Effects of an Angiotensin-Converting

Enzyme Inhibitor, Ramipril, on Death from

Cardiovascular Causes, Myocardial
Infarction, and Stroke in High-Risk
Patients
The Heart Outcomes Prevention Evaluation (HOPE)
Study Investigators
N Engl J Med, January 20, 2000

HOPE - Background
ACEIs improve the outcome in patients with LV
dysfunction, whether or not they have symptomatic
heart failure.
This study assessed the role of an ACEI, ramipril, in
patients who were at high risk for cardiovascular
events but who did not have LV dysfunction or heart
failure.
N Engl J Med, January 20, 2000

HOPE - Design
A total of 9,297 high-risk patients, > 55 years old, who had
evidence of vascular disease or diabetes plus one other
cardiovascular risk factor and who were not known to have a low
EF or heart failure were randomly assigned to receive ramipril
(10 mg per day) or matching placebo for a mean of 5 years.
The primary outcome was a composite of MI, stroke or death
from cardiovascular causes. Each of these endpoints were also
analyzed separately.
Secondary endpoints were death from any cause, the need for
revascularization, hospitalization for unstable angina or heart
failure, and complications related to diabetes.
N Engl J Med, January 20, 2000

HOPE - Baseline Characteristics

Characteristic

Ramipril Group
(n=4645)

Placebo Group
(4652)

Age- yr
Blood pressure - mm Hg
Heart rate - beats/min
Female sex - %
History of CAD - %
Stroke or TIA - %
Peripheral vascular disease - %
Hypertension - %
Diabetes - %
Documented elevated TC - %
Documented low HDL - %
Current cigarette smoking - %
LVH on ECG - %
8.2

66
139/79
69
27.5
79.5
10.8
42.3
47.6
38.9
65.4
18.1
13.9

66
139/79
69
25.8
81.3
11.0
44.8
46.1
38.0
66.4
19.0
14.5

N Engl J Med, January 20, 2000

8.7

HOPE - Baseline Characteristics

- Medications Characteristic
Medications - %
Beta-blockers
ASA or other platelet agents
Lipid-lowering agents
Diuretics
CCBs

N Engl J Med, January 20, 2000

Ramipril Group
(n=4645)

Placebo Group
(n=4652)

39.2
75.3
28.4
15.3
46.3

39.8
76.9
28.8
15.2
47.9

HOPE - Compliance
More patients in the ramipril group versus the placebo group
stopped treatment because of cough (7.3% versus 1.8%) or
hypotension or dizziness (1.9% versus 1.5%)
By contrast, more patients in the placebo group than in the
ramipril group stopped treatment because of uncontrolled
hypertension (3.9% versus 2.3%) or because of a clinical
event - a primary or secondary outcome (9.0% versus 6.7%)
5.3% of patients in the ramipril group and 7.2% of patients in
the placebo group received open label ACEI for heart failure

N Engl J Med, January 20, 2000

HOPE - Kaplan-Meier Estimates of the Composite

Endpoint of CV Death, MI or Stroke in the Ramipril
and Placebo Groups

% of Patients

0.2
Ramipril
Placebo

0.15

P<0.001
0.1
0.05
0
0

500

1000
Days of Follow-up

N Engl J Med, January 20, 2000

15000

HOPE - Primary Endpoint Results

Endpoint

Ramipril
(n=4645)

Placebo
(n=4652)

RR

P value

MI/Stroke/CV Death
CV Death
MI
Stroke
Non CV Death
Total Mortality

14.1%
6.1%
9.9%
3.4%
4.3%
10.4%

17.7%
8.1%
12.2%
4.9%
4.1%
12.2%

0.78
0.75
0.80
0.69
1.03
0.84

<0.001
<0.001
<0.001
<0.001
0.78
0.006

N Engl J Med, January 20, 2000

HOPE - Primary Endpoint Results

25

% with an event

20
15

Ramipril
Placebo

22% Risk Reduction

p<0.001

17.7
20% Risk Reduction
p=<0.001

14.1

25% Risk Reduction

p<0.001

10

8.1

12.2

12.2
10.4

9.9
31% Risk Reduction
0% Risk Reduction
p=<0.001
p=0.78

6.1
5
0

16% Risk
Reduction
p=0.006

3.4

MI/Stroke/
CV Death

CV Death

N Engl J Med, January 20, 2000

MI

4.9

Stroke

4.3 4.1

Non CV Death

Total
Mortality

Endpoint

HOPE - Secondary and Other Endpoint

Results

Secondary Outcomes - %
Revascularization
Hospitalization for UA
Complications/DM
Hospitalization for HF
Other Outcomes - %
Heart failure
Cardiac arrest
Worsening angina
New diagnosis of DM
Unstable angina with
ECG changes

Ramipril
(n=4645)

Placebo
(n=46532)

RR

P value

16.0
12.2
6.2
3.3

18.6
12.4
7.4
3.8

0.84
0.98
0.84
0.87

<0.001
0.68
<0.03
0.19

9.2
0.8
23.8
3.7

11.7
1.2
26.2
5.3

0.77
0.63
0.89
0.68

<0.001
0.03
0.003
0.002

3.9

4.0

0.96

0.72

UA = unstable angina; DM = diabetes mellitus; HF = heart failure

N Engl J Med, January 20, 2000

25

HOPE - Secondary and Other Endpoint

Results
16% Risk Reduction
p<0.001

18.6

20
% with an event

Ramipril
Placebo

16

23% Risk Reduction

p<0.001

15

16% Risk Reduction

p=0.03
7.4 13% Risk Reduction
p=0.19
6.2

10

9.2

3.3 3.8

5
0

11.7

Revascularization

DM
Complications

N Engl J Med, January 20, 2000

HF
Hospitalization

32% Risk Reduction

p=0.002

3.7

Heart Failure

5.3

New diagnosis of
Diabetes Mellitus

HOPE - Results in Patients with a Normal EF

Endpoint

Ramipril
n=2339

Placebo
n=2337

RR

P value

Primary Endpoint
CV Death
MI
Stroke
All HF

13.6%
5.0%
10.3%
2.9%
8.3%

18.3%
7.0%
13.5%
4.2%
10.4%

0.73
0.7
0.75
0.67
0.79

<0.001
0.0032
0.0009
0.010

G. Dagenais, ESC 1999

HOPE - Results in Patients with Normal EF

25

27% Risk Reduction

p=0.00002

% with an event

20
15

18.3
13.6

13.5
30% Risk Reduction
p=0.0032

10

10.3
33% Risk Reduction
p=0.010

7
5

5
0

25% Risk Reduction

p=0.0009

Ramipril
Placebo

2.9
MI/Stroke/
CV Death

G. Dagenais, ESC 1999

CV Death

MI

4.2

Stroke

HOPE - Results in Patients with Diabetes

Endpoint

Ramipril
n=1808

Placebo
n=1770

RR

P value

Primary Endpoint
CV Death

15.3%
6.0%

19.6%
9.6%

0.76
0.62

0.0007

G. Dagenais, ESC 1999

HOPE - Results in Patients with Diabetes

25

34% Risk Reduction

p=0.0007

19.6

20
% with an event

Ramipril
Placebo

15.3
15

38% Risk Reduction

9.6

10
6
5
0

MI/Stroke/CV Death

G. Dagenais, ESC 1999

CV Death

HOPE - BP Effects
Outcome

Baseline
(mmHg)

Change at 1
month (mmHg)

Change at 2
Change at end
months (mmHg) (mmHg)

Ramipril SBP
Placebo SBP
Ramipril DBP
Placebo DBP

139
139
79
79

-6.0
-2.0
-3.0
-1.0

-3.0
0.00
-3.0
-1.0

N Engl J Med, January 20, 2000

-2.0
0.00
-3.00
-2.00

HOPE - Vitamin E Outcomes Results

Vitamin E

Placebo

RR

16.0%

15.4%

1.04
(0.94-1.15)

All Cause Mortality 11.0%

11.0%

Primary Endpoint

G. Dagenais, ESC 1999

HOPE - Summary of Results

Patients randomized to ramipril had risk reductions
of:
MI, stroke, CV death
-22%
CV death
-25%
MI
-20%
Stroke
-31%
Revascularization procedures*
-16%
New onset of diabetes
-32%
*Revascularization procedures included PTCA, CABG or peripheral angioplasty
N Engl J Med, January 20, 2000

HOPE - Summary of Results (continued)

The beneficial effect of treatment with ramipril on the
composite outcome was consistently observed among the
following predefined subgroups:
patients with and without diabetes
men and women
those with and without evidence of cardiovascular disease
those < 65 years of age and those > 65 year of age
those with and without hypertension at baseline*
those with and without microalbuminuria
*A reduction of 2 mm Hg in diastolic blood pressure (as seen in this trial) might at best
account for about 40% of the reduction in the rate of stroke and about 25% of the reduction of MI.
N Engl J Med, January 20, 2000

HOPE - Summary of Results (continued)

There was a clear benefit of ramipril among patients:
with and without evidence of coronary artery disease at baseline
with and without a history of myocardial infarction
with a documented EF > 40% (27% risk reduction, p<0.001)

Benefits were also observed whether or not patients were also

taking (at randomization):
ASA or other antiplatelet agents
beta-blockers
lipid-lowering agents
antihypertensive agents

N Engl J Med, January 20, 2000

HOPE - Conclusions
Ramipril significantly reduces the rates of death,
myocardial infarction, and stroke in a broad range of
high-risk patients who are not known to have a low
ejection fraction or heart failure

N Engl J Med, January 20, 2000