,
Durand, and Kadri) and Hôpital
Bichat-Claude Bernard
(Dr Steg), Assistance
Publique–Hôpitaux de Paris,
Paris, Service de Biostatistique,
Hôpitaux de Lyon, Lyon
(Dr Cucherat), Service
de Pharmacologie, Centre
Hospitalier Universitaire,
Hôpitaux de Rouen, Rouen
(Dr Thuillez), France.
Results: Five trials included only patients with documented CAD. One trial included patients with documented CAD (80%) or patients who had diabetes mellitus
and 1 or more additional risk factors, and another trial included patients who had CAD, a history of transient ischemic attack, or intermittent claudication. Treatment with
angiotensin-converting enzyme inhibitors decreased overall mortality (odds ratio, 0.86; 95% confidence interval, 0.790.93), cardiovascular mortality (odds ratio, 0.81; 95% confidence interval, 0.73-0.90), myocardial infarction (odds
ratio, 0.82; 95% confidence interval, 0.75-0.89), and stroke
(odds ratio, 0.77; 95% confidence interval, 0.66-0.88). Other
end points, including resuscitation after cardiac arrest, myocardial revascularization, and hospitalization because of
heart failure, were also reduced.
Conclusion: Angiotensin-converting enzyme inhibitors reduce total mortality and major cardiovascular end
points in patients who have CAD and no left ventricular
systolic dysfunction or heart failure.
Arch Intern Med. 2006;166:787-796
NGIOTENSIN-CONVERTING
enzyme (ACE) inhibitors
are an undisputed treatment in patients who
have congestive heart
failure or coronary artery disease (CAD)
and concomitant left ventricular (LV)
dysfunction. 1,2 In patients who have
CAD without heart failure or frank LV
dysfunction, however, randomized trials
have yielded discrepant results.3-5 Inasmuch as other classes of medications are
beneficial in patients with CAD6-8 and
because only limited resources can be
allocated to secondary prevention in
these patients, it is important to determine whether routine use of ACE inhibitors in this patient population is useful
in preventing cardiovascular events and
if current recommendations9 are appropriate. The purpose of this analysis was
to assess the long-term effects of ACE
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787
inhibitor therapy in patients who have
CAD and no signs of heart failure or
severe LV dysfunction. The general goal
of the analysis was to provide information complementary to that provided by
previous meta-analyses in patients who
have CAD and either signs of heart failure or impaired systolic function.1,2
See also page 797
The present meta-analysis focuses on
all-cause mortality and major cardiovascular end points (ie, cardiovascular death,
myocardial infarction [MI], and stroke).
In addition, we studied the effects of ACE
inhibitor therapy on “softer” end points,
such as myocardial revascularization, hospitalization because of angina or congestive heart failure, and the development of
diabetes mellitus.
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1146 Potentially Relevant Publications
Screened
1017 Publications Excluded on
Basis of Title or Abstract
129 Publications Retrieved for
Detailed Review
72 Publications Excluded (Reviews,
Secondary Analyses, or Different
Target Populations)
57 Prospective Trials in Patients
With CAD
22 Post-MI Trials
19 Short-term Trials on Anti-Ischemic Effects
1 Post-CABG Trial With LV Dysfunction
1 Post-CABG Trial With 12-mo Follow-up
6 Post-PCI Trials With 6-mo Follow-up
1 Post-PCI Trial, Not Placebo-Controlled
7 Prospective Trials With ≥2-y
Follow-up
Figure 1. Diagram illustrating the search strategy for meta-analysis of
long-term administration of angiotensin-converting enzyme inhibitors in
patients with coronary artery disease (CAD) and no left ventricular (LV)
systolic dysfunction. CABG indicates coronary artery bypass grafting;
MI, myocardial infarction; and PCI, percutaneous coronary intervention.
METHODS
TRIAL SEARCH STRATEGY
To identify randomized controlled trials of ACE inhibitor therapy
vs placebo in patients who had stable CAD, we conducted a
systematic search of the MEDLINE database (National Library
of Medicine, Bethesda, Md; 1990-2004), limited to studies in
human beings, EMBASE (through 2004), and the Cochrane Controlled Trials Register (through 2004); and we reviewed secondary sources. The search was performed using Web-based
tools (PubMed, Embase.com, International Pharmaceutical Abstracts, Ovid, Medscape, and Scholar Google). Relevant articles were selected on the basis of their titles or abstracts and
were searched manually, particularly for the references cited
in reviews, commentaries, and other selected publications. National and international colleagues were contacted to limit the
risk for selection bias. We searched presentations at scientific
meetings (American Heart Association, American College of Cardiology, and European Society of Cardiology) in 2003 and 2004.
Search terms included angiotensin-converting enzyme inhibitors, coronary artery disease, randomi(s)zed controlled trials, clinical trials, and myocardial infarction.
TRIAL INCLUSION CRITERIA
Weincludedallplacebo-controlledrandomizedtrialswithafollowup of 2 years or longer performed in patients who had stable CAD
and either no signs or symptoms of heart failure or no documented
LV dysfunction (defined as left ventricular ejection fraction [LVEF]
⬍0.35). The rationale for all trials was to determine whether ACE
inhibitors would have an effect on the course of atherosclerotic disease. As for other classes of medications, such as statin drugs, a suf(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006
788
ficient duration of exposure to the study drug is required to document a protective effect. Because the events curves in HOPE (Heart
Outcomes Prevention Evaluation Study)3 and EUROPA (European
Trial on Reduction of Cardiac Events With Perindopril in Stable
Coronary Artery Disease)4 diverged only after 12 to 24 months,
we set the threshold for treatment duration at 2 years. However,
wefoundnotrialthatmetourinclusioncriteriaandthathadafollowupof1to2years.Alltrialsincludedeitherpatientswithdocumented
CAD4,5,10-12 or a high proportion with CAD,3,13 with the rest having other forms of atherosclerotic disease or being at high risk for
cardiovascular disease. Risk in these latter populations was similar to that in patients with documented CAD in the corresponding trials; in addition, in HOPE, the effect of ACE inhibitor therapy
was also highly significant when the analysis was restricted to the
subset of patients with documented CAD. The ejection fraction
threshold for defining clinically relevant LV dysfunction is usually 0.35 or, more frequently, 0.40. We accepted 0.35 as the lower
limit and excluded trials in which an upper limit for LVEF was set
(APRES [Angiotensin-converting Enzyme Inhibition Post Revascularization Study]).14 In both HOPE and EUROPA, measurement
of LVEF was not a prerequisite for inclusion. However, subsequent
analyses in patients in whom LVEF had been determined showed
that in both trials LVEF was greater than 0.40 in more than 90%
of patients.
The qualifying studies were checked for adequate blinding
of randomization, completeness of follow-up, and methods of
qualification of outcome events. All trials had to report information on the prespecified principal outcomes (all-cause mortality, cardiovascular death, or MI). We also analyzed secondary end points when reported similarly in at least 2 trials. These
included stroke, cardiac arrest, myocardial revascularization,
hospitalization because of unstable angina, hospitalization because of heart failure, and onset of diabetes mellitus in patients previously without diabetes mellitus. A QUOROM (Quality of Reporting of Meta-analyses)15 diagram of the study selection
process is shown in Figure 1. Among articles excluded on the
basis of their titles or abstracts, 49% were excluded because they
were not randomized, 32% because they did not involve ACE
inhibitors, 12% because the target population was different, and
7% because there were no placebo controls; many studies were
excluded for multiple causes.
To assess study quality, we evaluated trials for the adequacy of allocation concealment, blindness of patients and physicians to the treatment, and blind assessment of the outcome
of interest. We used the criteria recommended by Altman and
Schulz16 and Juni et al17 to decide whether treatment allocation was adequately concealed. Two physicians (N.D. and M.C.)
graded each of the trials included in the meta-analysis. We did
not use a summary score to identify trials of low or high quality, or perform weighting by quality scores because this practice has been discouraged by some investigators.17-19
STATISTICAL ANALYSIS
Because of lack of access to individual patient data from the trials,
we used the figures reported in the articles describing the trial
results, on intention-to-treat analyses. We used EasyMA 2001 software20 (developed by M.C.) for the analyses. The meta-analysis
was performed using odds ratios (ORs) as the parameter of efficacy. Odds ratios were combined using inverse varianceweighted averages of their logarithmics in fixed-effects models.
Other methods (relative risk random model, relative risk Greenland-Robins, Mantel-Haenszel test, or Peto’s method for OR) provided similar results. In the case of absence of an event in one
group of patients, a pseudo-count method was used to calculate
the OR, adding a value of 0.25 event in each group.
Between-study heterogeneity was analyzed using standard ␹2
tests (Cochran), with P⬍.05 deemed statistically significant. Where
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no significant statistical heterogeneity was identified, the fixedeffect estimate was used preferentially as the summary measure.
In addition, sensitivity analyses were performed to assess the contribution of each study by excluding individual trials one at a time
and recalculating the pooled ORs for the remaining trials. Publication bias was assessed graphically using a funnel plot of the
logarithm of effect size vs the standard error for each trial, and
mathematically using an adjusted rank correlation test, according to the method of Begg and Mazumdar.21
RESULTS
We identified 7 trials that met our inclusion criteria.3-5,10-13 Five trials4,5,10-12 enrolled only patients with documented CAD. One trial3 enrolled patients with coronary
disease or patients with diabetes mellitus who were 55
years or older and who had at least 1 additional risk factor. In this trial, however, 80% of the population enrolled had documented CAD. The last trial13 enrolled patients who had CAD (68% of the trial population),
intermittent claudication, or transient ischemic attack.
The trial names, acronyms, designs, and main baseline
characteristics of the patients included are summarized
in Table 1 and Table 2. Five ACE inhibitors were tested,
and 2 of the trials3,4 used doses higher than those usually necessary for antihypertensive therapy. The study
populations ranged from 460 to 12 218 patients (total,
33 960 patients), and the duration of follow-up ranged
from 2 to 5 years (mean, 4.4 years). One trial11 had a 3-arm
treatment design and compared the effectiveness of enalapril with amlodipine and placebo; for the purpose of our
analysis, only data from the enalapril and placebo treatment arms were considered. Another trial12 had a 2⫻2factorial design that compared enalapril treatment with
placebo and simvastatin treatment with placebo.
The primary end point of each trial differed, but all
trials reported all-cause mortality, cardiovascular mortality, and MI. Cardiovascular mortality in the PEACE
(Prevention of Events With Angiotensin Converting Enzyme Inhibition) trial 5 did exclude death from unknown causes. Stroke was not a reported end point in
QUIET (Quinapril Ischemic Event Trial),10 and a combination of stroke and transient ischemic attack was reported in the CAMELOT (Comparison of Amlodipine vs
Enalapril to Limit Occurrences of Thrombosis) trial.11
The overall quality of the trials was assessed by analysis of data given in the protocol and design publications,
and the main publications presenting the results of the
trials.3-5,10-13,22-27 Both graders (N.D. and M.C.) were concordant in attributing a score of 5 to all trials. We found
no consistent visual or statistical evidence of publication
bias (P value of Begg and Mazumdar21 and test range from
0.18-0.65).
ALL-CAUSE AND
CARDIOVASCULAR MORTALITIES
All-cause mortality (Figure 2A) was lower in the treatment arms compared with the placebo arms of all trials
except one,11 and the reduction was statistically significant in HOPE.3 There was no heterogeneity among the
trials, and the meta-analysis showed a 14% reduction in
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789
mortality (P⬍.001). Likewise, cardiovascular mortality
(Figure 2B) was consistently reduced by ACE inhibition across all trials except CAMELOT,11 with a significant reduction in HOPE and a highly significant 19% reduction in the meta-analysis (P⬍.001). Sensitivity analyses
were performed after individual exclusion of HOPE,
EUROPA, and PEACE. After exclusion of HOPE, the OR
for all-cause mortality was slightly less at 0.88 (95% confidence interval [CI], 0.79-0.98) but remained statistically significant, and the OR for cardiovascular mortality was 0.88 (95% CI, 0.76-1.01; P=.07). After exclusion
of EUROPA, the respective ORs were 0.85 (95% CI, 0.770.94) and 0.79 (95% CI, 0.70-0.90). Conversely, exclusion of PEACE yielded slightly higher risk reductions in
total and cardiovascular mortalities.
MI AND STROKE
Significant reductions in acute MI with ACE inhibitor
therapy were found in both HOPE and EUROPA
(Figure 3A).3,4 Angiotensin-converting enzyme inhibition seemed to have had no effect on the MI rate in
PEACE,5 and nonsignificant reductions were observed
in the other trials.10-13 Overall, there was an 18% reduction in MI (P⬍.001) with ACE inhibitor therapy. Stroke
was less frequent in patients receiving ACE inhibitors in
all trials except PART-2 (Prevention of Atherosclerosis
with Ramipril Trial-2)13 (Figure 3B), and the reduction
achieved statistical significance in HOPE.3 Overall, ACE
inhibitors resulted in a 23% relative reduction in the occurrence of stroke (or transient ischemic attack in
CAMELOT) (P⬍.001). The sensitivity analyses after exclusion of either HOPE or EUROPA resulted in an attenuation of the benefit in terms of MI (OR, 0.85; 95%
CI, 0.76-0.95, and OR, 0.84; 95% CI, 0.76-0.93, respectively), but the reduction remained statistically significant. For stroke, the OR was 0.85 (95% CI, 0.70-1.04)
after exclusion of HOPE and 0.71 (95% CI, 0.60-0.83)
after exclusion of EUROPA. Conversely, exclusion of
PEACE resulted in slightly higher risk reductions.
OTHER CARDIOVASCULAR
AND METABOLIC END POINTS
Five trials3-5,11,13 analyzed the occurrence of hospitalization because of congestive heart failure (Figure 4A) and
showed a reduction in this end point in patients receiving ACE inhibitors. The reduction was significant in
EUROPA4 and PEACE.5 Overall, the risk was reduced by
23% (P⬍.001). Hospitalization because of unstable angina was reported in 4 trials3,4,10,13 (Figure 4B), and the
effect of ACE inhibitor therapy on this end point was neutral (3% risk reduction; P =.06). In the 6 trials3-5,10-12 in
which rates of myocardial revascularization were reported (Figure 4C), the risk was reduced by 8% (P⬍.01).
Cardiac arrest was a rare event in all trials, with a significant (P⬍.001) 42% risk reduction in the metaanalysis. Two trials3,4 reported the rate of new onset of
diabetes mellitus in patients initially without diabetes
mellitus (Figure 4D) and found an overall 23% reduction with ACE inhibitor therapy compared with placebo
(P⬍.001).
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Table 1. Main Features of Randomized Trials Included in Meta-analysis
HOPE3
Feature
QUIET10
PART-213
SCAT12
EUROPA4
PEACE5
CAMELOT11
Main inclusion
and exclusion
criteria
Age ⱖ55 y;
Age range,
Age ⱕ75 y;
Age ⱖ21 y;
Age ⬎18 y;
Age ⱖ40 y;
Age range,
history of CAD,
18-75 y;
history of acute
documented CAD
documented
documented
30-79 y; CAG
stroke, PVD or
successful
MI; angina with
on coronary
CAD without
CAD with LVEF
and ⱖ1 stenosis
DM with ⱖ1
PCI; LDL-C
positive
angiograph; LVEF
heart failure;
⬎40%; no
⬎20%; LVEF
RF; no heart
level, ⱕ4.3
angiograph or
ⱖ35%; total
no recent MI
recent ACS
ⱖ40%; no heart
failure; LVEF
mmol/L; no
positive
cholesterol level,
(3 mo) or
(2 mo) or recent
failure; DBP not
not known to
previous
exercise test
4.1-6.2 mmol/L;
revascularization
revascularization
ⱖ100 mm Hg;
be ⬍40%; no
CABG; SBP
results; TIA;
HDL-C level ⬍2.2
(6 mo); and SBP
(3 mo); serum
no ACE-I therapy;
uncontrolled
ⱖ100 mm Hg
intermittent
mmol/L;
ⱕ180 mm Hg or
creatinine level
and no ARB or
hypertension;
and ⱕ160
claudication; no
triglyceride levels
DBP ⬎100
⬎2.0 mg/dL;
CCB therapy
no recent (4
mm Hg; DBP
CHF; SBP
⬍4 mmol/L; no
mm Hg
and no ARB
wk) MI or
ⱕ100 mm Hg;
ⱕ160 mm Hg;
PCI or CABG
therapy
stroke; and no
LVEF not
DBP ⱕ100
(⬍6 mo); and no
ACE-I therapy
⬍40%; no
mm Hg; and no
clinical instability
recent MI
specific
(⬍7 d) or
indication or
other PCI
contraindication
(⬍3 mo); no
for ACE-I
LLDs; no
therapy
CCBs; and no
ACE-I therapy
Medication tested
Ramipril, 10 mg Quinapril
Ramipril,
(administered
hydrochloride,
5-10 mg
in evening) for
20 mg
7-10 d at 2.5
mg, followed
by placebo for
10-14 d
Primary end point
CV death, MI, or
stroke
Cardiac death,
Ultrasound
Angiographic end
CV death, MI, or
resuscitated
measurements
point: average
cardiac arrest
cardiac arrest,
of carotid far
per patient
nonfatal MI,
wall thickness
change between
CABG, PCI, or
and left
baseline and
hospitalization
ventricular
closeout
because of
mass; and
angiograms;
angina
clinical events
recorded
recorded
individual clinical
events: death,
acute MI, stroke,
hospitalization
because of
angina,
revascularization,
or cancer
CV death, MI, or
CV death, MI,
coronary
resuscitated
revascularization
cardiac arrest,
coronary
revascularization,
stroke,
hospitalization
because of
angina or heart
failure, TIA, or
new peripheral
vascular disease
Population size,
No. who were
treated/No. who
received placebo
4645/4652
878/872
308/309
4158/4132
Decrease in SBP,
active treatment
vs placebo
3 mm Hg at 2 y
and end of
study
NA
6 mm Hg at 2 y,
3.9 mm Hg, average 5 mm Hg, average 3.0 mm Hg at
5 mm Hg at 5 y
during follow-up
during follow-up
36 mo
5.6 mm Hg, average
during follow-up
Follow-up, y
5
27
4.7
4
4.2 (mean)
4.8 (median)
2
2.2
1.6
4.3*
0.7
0.7
2.8
1.7
1.2
NA
1.2
0.75
2.1†
1.7
1.0
2.4
1.8
0.8
1.9
0.45
0.15
1.9*
Annual event rates
in placebo groups, %
All-cause death
CV death
CV death, MI,
cardiac arrest
Enalapril maleate,
Perindopril,
10 mg twice a
8 mg, for 4 wk
day (2 ⫻ 2
factorial design
with simvastatin,
40 mg)
229/231
6110/6108
Trandolapril,
Enalapril maleate,
2 mg, for 6 mo,
10 mg twice a
then either 2 mg
day (third arm,
or 4 mg at
amlodipine
discretion of
maleate, 5 mg)
investigators if
twice a day
SBP ⱖ110
mm Hg, for 2 wk
673/655
Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CABG, coronary artery
bypass grafting; CAD, coronary artery disease; CAG, coronary angiography; CAMELOT, Comparison of Amlodipine vs Enalapril to Limit Occurrences of
Thrombosis; CCB, calcium channel blocker; CHF, congestive heart failure; CV, cardiovascular; DBP, diastolic blood pressure; DM, diabetes mellitus;
EUROPA, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; HDL-C, high-density lipoprotein cholesterol;
HOPE, Heart Outcomes Prevention Evaluation study; LDL-C, low-density lipoprotein cholesterol; LLDs, lipid-lowering drugs; LVEF, left ventricular ejection fraction;
MI, myocardial infarction; NA, not available or not applicable; PART-2, Prevention of Atherosclerosis with Ramipril Trial; PCI, percutaneous coronary intervention;
PEACE, Prevention of Events With Angiotensin Converting Enzyme Inhibition; PVD, peripheral vascular disease; QUIET, QUinapril Ischemic Events Trial;
RF, risk factor; SBP, systolic blood pressure; SCAT, Simvastatin/Enalapril Coronary Atherosclerosis Trial; TIA, transient ischemic attack.
SI conversion factors: To convert cholesterol to millimoles per liter multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113.
*Composite of numbers of CV deaths, MIs, and cardiac arrests.
†Composite of numbers of CV deaths and nonfatal MIs.
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Table 2. Main Characteristics of Patients Included in Randomized Trials Included in Meta-analysis*
Characteristic
HOPE3
Age, y
Sex, M/F
BMI
SBP at enrollment, mm Hg
DBP at enrollment, mm Hg
Previous MI
Previous PCI
Previous CABG
Previous revascularization
Stroke or TIA
Current smoking
Hypertension
Diabetes mellitus
Hyperlipidemia
66
73/27
28
139
79
53
18
26
NA
11
14
47
38
66
LDL-C level, mg/dL
Total cholesterol level, mg/dL
Serum creatinine level, mg/dL
LLDs
NA
NA
NA
29
␤-Blockers
Antiplatelet agents
Calcium channel blockers
Diuretics
40
76
47
15
QUIET10
58
82/18
26
123
74
49
100
0
100
NA
22
47
16
NA
PART-213
SCAT12
EUROPA4
61
82/18
NA
133
79
42
NA
NA
NA
10
16
NA
9
NA
61
89/11
NA
130
78
70
NA
NA
NA
NA
15
36
11
NA
NA
NA
NA
29
130
200
NA
Randomization to
simvastatin vs
placebo
47
90
14
NA
124
194
1.3
0.1
26
73 (Aspirin)
0
NA
43
81
25
NA
60
85/15
NA
137
82
65
29
29
55
3
?
27
12
63 (Cholesterol
⬎6.5 mmol/L
or LLDs)
NA
NA
NA
58
62
92
31
9
PEACE5
CAMELOT11
64
82/18
NA
133
78
55
41.5
39
72
6.5
14.5
45.5
17
NA
58
72/28
30
129
77
39
29
7.5
NA
4 (Stroke)
26
60
19
NA
NA
192
1.0
70
101
60
90
35
13
NA
NA
83 (Statins)
77
95 (Aspirin)
9
30
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); CABG, coronary artery bypass grafting;
CAMELOT, Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis; DBP, diastolic blood pressure; EUROPA, European Trial on Reduction of
Cardiac Events With Perindopril in Stable Coronary Artery Disease; HOPE, Heart Outcomes Prevention Evaluation study; LDL-C, low-density lipoprotein
cholesterol; LLDs, lipid-lowering drugs; MI, myocardial infarction; PART-2, Prevention of Atherosclerosis with Ramipril; PCI, percutaneous coronary intervention;
PEACE, Prevention of Events With Angiotensin-Converting Enzyme Inhibition; QUIET, QUinapril Ischemic Event Trial; SCAT, Simvastatin/Enalapril Coronary
Atherosclerosis Trial; SBP, systolic blood pressure; TIA, transient ischemic attack.
SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; serum creatinine to micromoles per liter, multiply by 88.4.
*Data are given as percentages unless otherwise indicated.
COMMENT
In our meta-analysis of patients with either no heart failure or no LV systolic dysfunction, we found a significant reduction in all-cause mortality, cardiovascular mortality, MI, and stroke, as well as in several softer end points,
such as hospitalization because of heart failure, myocardial revascularization, or new onset of diabetes mellitus
(Table 3). These results confirm and extend those of a
recently published meta-analysis of HOPE, EUROPA, and
PEACE.28
TRIALS WITH ACE INHIBITORS EXCLUDED
FROM META-ANALYSIS
The ability of ACE inhibitors to prevent cardiovascular
events in patients with CAD was assessed first in patients
with poor LV function or heart failure. The meta-analysis
of the trials including such patients1 showed a reduction
in death (OR, 0.80; 95% CI, 0.74-0.87), repeat MI (OR, 0.79;
95% CI, 0.70-0.89), and hospital readmission because of
heart failure (OR, 0.67; 95% CI, 0.61-0.74) but no significant difference for stroke (OR, 0.96; 95% CI, 0.80-1.15).
The magnitude of risk reduction in our meta-analysis was
nearly identical to that observed in the subgroup of 1428
patients with LVEF greater than 35% in the previous meta(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006
791
analysis of ACE inhibitors in patients who had coronary
disease with poor LV function.1
Trials excluded from the meta-analysis are summarized in Table 4. In addition to the trials included in
our systematic review, one trial14 included 159 patients
with moderate LV dysfunction (LVEF, 0.30-0.50) randomized to receive ramipril or placebo for 33 months;
ramipril therapy was associated with significantly fewer
major cardiac events. Seven other trials29-35 compared
short-term (6-12 months) administration of ACE inhibitors vs placebo in patients who had undergone coronary artery bypass surgery or coronary angioplasty. Clinical event rates in any of these short-term studies did not
differ between patients who did or did not receive ACE
inhibitors.
POSSIBLE EXPLANATIONS FOR THE LACK OF
STATISTICAL SIGNIFICANCE IN SOME TRIALS
Methodologic Considerations
In both QUIET and CAMELOT,10,11 the duration of follow-up may have been too short to demonstrate any benefit of ACE inhibitor therapy in terms of secondary prevention. In SCAT (Simvastatin/Enalapril Coronary
Atherosclerosis Trial)12 and PART-2,13 follow-up was longer
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All-Cause Death
A
Myocardial Infarction
A
OR, Fixed Model
[Bilateral CI, 95% for Trials; 95% for MA]
OR, Fixed Model
[Bilateral CI, 95% for Trials; 95% for MA]
OR
OR
QUIET
0.99 [0.58-1.70]
QUIET
0.89 [0.56-1.41]
HOPE
0.83 [0.73-0.95]
HOPE
0.79 [0.69-0.90]
PART-2
0.62 [0.33-1.19]
PART-2
0.95 [0.49-1.84]
SCAT
0.72 [0.29-1.84]
SCAT
0.575 [0.22-1.49]
EUROPA
0.88 [0.77-1.02]
EUROPA
0.77 [0.66-0.90]
PEACE
0.88 [0.75-1.04]
PEACE
1.00 [0.82-1.22]
CAMELOT
1.30 [0.45-3.77]
CAMELOT
0.56 [0.26-1.18]
Total
0.86 [0.79-0.93]
Total
0.82 [0.75-0.89]
Cochran Q het P = .87
Cochran Q het P = .87
0.6
0.8
1.0
1.2
0.6
0.8
1.0
OR
B
1.2
OR
B
Cardiovascular Death
Stroke
OR, Fixed Model
[Bilateral CI, 95% for Trials, 95% for MA]
OR, Fixed Model
[Bilateral CI, 95% for Trials, 95% for MA]
OR
OR
QUIET
0.92 [0.42-2.02]
HOPE
0.68 [0.55-0.84]
HOPE
0.73 [0.63-0.86]
PART-2
1.77 [0.51-0.12]
PART-2
0.43 [0.19-1.01]
SCAT
0.22 [0.05-1.02]
SCAT
0.57 [0.16-1.97]
EUROPA
0.96 [0.73-1.27]
EUROPA
0.86 [0.71-1.03]
PEACE
0.76 [0.56-1.04]
PEACE
0.95 [0.76-1.20]
CAMELOT
0.65 [0.26-1.59]
CAMELOT
2.44 [0.47-12.65]
Total
0.77 [0.66-0.88]
0.81 [0.73-0.90]
Total
Cochran Q het P = .24
Cochran Q het P = .15
0.6
0.8
1.0
1.2
OR
0.6
0.8
1.0
1.2
OR
Figure 2. All-cause mortality (A) and cardiovascular mortality (B) in patients
with coronary artery disease and no left ventricular systolic dysfunction
randomized to long-term angiotensin-converting enzyme inhibitor therapy or
placebo. CAMELOT, Comparison of Amlodipine vs Enalapril to Limit
Occurrences of Thrombosis11; CI, confidence interval; EUROPA, European
Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary
Artery Disease4; het, heterogeneity; HOPE, Heart Outcomes Prevention
Evaluation study3; MA, meta-analysis; OR, odds ratio; PART-2, Prevention of
Atherosclerosis with Ramipril13; PEACE, Prevention of Events With
Angiotensin-Converting Enzyme Inhibition5; QUIET, QUinapril Ischemic Event
Trial10; SCAT, Simvastatin/Enalapril Coronary Atherosclerosis Trial.12
and there was a trend favoring ACE inhibitors; however,
neither trial had enough statistical power to document a
significant effect for clinical events. In contrast, HOPE,3
EUROPA,4 and PEACE5 had both a long follow-up and a
large population. However, in PEACE, the initial primary
end point (cardiovascular death or MI) was modified during the course of the trial to include softer end points.
Differences in Baseline Risk
It has been suggested that the difference in outcomes in
PEACE5 vs HOPE3 and EUROPA4 might be related to differences in baseline risk. Although mortality was higher in
HOPE, both mortality and cardiovascular mortality were
(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006
792
Figure 3. Nonfatal myocardial infarction (A) and stroke (B). Occurrence of
stroke was not reported in the QUIET Trial. For an explanation of the
abbreviations see the legend to Figure 2.
similar in EUROPA and PEACE (Table 1). Furthermore,
in HOPE and EUROPA, outcomes were consistent throughout subgroups defined according to the patients’ initial risk
profile, including age, previous MI, or presence of peripheral vascular disease, or according to concomitant secondary prevention medications. The percentages of patients receiving antiplatelet agents, ␤-blockers, and lipid-lowering
agents were similar in EUROPA and PEACE.
Effect of Blood Pressure Reduction
The effect of the active treatment on blood pressure was reported in 6 of 7 trials (Table 1).There was no obvious relationship between the magnitude of blood pressure reduction and clinical events in the trials. Blood pressure reduction per se is not necessarily associated with cardiovascular
protection in patients who have stable CAD and preserved
LV function. ACTION (A Coronary Disease Trial Investigating Outcome With Nifedipine gastrointestinal therapeutic system)56 failed to show a decrease in mortality and MI
in patients receiving nifedipine, despite a reduction of 6
mm Hg in systolic blood pressure with this medication.
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Hospitalization Because of CHF
A
Hospitalization Because of UA
B
OR, Fixed Model
[Bilateral CI, 95% for Trials; 95% for MA]
OR, Fixed Model
[Bilateral CI, 95% for Trials; 95% for MA]
OR
OR
HOPE
0.88 [0.70-1.11]
QUIET
1.16 [0.77-1.74]
MacMahon
0.78 [0.29-2.11]
HOPE
0.98 [0.86-1.11]
EUROPA
0.61 [0.44-0.83]
MacMahon
1.09 [0.69-1.71]
PEACE
0.75 [0.58-0.95]
EUROPA
0.93 [0.80-1.08]
CAMELOT
0.78 [0.21-2.91]
Total
0.97 [0.89-1.07]
Total
0.76 [0.66-0.88]
Cochran Q het P = .73
0.6
Cochran Q het P = .48
0.8
1.0
1.2
OR
0.6
0.8
1.0
1.2
OR
Revascularization
C
New-Onset Diabetes Mellitus
D
OR, Fixed Model
[Bilateral CI, 95% for Trials; 95% for MA]
OR, Fixed Model
[Bilateral CI, 95% for Trials; 95% for MA]
OR
OR
QUIET
0.94 [0.78-1.14]
HOPE
0.65 [0.51-0.84]
HOPE
0.85 [0.76-0.95]
PEACE
0.82 [0.70-0.96]
SCAT
0.62 [0.32-1.19]
Total
0.77 [0.68-0.88]
EUROPA
0.96 [0.85-1.08]
PEACE
0.99 [0.88-1.10]
CAMELOT
0.88 [0.65-1.19]
Total
0.92 [0.87-0.98]
Cochran Q het P = .13
0.6
0.8
1.0
1.2
OR
Cochran Q het P = .48
0.6
0.8
1.0
1.2
OR
Figure 4. Hospitalization because of congestive heart failure (CHF) (A) or unstable angina (UA) (B); hospitalization for subsequent myocardial revascularization in
patients with coronary artery disease and no left ventricular systolic dysfunction randomized to receive angiotensin-converting enzyme inhibitors (C); and development
of diabetes mellitus in patients without diabetes mellitus at inclusion in the study (D). For an explanation of the abbreviations see the legend to Figure 2.
Table 3. Meta-analysis of Main Clinical End Points in Trials
End Point
All-cause death
CV death
MI
Stroke*
Cardiac arrest
Hospitalization because of unstable angina†
Myocardial revascularization
Hospitalization because of heart failure*
Onset of DM‡
Active Treatment/Placebo
Odds Ratio (95% CI)
P Value
P Value for Heterogeneity
1215/1392
673/819
1048/1258
342/445
46/82
993/1019
2622/2788
330/429
437/554
0.86 (0.79-0.93)
0.81 (0.73-0.90)
0.82 (0.75-0.89)
0.77 (0.66-0.88)
0.58 (0.41-0.84)
0.97 (0.89-1.07)
0.92 (0.87-0.98)
0.76 (0.66-0.88)
0.77 (0.68-0.88)
⬍.001
⬍.001
⬍.001
⬍.001
⬍.001
.06
.008
⬍.001
⬍.001
.87
.24
.31
.15
.76
.73
.35
.48
.13
Abbreviations: CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; MI, myocardial infarction.
*End point not reported in QUIET (QUinapril Ischemic Event Trial).10
†End point not reported in PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibition)5 and CAMELOT (Comparison of Amlodipine vs
Enalapril to Limit Occurrences of Thrombosis).11
‡End point not reported in QUIET,10 EUROPA (European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease),4 CAMELOT,11
PART-2 (Prevention of Atherosclerosis with Ramipril),13 and SCAT (Simvastatin/Enalapril Coronary Atherosclerosis Trial).12
Individual Pharmacologic Properties of Agents
Inasmuch as 5 different ACE inhibitors were tested
in the trials, the individual properties of the ACE
inhibitors57-59 may, at least in part, account for the dif(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006
793
ferences in clinical outcome. However, there is no
obvious relationship between the pharmacologic properties (tissue affinity and lipophilicity) of the individual medications and their clinical benefit in the
trials.
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Table 4. Trials Assessing ACE Inhibitors in Patients With Coronary Artery Disease Excluded From Meta-analysis
Source
General Design
Kjoller-Hansen et al14
Oosterga et al29
Multicenter European Research
Trial With Cilazapril After
Angioplasty to Prevent
Transluminal Coronary
Obstruction and Restenosis
(MERCATOR) Study Group30
Faxon; Multicenter American
Research Trial With Cilazapril
After Angioplasty to Prevent
Transluminal Coronary
Obstruction and Restenosis
(MARCATOR) Study Group31
Desmet et al32
33
Meurice et al
34
Kaul et al
35
Yamabe et al
Otsuka et al36
Sadamatsu et al37
Di Mario et al38
Mancini et al39
40
Esper et al
41
Anderson et al
Toyofyuku et al42
43
Koh et al
44
Thurmann and Rietbrock N
Kaski et al45
van den Heuvel et al46
Pepine et al47
Morishita et al48
49
Dhawan et al
Thurmann et al50
Bartels et al51
No. of
Patients
Follow-up;
Comment
159
33 mo; Mild to moderate impairment
of left ventricular function
149
12 mo
735
6 mo
1436
6 mo
304
6 mo
91
6 mo
95
6 mo
167
6 mo
Ramipril; double-blind, randomized, placebo-controlled trial in patients with
chronic stable angina, no heart failure, and left ventricular ejection fraction
0.30-0.50 undergoing myocardial revascularization; and assessment of
clinical events
Quinapril; randomized, double-blind, placebo-controlled trial in patients who
underwent coronary bypass surgery; exercise test and clinical events at 1 y
Cilazapril; randomized, double-blind, placebo-controlled trial; assessment of
restenosis on coronary angiogram at 6 mo
Cilazapril; randomized, double-blind, placebo-controlled trial; assessment of
restenosis on coronary angiogram at 6 mo
Fosinopril sodium; randomized, double-blind, placebo-controlled trial;
assessment of restenosis on coronary angiogram
Quinapril; randomized, placebo-controlled trial in patients with DD genotype;
assessment of restenosis on coronary angiogram
Enalapril; randomized open trial; assessment of restenosis on coronary
angiogram at 6 mo
Cilazapril begun 7 d before percutaneous transluminal coronary angioplasty;
angiographic end point
Quinapril; randomized, nonplacebo-controlled open trial in patients after
percutaneous coronary interventions; clinical outcomes at 4.8 y
Enalapril; randomized open trial with control group; assessment of macrophage
colony-stimulating factor
Cilazapril 20 mg; randomized, double-blind, placebo-controlled trial; assessment
of coronary vasomotion during coronary angiography at 6 mo
Quinapril; double-blind, placebo-controlled trial; assessment of response of
coronary arteries to acetylcholine at 6 mo
Enalapril; randomized, double-blind, placebo-controlled trial; assessment of
brachial artery vasodilation after 16 wk
Quinapril, enalapril; double-blind trial; comparison of quinapril, enalapril,
losartan potassium, and amlodipine; assessment of flow-mediated
vasodilation
Quinapril; randomized open trial; assessment with coronary angiography at 6
mo after percutaneous coronary angioplasty
Ramipril; randomized, double-blind, placebo-controlled, crossover trial;
assessment of flow-mediated vasodilation
Spirapril hydrochloride; randomized, placebo-controlled, crossover trial;
repeated exercise tests to assess myocardial ischemia
Enalapril; randomized crossover trial; repeated exercise test after 2 wk
Enalapril; double-blind, placebo-controlled trial; repeated exercise tests
Quinapril; randomized, double-blind, multicenter, placebo-controlled trial;
repeated exercise tests
Perindopril; randomized open trial; evaluation with dobutamine stress
echocardiography
Captopril; randomized, double-blind trial; repeated exercise tests
Benazepril hydrochloride; randomized, double-blind, placebo-controlled,
crossover trial; repeated exercise tests
Perindoprilat; randomized, placebo-controlled trial; assessment of
hemodynamic effects
253
4.8 y
30
16 wk; No clinical events reported
34
6 mo
129
6 mo
38
16 wk
80
8 wk
253
6 mo
32
2 mo
19
2 wk
10
43
336
2 wk
12 wk
16 wk
12
3 mo
33
11
6 wk
2 wk
25
Watanabe et al52
Enalapril; acute evaluation of coronary artery diameter in patients treated with
nitrates or enalapril plus nitrates, and in control subjects
60
Metelitsa et al53
Captopril, with or without isosorbide dinitrate; randomized single-blind trial;
repeated exercise tests
14
Klein et al54
Benazepril; randomized, double-blind, placebo-controlled, crossover trial;
repeated exercise tests
29
Unterberg et al55
Ramipril; randomized, double-blind, placebo-controlled trial; repeated exercise
tests
18
Abbreviation: ACE, angiotensin-converting enzyme.
(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006
794
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Acute effects following single
administration during
catheterization
Acute effects following single
administration during
catheterization
Acute effects on exercise test
parameters assessed after a
single-dose administration of the
ACE inhibitor
Acute effects on exercise test
parameters assessed after a
single-dose administration of the
ACE inhibitor
Acute effects on exercise test
parameters assessed after a
single-dose administration of the
ACE inhibitor
or market ACE inhibitors and was not supported, directly or indirectly, by grant money from sponsors.
Dosage
The dosage used in each of the trials differed, with the
highest doses in HOPE3 and EUROPA.4 In PEACE,5 the
initial dose of trandolapril was low (2 mg) and could be
maintained at 2 mg or increased to 4 mg after 6 months,
at the discretion of the physician, so that fewer than 69%
of the patients received the 4-mg dose at any time during the trial. Because the 50% inhibitory concentration
for plasma ACE for ramipril, perindopril, and trandolapril is similar,60-62 the 2- to 4-mg dose of trandolapril is
comparatively less than the 10-mg dose of ramipril or the
8-mg dose of perindopril. Therefore, the 2 trials with definitely positive results used the highest doses. The clinical situation in which the therapeutic target is controlling the atherothrombotic process is different from that
of heart failure, in which the level of activation of the renin-angiotensin system is such that even rather low doses
of ACE inhibitors are effective. There is evidence that only
the larger doses of ACE inhibitors can slow the progression of atherosclerotic disease. In SECURE (Study to
Evaluate Carotid Ultrasound Changes in Patients With
Ramipril and Vitamin E),63 2 doses of ramipril (2.5 mg
and 10 mg) that yielded similar reductions in blood pressure were tested against placebo; only the 10-mg dose
was associated with significant slowing of carotid atherosclerosis progression.
CONCLUSIONS
In this overview of randomized trials of ACE inhibitors
for the long-term secondary prevention of CAD in patients without LV dysfunction or heart failure, active treatment was associated with a highly significant reduction
in all-cause mortality and all major cardiovascular events.
These results, along with those previously reported in patients who have CAD with LV dysfunction or heart failure, suggest that ACE inhibitor therapy should be systematically used in all patients with documented CAD
and that continued efforts should be made to implement current secondary prevention guidelines.
Accepted for Publication: October 5, 2005.
Correspondence: Nicolas Danchin, MD, FESC, Department of Cardiology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France (nicolas.danchin
@egp.ap-hop-paris.fr).
Financial Disclosure: Dr Danchin has been a speaker and
has served on steering committees of studies sponsored
by Sanofi-Aventis, Paris, France, which markets ramipril,
and by Servier Medical, Neuilly-sur-Seine, France, which
markets perindopril. Dr Cucherat has been a consultant
for Servier Medical. Dr Thuillez has been a speaker for
Sanofi-Aventis and Servier Medical and has received research grants from Servier Medical. Dr Steg has been a
speaker and consultant for Sanofi-Aventis and for Servier
Medical and has received research grants from Aventis
Pharma, Paris. He was a member of the Critical Events
Committee for the EUROPA trial.
Role of the Sponsor: This analysis was performed independently of all pharmaceutical firms that manufacture
(REPRINTED) ARCH INTERN MED/ VOL 166, APR 10, 2006
795
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