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) 66 139/79 69 27.5 79.5 11.0 42.3 47.6 38.9 65.4 19.0 13.9 8.7 14.5 44.8 46.1 38.0 66.4 Placebo Group (4652) 66 139/79 69 25.8 81.3

Age- yr Blood pressure - mm Hg Heart rate - beats/min Female sex - % History of CAD - % Stroke or TIA - % 10.8 Peripheral vascular disease - % Hypertension - % Diabetes - % Documented elevated TC - % Documented low HDL - %18.1 Current cigarette smoking - % LVH on ECG - % 8.2
N Engl J Med, January 20, 2000

HOPE - Baseline Characteristics - Medications Characteristic Ramipril Group (n=4645) Placebo Group (n=4652)

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

39.2 75.3 28.4 15.3 46.3

39.8 76.9 28.8 15.2 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 0.15 0.1 0.05 0 0 500 Days of Follow-up
N Engl J Med, January 20, 2000

% of Patients

Ramipril Placebo

P<0.001

1000

15000

HOPE - Primary Endpoint Results

Endpoint Ramipril (n=4645) 14.1% 6.1% 9.9% Placebo (n=4652) 17.7% 8.1% 12.2% RR P value

MI/Stroke/CV Death CV Death MI

0.78 0.75 0.80

<0.001 <0.001 <0.001

Stroke
Non CV Death Total Mortality
N Engl J Med, January 20, 2000

3.4%
4.3% 10.4%

4.9%
4.1% 12.2%

0.69
1.03 0.84

<0.001
0.78 0.006

HOPE - Primary Endpoint Results

25 20
% with an event
22% Risk Reduction p<0.001

17.7 14.1 8.1 6.1

20% Risk Reduction p=<0.001 25% Risk Reduction p<0.001

Ramipril Placebo
16% Risk Reduction p=0.006

15 10 5 0

12.2 9.9
31% Risk Reduction 0% Risk Reduction p=<0.001 p=0.78

12.2 10.4 4.9

3.4

4.3 4.1

MI/Stroke/ CV Death

CV Death

MI

Stroke

Non CV Death

Total Mortality

N Engl J Med, January 20, 2000

HOPE - Secondary and Other Endpoint Results

Endpoint 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) 16.0 12.2 6.2 3.3 9.2 0.8 23.8 3.7 3.9 Placebo (n=46532) 18.6 12.4 7.4 3.8 11.7 1.2 26.2 5.3 4.0 RR P value

0.84 0.98 0.84 0.87 0.77 0.63 0.89 0.68 0.96

<0.001 0.68 <0.03 0.19 <0.001 0.03 0.003 0.002 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 20
% with an event
16% Risk Reduction p<0.001

18.6 16

Ramipril Placebo
23% Risk Reduction p<0.001

15 10 5 0

16% Risk Reduction p=0.03 7.4 13% Risk Reduction p=0.19 6.2

11.7 9.2
32% Risk Reduction p=0.002

3.3 3.8

3.7

5.3

Revascularization

DM Complications

HF Hospitalization

Heart Failure

New diagnosis of Diabetes Mellitus

N Engl J Med, January 20, 2000

HOPE - Results in Patients with a Normal EF

Endpoint Ramipril n=2339 13.6% 5.0% 10.3% 2.9% Placebo n=2337 18.3% 7.0% 13.5% 4.2% RR P value

Primary Endpoint CV Death MI Stroke

0.73 0.7 0.75 0.67

<0.001 0.0032 0.0009 0.010

All HF

8.3%

10.4%

0.79

G. Dagenais, ESC 1999

HOPE - Results in Patients with Normal EF

25 20
% with an event
27% Risk Reduction p=0.00002

18.3 13.6
30% Risk Reduction p=0.0032

25% Risk Reduction p=0.0009

Ramipril Placebo

15 10 5 0

13.5 10.3
33% Risk Reduction p=0.010

7 5

2.9

4.2

MI/Stroke/ CV Death

CV Death

MI

Stroke

G. Dagenais, ESC 1999

HOPE - Results in Patients with Diabetes

Endpoint Ramipril n=1808 15.3% 6.0% Placebo n=1770 19.6% 9.6% RR P value

Primary Endpoint CV Death

0.76 0.62

0.0007

G. Dagenais, ESC 1999

HOPE - Results in Patients with Diabetes

25 20
% with an event
34% Risk Reduction p=0.0007

19.6

Ramipril Placebo

15.3 15 10 6 5 0
38% Risk Reduction

9.6

MI/Stroke/CV Death

CV Death

G. Dagenais, ESC 1999

HOPE - BP Effects
Outcome Baseline (mmHg) 139 139 79 79 Change at 1 month (mmHg) -6.0 -2.0 -3.0 -1.0 Change at 2 Change at end months (mmHg) (mmHg) -3.0 0.00 -3.0 -1.0 -2.0 0.00 -3.00 -2.00

Ramipril SBP Placebo SBP Ramipril DBP Placebo DBP

N Engl J Med, January 20, 2000

HOPE - Vitamin E Outcomes Results

Vitamin E Placebo RR

Primary Endpoint

16.0%

15.4%
11.0%

1.04 (0.94-1.15)

All Cause Mortality 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