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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 Placebo Group
(n=4645) (4652)

Age- yr 66 66
Blood pressure - mm Hg 139/79 139/79
Heart rate - beats/min 69 69
Female sex - % 27.5 25.8
History of CAD - % 79.5 81.3
Stroke or TIA - % 10.8 11.0
Peripheral vascular disease - % 42.3 44.8
Hypertension - % 47.6 46.1
Diabetes - % 38.9 38.0
Documented elevated TC - % 65.4 66.4
Documented low HDL - % 18.1 19.0
Current cigarette smoking - % 13.9 14.5
LVH on ECG - % 8.2 8.7
N Engl J Med, January 20, 2000
HOPE - Baseline Characteristics
- Medications -

Characteristic Ramipril Group Placebo Group


(n=4645) (n=4652)

Medications - %
Beta-blockers 39.2 39.8
ASA or other platelet agents 75.3 76.9
Lipid-lowering agents 28.4 28.8
Diuretics 15.3 15.2
CCBs 46.3 47.9

N Engl J Med, January 20, 2000


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
0.2
Ramipril
0.15 Placebo
% of Patients

P<0.001
0.1

0.05

0
0 500 1000 15000
Days of Follow-up
N Engl J Med, January 20, 2000
HOPE - Primary Endpoint Results

Endpoint Ramipril Placebo RR P value


(n=4645) (n=4652)

MI/Stroke/CV Death 14.1% 17.7% 0.78 <0.001


CV Death 6.1% 8.1% 0.75 <0.001
MI 9.9% 12.2% 0.80 <0.001
Stroke 3.4% 4.9% 0.69 <0.001
Non CV Death 4.3% 4.1% 1.03 0.78
Total Mortality 10.4% 12.2% 0.84 0.006

N Engl J Med, January 20, 2000


HOPE - Primary Endpoint Results
25
22% Risk Reduction Ramipril
p<0.001
20 Placebo
17.7 16% Risk
20% Risk Reduction Reduction
% with an event

15 14.1 p=<0.001 p=0.006

25% Risk Reduction


12.2 12.2
p<0.001 9.9 10.4
10 8.1 31% Risk Reduction
0% Risk Reduction
p=<0.001
6.1 p=0.78
4.9 4.3 4.1
5 3.4

0
MI/Stroke/ CV Death MI Stroke Non CV Death Total
CV Death Mortality
N Engl J Med, January 20, 2000
HOPE - Secondary and Other Endpoint
Results
Endpoint Ramipril Placebo RR P value
(n=4645) (n=46532)

Secondary Outcomes - %
Revascularization 16.0 18.6 0.84 <0.001
Hospitalization for UA 12.2 12.4 0.98 0.68
Complications/DM 6.2 7.4 0.84 <0.03
Hospitalization for HF 3.3 3.8 0.87 0.19
Other Outcomes - %
Heart failure 9.2 11.7 0.77 <0.001
Cardiac arrest 0.8 1.2 0.63 0.03
Worsening angina 23.8 26.2 0.89 0.003
New diagnosis of DM 3.7 5.3 0.68 0.002
Unstable angina with
ECG changes 3.9 4.0 0.96 0.72
UA = unstable angina; DM = diabetes mellitus; HF = heart failure
N Engl J Med, January 20, 2000
HOPE - Secondary and Other Endpoint
Results
25
16% Risk Reduction
p<0.001 Ramipril
20 18.6 Placebo
16 23% Risk Reduction
% with an event

p<0.001
15
16% Risk Reduction 11.7
p=0.03 9.2 32% Risk Reduction
10
7.4 13% Risk Reduction p=0.002
6.2 p=0.19
5.3
5 3.3 3.8 3.7

0 Revascularization DM HF Heart Failure New diagnosis of


Complications Hospitalization Diabetes Mellitus
N Engl J Med, January 20, 2000
HOPE - Results in Patients with a Normal EF

Endpoint Ramipril Placebo RR P value


n=2339 n=2337

Primary Endpoint 13.6% 18.3% 0.73 <0.001


CV Death 5.0% 7.0% 0.7 0.0032
MI 10.3% 13.5% 0.75 0.0009
Stroke 2.9% 4.2% 0.67 0.010
All HF 8.3% 10.4% 0.79

G. Dagenais, ESC 1999


HOPE - Results in Patients with Normal EF
25
27% Risk Reduction
p=0.00002 Ramipril
20 18.3 Placebo
25% Risk Reduction
p=0.0009
% with an event

15 13.6 13.5
30% Risk Reduction
p=0.0032 10.3
10 33% Risk Reduction
7 p=0.010
5 4.2
5 2.9

0
MI/Stroke/ CV Death MI Stroke
CV Death
G. Dagenais, ESC 1999
HOPE - Results in Patients with Diabetes

Endpoint Ramipril Placebo RR P value


n=1808 n=1770

Primary Endpoint 15.3% 19.6% 0.76 0.0007


CV Death 6.0% 9.6% 0.62

G. Dagenais, ESC 1999


HOPE - Results in Patients with Diabetes
25
34% Risk Reduction
p=0.0007 Ramipril
19.6
20 Placebo
15.3
% with an event

15
38% Risk Reduction

9.6
10
6
5

0
MI/Stroke/CV Death CV Death

G. Dagenais, ESC 1999


HOPE - BP Effects

Outcome Baseline Change at 1 Change at 2 Change at end


(mmHg) month (mmHg) months (mmHg) (mmHg)

Ramipril SBP 139 -6.0 -3.0 -2.0


Placebo SBP 139 -2.0 0.00 0.00
Ramipril DBP 79 -3.0 -3.0 -3.00
Placebo DBP 79 -1.0 -1.0 -2.00

N Engl J Med, January 20, 2000


HOPE - Vitamin E Outcomes Results

Vitamin E Placebo RR

Primary Endpoint 16.0% 15.4% 1.04


(0.94-1.15)
All Cause Mortality 11.0% 11.0%

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