Download Prevention of Heart Failure in Patients in the Heart

Prevention of Heart Failure in Patients in the Heart
Outcomes Prevention Evaluation (HOPE) Study
J. Malcolm O. Arnold, MD; Salim Yusuf, MD; James Young, MD; James Mathew, MD;
David Johnstone, MD; Alvaro Avezum, MD; Eva Lonn, MD; Janice Pogue, MSc; Jackie Bosch, MSc;
on behalf of the HOPE Investigators
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Background—Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction
or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development
of heart failure in high-risk patients without known low ejection fraction or heart failure.
Methods and Results—We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching
placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE
inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and
was associated with a 4.01-fold increase in the risk of death (P⬍0.0001). The rate of developing heart failure was
significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy
(1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5%
to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; P⬍0.0001). Ramipril consistently reduced heart failure rate both in
those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also
reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative
risk, 0.67) compared with those below the median (relative risk, 0.91; P⫽0.024 for interaction of group by treatment).
Conclusion—Ramipril significantly reduces the rate of development of heart failure in patients at high risk of
cardiovascular events. (Circulation. 2003;107:1284-1290.)
Key Words: heart failure 䡲 prevention 䡲 drugs 䡲 atherosclerosis 䡲 trials
H
mortality in patients with low ejection fraction with and
without heart failure.12–16 However, there are no data on the
impact of ACE inhibitors on heart failure and the outcomes in
patients without preexisting heart failure, low ejection fraction, or hypertension. Based on subgroup analysis of previous
studies12,15,16 and several proposed mechanisms of action,17
the potential for the ACE inhibitor ramipril to reduce mortality and morbidity in patients at high risk of cardiovascular
events but without heart failure or known low left ventricular
ejection fractions was prospectively evaluated in the Heart
Outcomes Prevention Evaluation (HOPE) study.18 The study
was discontinued where there was clear and overwhelming
evidence of a beneficial effect of ramipril on the primary
outcome of the composite of myocardial infarction, stroke, or
death from cardiovascular causes. Heart failure, a predefined
outcome, was also significantly reduced by 23%.
In this study, we report in detail the predictors of heart failure
within the HOPE cohort of patients, the impact of ramipril to
prevent heart failure in patients at high risk of cardiovascular
events, and the magnitude of benefit in relevant subgroups.
eart failure is presently the commonest cause of hospital
admission in patients older than 65 years of age in the
United States,1,2 where it has a prevalence of 2 million and an
annual incidence of 400 000.3 Globally, atherosclerosis and
coronary artery disease are expected to increase across the
world in the next 2 decades4,5 as the levels of obesity,
diabetes, and hypertension increase. In addition, more patients are surviving acute myocardial infarction but with
damaged hearts, and life expectancy is predicted to increase.4
Therefore, the individual, community, health care, and economic burden of heart failure will continue to rise.
See p 1234
Once diagnosed, heart failure can have a 1-year mortality
as high as 20% to 50%.6 –10 Coronary artery disease and
hypertension account for most heart failure cases,10,11 but
despite major improvements in the detection and treatment of
these conditions, heart failure incidence, morbidity, and
mortality remain high.6 Angiotensin-converting enzyme
(ACE) inhibitors have been proven to reduce morbidity and
Received June 17, 2002; revision received December 5, 2002; accepted December 5, 2002.
From London Health Sciences Centre (J.M.O.A.), London, Canada; Hamilton General Hospital (S.Y., E.L., J.P., J.B.), Hamilton, Canada; Cleveland
Clinic (J.Y.), Cleveland, Ohio; University of Iowa College of Medicine (J.M.), Iowa City, Iowa; Dalhousie University (D.J.), Halifax, Canada; and Dante
Pazzanese Cardiology Institute (A.A.), São Paulo, Brazil.
Correspondence to Dr Malcolm Arnold, Room S226A, Victoria Campus, London Health Sciences Centre, 375 South St, London, Ontario, Canada N6A
4G5. E-mail [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000054165.93055.42
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Arnold et al
Ramipril and Heart Failure Prevention
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Methods
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The HOPE study was a double-blind, placebo-controlled, randomized trial with a two-by-two factorial design conducted to evaluate
the effects of ramipril and vitamin E in 9541 patients at high risk of
cardiovascular events enrolled at 267 centers in 19 countries from
Europe and the Americas. Men and women who were at least 55
years old were eligible if they had a history of coronary artery
disease, stroke or peripheral vascular disease, or diabetes plus one
other cardiovascular risk factor (hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level, cigarette
smoking, or documented microalbuminuria). Patients were excluded
if they had a history of heart failure, were known to have a low left
ventricular ejection fraction ⬍0.40, were taking an ACE inhibitor,
had uncontrolled hypertension or overt nephropathy, or had a
myocardial infarction or stroke within 4 weeks before entering the
study. Of these patients, 244 were randomly assigned to receive only
low-dose ramipril, 2.5 mg per day as part of a prospective substudy.19 We report the results of 9297 patients randomly assigned to
receive ramipril 10 mg once per day or matching placebo. Additional
details of the study design and methods have been reported
previously.20
The primary outcome was a composite of myocardial infarction,
stroke, and death from cardiovascular causes and was significantly
reduced by 22% in the ramipril group.18 Hospitalization for heart
failure was a predefined secondary outcome. All heart failure was
defined as heart failure causing death, heart failure requiring hospitalization, heart failure requiring open-label ACE inhibition, or
development of typical symptoms and signs as determined by the
investigator. The first two were independently adjudicated in a
blinded fashion by the End-Points Adjudication Committee.
In this large study, it was impractical to mandate left ventricular
ejection fraction measurement in all patients. However, echocardiograms were prospectively obtained as a substudy at 3 centers in 496
enrolled patients. Of these patients, 97.4% had a baseline ejection
fraction ⱖ0.40 and 2.6% had an ejection fraction ⬍0.40. Mean left
ventricular ejection fraction in the echocardiographic substudy was
58%.22 A subsequent review of the charts of randomized patients
showed that ventricular function had been evaluated before randomization in 5193. Of these patients, 4772 (91.9%) were documented to
have a normal ejection fraction, only 421 (8.1%) had a low ejection
fraction, and none had documented heart failure before randomization. Left ventricular hypertrophy was considered to be present if the
sum of the amplitude of S wave in V1 and R wave in V5/V6
exceeded 3.5 mV.
Statistical Analysis
The study was originally designed to follow participants for a mean
of 3.5 years. However, before the end of this period, the steering
committee (whose members were unaware of any of the results)
recommended increasing the duration of follow-up to 5 years to
account for the impact of a possible lag before treatment had its full
effect. All analyses are intention to treat. Time to first occurrence of
outcomes are presented as Kaplan-Meier estimates and compared by
treatment group using log-rank statistics. Hazard ratios for treatment
effect and 95% confidence intervals were derived using Cox regression, stratified for allocation to the vitamin E arm of the factorial
design. Events following development of heart failure or myocardial
infarction were analyzed as time-dependent covariates in a Cox
regression.
Differences in baseline characteristics or between patients who
developed heart failure and those who did not were compared using
t tests for continuous variables and ␹2 tests for discrete variables.
Independent factors that predicted heart failure were selected from
known risk factors using Cox regression using a backward elimination technique. Subgroup analyses were conducted with the use of
tests for interactions in the Cox regression model.
On March 22, 1999, the monitoring board recommended early
termination of the study because of the clear evidence of a beneficial
effect of ramipril (consistent crossing of the monitoring boundaries
in two consecutive reviews). The data at that time showed a 20%
Figure 1. Risk of death after development of heart failure. Day
1251 was median time during follow-up to heart failure development and was used as a reference time for those who did not
develop heart failure.
reduction in the relative risk of the primary outcome (95% confidence interval, 12% to 28%; z statistic, ⫺4.5; P⬍0.001). The cutoff
date for all events included in the main analysis was set for April 15,
1999, and final visits were scheduled to be completed by June 30,
1999. Vital status was ascertained for 9535 of the 9541 randomized
patients (99.9%) at the end of the study.
Results
Detailed baseline characteristics of the population have been
reported previously.20 Briefly, mean age was 66 years, 73%
were male, 53% had a previous myocardial infarction, 47%
had a history of hypertension, and 38% had a history of
diabetes mellitus.
Rate of Heart Failure Development
Any heart failure (composite of heart failure death, heart
failure requiring hospitalization, heart failure requiring ACE
inhibitor, or any reported heart failure) occurred in 951
patients (10.2% of all randomized patients) during a median
follow-up of 4.6 years. The patients with documented normal
left ventricular ejection fractions did not have a lower rate of
heart failure occurrence (11.7%) than that seen in the main
trial. Development of heart failure was associated with a
4.01-fold (95% confidence interval, 3.42 to 4.71) increase in
the rate of death (P⬍0.0001) (Figure 1) and a 4.35-fold (3.56
to 5.31) increase in the rate of cardiovascular death
(P⬍0.0001). Heart failure occurred in 267 (27.2%) of patients with and 684 (8.2%) of patients without an interim
myocardial infarction, resulting in an 8.65-fold (7.44 to
10.07) increased risk of heart failure if a myocardial infarction occurred (P⬍0.0001). Hospitalization for heart failure
occurred in 302 patients for a total of 434 heart failure
hospitalizations. Of patients hospitalized with heart failure,
72% were hospitalized once, 24% on 2 to 3 occasions, and
4% on 4 or more occasions.
Relationship of Baseline Characteristics and
Heart Failure
The prevalence of baseline characteristics in patients who did
or did not develop any heart failure is shown in Table 1.
Patients who developed heart failure were significantly older,
had a higher body mass index, higher systolic pressure, pulse
pressure, and heart rate, and were more likely to have one of
the trial indicators of vascular disease or its complications.
Baseline characteristics that were independently associated
with the development of heart failure are given in Table 2.
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March 11, 2003
TABLE 1. Baseline Characteristics of Patients Who Did or Did Not Develop Any
Heart Failure
No Heart Failure
During Treatment
(n⫽8346)
Age, y
Systolic blood pressure, mm Hg
Pulse pressure, mm Hg
Any Heart Failure
During Treatment
(n⫽951)
P,
Heart Failure
vs None
65.6⫾6.7
67.9⫾7.1
⬍0.0001
138.3⫾19.5
141.6⫾21.0
⬍0.0001
59.4⫾15.8
63.0⫾18.1
⬍0.0001
Heart rate, bpm
68.6⫾11.2
70.0⫾12.2
Body mass index, kg/m2
27.6⫾4.3
28.3⫾4.6
⬍0.0001
0.0006
Female sex
2227 (26.7)
253 (26.6)
0.96
Current smoker
1189 (14.2)
130 (13.7)
0.63
657 (7.9)
128 (13.5)
⬍0.001
1627 (19.5)
336 (35.3)
⬍0.001
Coronary artery disease
6651 (79.7)
826 (86.9)
⬍0.001
Coronary artery bypass graft
2083 (25.0)
316 (33.2)
⬍0.001
868 (10.4)
145 (15.2)
⬍0.001
Peripheral vascular disease
3349 (40.1)
479 (50.4)
⬍0.001
Hypertension
3843 (46.0)
512 (53.8)
⬍0.001
Diabetes
3144 (37.7)
433 (45.5)
⬍0.001
Left ventricular hypertrophy
Microalbuminuria
History of
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Stroke/transient ischemic attack
Values are mean⫾SD or number (%) of patients.
For each additional risk factor, the statistical model predicted
that heart failure occurrence was increased on average 37%
(relative risk, 1.37; 95% confidence interval, 1.32 to 1.41;
P⬍0.0001). Some baseline characteristics could be expressed
as continuous variables, and their influence on development
of all heart failure is shown by quartile in Figure 2. Increasing
age, body mass index, systolic pressure, and pulse pressure all
significantly increased the rate of heart failure, although the
most striking effect was that of age, where the rate more than
doubled in patients ⬎72 years of age compared with those
⬍62 years of age. The highest baseline quartile for heart rate
was also associated with an increased rate of heart failure
(⬍61 bpm, 10.1%; 61 to 68 bpm, 9.2%; 69 to 76 bpm, 9.5%;
77⫹ bpm, 12.4% rate of heart failure; P⬍0.002 across
quartiles).
There was no significant interaction (P⫽0.4) between
coronary artery disease and systolic hypertension in predicting the rate of heart failure development. Using only coronary
heart disease, systolic hypertension, and pulse pressure, these
factors had 68% explanatory power for future heart failure
development.
Effect of Ramipril on Heart Failure Rate
TABLE 2. Baseline Characteristics Independently Associated
With the Development of Heart Failure
Variable
Risk Ratio
Lower
Upper
Coronary artery disease
2.17
1.76
2.67
Microalbuminuria
1.82
1.58
2.10
Diuretic use
1.76
1.52
2.04
Left ventricular hypertrophy
1.47
1.21
1.78
Age (for 10-y difference)
1.37
1.25
1.49
Diabetes
1.36
1.18
1.57
Total cholesterol ⬎5.2, no treatment
1.32
1.12
1.56
Coronary artery bypass graft
1.32
1.14
1.52
Stroke/transient ischemic attack
1.31
1.09
1.57
No ramipril
1.27
1.12
1.44
Peripheral vascular disease
1.25
1.09
1.42
Body mass index (for 4-unit difference)
1.10
1.04
1.16
Heart rate (for 10-beat difference)
1.09
1.03
1.15
Pulse pressure (10-mm Hg difference)
1.06
1.01
1.10
Model predicts a 37% increase for each additional risk factor.
Relative risk⫽1.37; 95% confidence interval (1.33 to 1.42); P⬍0.0001.
Allocation of treatment to ramipril significantly reduced the
rate of all heart failure by 23% (Figure 3) and the rate of
combined cardiovascular death and all heart failure by 24%
(Table 3). When analyzed separately, each component of the
composite heart failure end point showed benefit in favor of
ramipril, although the total number of events for heart failure
hospitalization, fatal heart failure, and other reported heart
failure was smaller; therefore, the benefit did not reach
statistical significance separately. The introduction of angiotensin II antagonists for the treatment of new heart failure was
very low in the study, 0.97% in placebo and 0.65% in ramipril
groups. In the subgroup of 4775 patients with documented
normal left ventricular ejection fractions, the benefits of
ramipril were similar to the whole group, with a reduction in
the rate of all heart failure by 24% (relative risk, 0.76; 95%
confidence interval, 0.64 to 0.89; P⫽0.001), prescription of
an ACE inhibitor for heart failure by 29% (0.71; 0.57 to 0.88),
hospitalization for heart failure by 15% (0.85; 0.63 to 1.14),
death from heart failure by 32% (0.68; 0.32 to 1.47), and
combined cardiovascular death and all heart failure by 25%
(0.75; 0.65 to 0.86; P⬍0.0001).
Arnold et al
Ramipril and Heart Failure Prevention
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Figure 2. Rate of developing heart failure and
baseline characteristics expressed as quartiles.
BMI indicates body mass index; SBP, systolic
blood pressure; and PP, pulse pressure.
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The benefits of ramipril in reducing all heart failure were
consistent across major relevant subgroups (Figure 4). A
significant interaction was observed between baseline systolic pressure and treatment group (P⫽0.024). Ramipril reduced
the rate of all heart failure by 9% (relative risk, 0.91; 95%
confidence interval, 0.75 to 1.10) in patients with baseline
systolic pressure below the median (139 mm Hg) compared
with 33% (relative risk, 0.67; 0.57 to 0.80) in patients with
baseline systolic pressure at or above the median. There was
no interaction between vitamin E and ramipril on the rate of
heart failure development.
Effects of Ramipril in Patients With and Without
a Myocardial Infarction During the Study
Patients who had myocardial infarction during the study
(n⫽1029) were at increased relative risk of developing heart
failure. Ramipril favorably reduced the rate of heart failure
after myocardial infarction by 13% (relative risk, 0.87; 95%
confidence interval, 0.66 to 1.15) (Figure 5A). Ramipril also
significantly reduced the rate of heart failure by 22% in the
much larger group of patients (n⫽8315) who did not have an
interim myocardial infarction (relative risk, 0.78; 95% confidence interval, 0.62 to 0.97) (Figure 5B).
Discussion
ACE inhibitors have been shown to reduce mortality across a
broad range of patients with chronic symptomatic systolic
heart failure attributable to left ventricular systolic dysfunc-
Figure 3. Ramipril effects on rate of developing all heart failure.
tion,7,15 to reduce recurrent episodes of heart failure in
patients with acute heart failure or significant left ventricular
systolic dysfunction after an acute myocardial infarction,12–14
and to reduce the development of symptomatic heart failure
in patients with asymptomatic left ventricular systolic dysfunction.16 The present results with ramipril extend additionally the benefits of ACE inhibition to an even broader range
of patients at high risk of cardiovascular events but without a
history of heart failure or known left ventricular ejection
fraction ⬍0.40. Because ramipril has also been shown to
reduce the rates of death, myocardial infarction, and stroke in
this population,18 the additional benefits in reducing the rates
of heart failure strongly support its role in broad-based
cardiovascular protection in high-risk patients. By intention
to treat analysis, treating 40 such patients for 4.5 years would
prevent 1 new episode of heart failure, including that associated with hospitalization or death. These benefits are mostly
additional to the already-reported reduction in cardiovascular
death, myocardial infarction, and strokes as well as revascularization procedures. Taking all events into account, treating
13 patients prevents 1 of the above important clinical
outcomes.
Heart failure as an outcome was included if it was severe
enough to cause withdrawal of study drug to introduce
open-label ACE inhibitor, to be the direct cause of a hospital
admission, or to be attributed as the cause of death. These
reasons accounted for 97% of all recorded episodes of heart
failure. The reported results may underestimate the benefits
of ramipril to prevent less-severe episodes of heart failure.
Only heart failure hospital admissions or heart failure death
were independently adjudicated in a blinded fashion by the
End-Points Adjudication Committee. The number of these
adjudicated events represented 37% of all predefined heart
failure events. The clinical relevance and importance of all
heart failure events in our study is emphasized by the
associated high total mortality (4.0-fold increase) and high
cardiovascular mortality (4.4-fold increase). The risk of
developing heart failure was not likely to be increased by the
inadvertent inclusion of patients with poor left ventricular
function at study entry, because the results were consistent in
the large subgroup of 4772 patients with documented pre-
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TABLE 3.
March 11, 2003
Incidence of Heart Failure and Influence of Ramipril
Placebo, %
(n⫽4652)
Ramipril, %
(n⫽4645)
RR (95% CI)
P
11.5
9.0
0.77 (0.68 to 0.87)
⬍0.0001
ACE-I for heart failure*
7.0
5.2
0.72 (0.61 to 0.85)
⬍0.0001
Heart failure hospitalization*
3.5
3.0
0.87 (0.69 to 1.09)
Fatal heart failure*
0.6
0.5
0.88 (0.51 to 1.53)
Heart failure signs and symptoms†
2.6
2.5
0.95 (0.74 to 1.23)
Cardiovascular death plus all heart failure
17.4
13.4
0.76 (0.69 to 0.84)
All heart failure
⬍0.0001
RR indicates relative risk; CI, confidence interval.
*All patients with this outcome are included.
†Excludes patients who had ACE-I use, heart failure hospitalization, or fatal heart failure.
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served ventricular function. The specific contributions of
systolic and diastolic dysfunction were not recorded as
measurement of left ventricular ejection fraction, and diastolic filling patterns were not required within the protocol.
We found that the subsequent risk of heart failure was
increased 8- to 9-fold after myocardial infarction. Reducing
the rate of myocardial infarction18 will have reduced the left
ventricular damage that clearly predisposes to episodes of
heart failure. In the patients who did have a myocardial
infarction during the study, the risk of subsequent heart
failure was reduced, consistent with previous trials of ACE
inhibitors.12–14 In most patients who did not have an interim
myocardial infarction, the results showed a significant beneficial effect of ramipril to prevent heart failure. Seventy-two
percent of all heart failure occurred in this group, consistent
with a high population-attributable risk. Hence, treatment
with ramipril in this group will be expected to prevent more
heart failure events than those prevented simply by reducing
the rest of myocardial infarctions. In these patients, other risk
factors for heart failure, such as hypertension and diabetes,
may have played a role. The results demonstrated a significant interaction between ramipril treatment and baseline
systolic pressure. The risk of developing heart failure ranged
from 12.3% to 9.1% between the highest to the lowest
quartile of baseline systolic pressure, and ramipril significantly reduced the rate of heart failure by 33% versus 9% in
patients with baseline systolic pressure above or below the
median. Diabetes was more prevalent in patients developing
heart failure, and ramipril reduces the risk of complications
related to diabetes and of diabetes itself.18,21 Direct effects of
Figure 4. Relative risk of ramipril versus placebo
on selected characteristics. BP indicates blood
pressure; Hypert, hypertension; CAD, coronary
artery disease; MI, myocardial infarction; LVEF, left
ventricular ejection fraction; and BB, ␤-blocker.
Arnold et al
Ramipril and Heart Failure Prevention
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sion or dizziness (1.9% versus 1.5%) requiring discontinuation of double-blind treatment.18 The percentage of patients
who were receiving ramipril 10 mg was 82.9% at 1 year and
62.4% at 4 years.18
The benefits of ramipril to reduce the rates of heart failure
were consistent in all important subgroups, including patients
⬎65 years of age, females, and patients without known
hypertension or diabetes at baseline and were independent of
concomitant baseline use of aspirin, diuretics, or ␤-blockers.
In a previous analysis of SOLVD,23 a reduced effect of the
ACE inhibitor enalapril was observed in those taking antiplatelet agents, although this had not been a predefined
interaction. Also, patients in SOLVD were different from
those in HOPE, because all had a low left ventricular ejection
fraction ⬍0.35 and all patients in the treatment trial had
symptoms of heart failure before randomization. The results
of our study broaden the cardiovascular protection and use of
ramipril to a population of high-risk patients with vascular
disease or diabetes plus at least one other cardiovascular risk
factor, but without heart failure or known low left ventricular
ejection fraction, and undergoing concomitant medical therapy. This study is the first to show that an ACE inhibitor can
prevent heart failure in these patients. The prevention of heart
failure in this population will reduce the high burden of
mortality, morbidity, hospitalizations, and associated costs.
Figure 5. Ramipril effects on rate of heart failure in patients after
a myocardial infarction occurred during follow-up (A) and in
patients who did not develop a myocardial infarction during the
study (B). Day 710 was the median time during the follow-up
that a myocardial infarction occurred and was used as a reference time for those patients who did not develop an infarction.
ACE inhibition on the myocardium or vasculature to reduce
hypertrophy, atherosclerosis progression, plaque rupture,
thrombotic/fibrinolytic balance, or other mechanisms17 may
also have played a role and require additional study.
The echocardiographic substudy of HOPE included baseline and study-end examinations and showed decreased left
ventricular end-systolic and end-diastolic volumes and improved left ventricular ejection fraction in the ramipril versus
the placebo group. These findings persisted after controlling
for BP changes and support a broad beneficial effect of ACE
inhibition on left ventricular remodeling.22
A limitation of the study design is the inclusion of a small
percentage of patients who, on comprehensive chart review,
had a left ventricular ejection fraction ⬍0.40, but none had
documented heart failure symptoms. These patients did not
change the overall results, as repeat analysis excluding them
still showed the same significant reduction in the rate of heart
failure development. Although a preserved left ventricular
ejection fraction of ⬎0.40 by itself would not exclude the
possibility of diastolic dysfunction at baseline, those patients
also would not have been entered into the trial if they had
previous symptoms consistent with heart failure. Arm systolic
blood pressure was recorded, usually by a nurse or study
coordinator, on one occasion as baseline arterial pressure
using a standardized protocol in duplicate after the patient
had been recumbent for 5 minutes. Treatment with ramipril
was well tolerated but was associated with an increase in
cough (7.3% versus 1.8%) and a small increase in hypoten-
Acknowledgments
Funded by the Medical Research Council of Canada, HoechstMarion Roussel, Astra-Zeneca, King Pharmaceuticals, Natural
Source Vit E Association and Negema, and the Heart and Stroke
Foundation of Ontario.
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Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation
(HOPE) Study
J. Malcolm O. Arnold, Salim Yusuf, James Young, James Mathew, David Johnstone, Alvaro
Avezum, Eva Lonn, Janice Pogue and Jackie Bosch
on behalf of the HOPE Investigators
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Circulation. 2003;107:1284-1290; originally published online February 24, 2003;
doi: 10.1161/01.CIR.0000054165.93055.42
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Copyright © 2003 American Heart Association, Inc. All rights reserved.
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