1. Role of RAAS Modulation: Recent Clinical Trials
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Role of RAAS Modulation: Recent Clinical Trials
The slides in this section describe clinical trials of ACE inhibitors in patients with CAD and diabetes.
Studies of ARBs are also highlighted.
CAD
Diabetes
ACEIs and ARBs

2. Benefit of ACE inhibition in CAD
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SOLVD SAVE AIRE TRACE
Post-MI, HF, LVEF <40%
HOPE
SOLVD
(prev)
A number of large multicenter, randomized trials have established the important role of ACE inhibitors at different stages of the pathophysiologic continuum of CV diseases.1
Earlier long-term trials such as SOLVD and SAVE showed that ACE inhibitors could prevent major adverse CV events in acute MI patients with heart failure or LV dysfunction. The SOLVD-prevention trial extended these findings to CAD patients with LV dysfunction.
The HOPE study extended the role of ACE inhibition to patients age >55 years who were at high risk of CV events without heart failure or LV dysfunction, but with a prior history of vascular disease or diabetes plus another risk factor.
EUROPA has recently shown that ACE inhibition is beneficial in a broad population of patients at low risk and with stable CAD and no apparent heart failure. Results support the use of ACE inhibitors for secondary prevention in all CAD patients.
High risk
EUROPA
All CAD patients
Bertrand ME. Curr Med Res Opin. 2004;20:
1. Bertrand ME. Provision of cardiovascular protection by ACE inhibitors: A review of recent trials. Curr Med Res Opin. 2004;20:

3. VBWG
EUROPA: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease
Objective: Assess effects of the ACEI perindopril on CV risk in a broad-spectrum population with stable CAD and without HF
Design: N = 12,218, age ≥18 years, with CAD/without HF at randomization
Treatment: Perindopril 8 mg or placebo
Follow-up: 4.2 years
Primary
outcome: CV death, nonfatal MI, cardiac arrest
EUROPA investigators reasoned that the multifactorial antiatherosclerotic profile of ACE inhibition suggests that it should not be restricted to patients with established CAD and with impaired LV function, heart failure, or at high risk of atherosclerotic events.1
Patients (N = 12,218) with CAD and without heart failure were randomized to perindopril 8 mg/day (n = 6110) or placebo (n = 6108) and followed for a mean of 4.2 years.
The primary outcome was the effect of treatment on CV death, MI, or cardiac arrest.
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

4. EUROPA: Baseline characteristics
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EUROPA: Baseline characteristics
Female
History of CAD
– MI
– PCI
– CABG
Documented CAD
– Angiographic evidence (stenosis >70% )
14.5
100
64.9
29.0
29.3
60.4
14.7
64.7
29.5
29.4
60.5
– Positive stress test
(in men w/chest pain)
History of stroke/TIA
PVD
Hypertension
Diabetes
Hypercholesterolemia
22.6
3.4
7.1
27.0
11.8
63.3
23.3
3.3
7.4
27.2
12.8
Perindopril (%)
(n = 6110)
Placebo (%)
(n = 6108)
The EUROPA study included men and women ≥18 years of age (mean age, 60 years).1
All patients had documented CAD: 65% had a previous MI; 55% had undergone percutaneous or surgical coronary revascularization; some had undergone both procedures.
The study also recruited patients with CAD with ≥70% stenosis (documented by angiographic evidence). Men were recruited if they had a history of chest pain and a positive stress test.
At randomization, 12% had diabetes, 27% had hypertension, and 63% had hypercholesterolemia.
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

5. EUROPA: Concomitant medications
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EUROPA: Concomitant medications
Platelet inhibitors
Beta-blockers
Lipid-lowering agents
Nitrates
Calcium channel blockers
Diuretics 92 62 58 43 32 9 91 63 69 NA
Baseline (%)
3 Years (%)*
At the time of randomization, a large proportion of the 12,218 EUROPA patients were taking other cardioprotective therapy: platelet inhibitors 92%; beta-blockers 62%; and lipid-lowering therapy 58%.1
At 3 years, concomitant medication was recorded in 11,547 patients. Use of platelet inhibitors and beta-blockers was similar to baseline, but the use of lipid-lowering agents had increased to 69%.
*Concomitant medications recorded in 11,547 patients
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

6. EUROPA: Primary outcome
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EUROPA: Primary outcome
CV death, MI, cardiac arrest 14
RRR 20% (95% CI: 9%–29%) AR 8.0% vs 9.9%
P = 12
Placebo 10
Perindopril 8 mg
EUROPA results showed that 603 (10%) placebo patients and 488 (8%) perindopril patients experienced the primary endpoint of CV death, nonfatal MI, and resuscitated cardiac arrest, which yields a relative risk reduction of 20% (95% confidence interval [CI], 9%–29%; P = 0.003) and a 1.9% absolute risk reduction.1
The onset of benefits with perindopril became apparent after 1 year and reached statistical significance at 3 years and beyond. For primary outcome at 3 years, relative risk reduction was 14% (95% CI, 0.5%–25.2%).2
Primary outcome
(%) 8 6
20% 4
14%
P < 0.05
11% 2
10%
P = 0.35 1 2 3 4 5
Time (years)
EUROPA Investigators. Lancet. 2003;362:782-8.
Fox KM. Br J Cardiol. 2004;11:
AR = absolute risk (perindopril vs placebo)
EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled multicentre trial (the EUROPA study). Lancet. 2003;362:
Fox K. Management of coronary artery disease: Implications of the EUROPA trial. Br J Cardiol. 2004;11:

7. EUROPA: Effect of ACEI on fatal/nonfatal MI and HF hospitalizations
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EUROPA: Effect of ACEI on fatal/nonfatal MI and HF hospitalizations
Fatal and nonfatal MI
HF hospitalization 10
RRR 24%
AR 5.2% vs 6.8% P < 0.001
2.0
RRR 39% AR 1.0% vs 1.7%
P = 0.002
Placebo
There were fewer fatal and nonfatal MIs (5.2%) in the perindopril group compared with placebo (6.8%); the relative risk reduction associated with perindopril was 24% (P < 0.001).1
Heart failure requiring hospital admission occurred in 1.0% of the perindopril group vs 1.7% of the placebo group, yielding a relative risk reduction of 39% (P = 0.002).
Placebo 8
1.5 6
Perindopril 8 mg
Perindopril 8 mg
Events
(%)
1.0 4
0.5 2
0.0 1 2 3 4 5 1 2 3 4 5
Years
Years
AR = absolute risk (perindopril vs placebo)
EUROPA Investigators. Lancet. 2003;362:782–8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

8. EUROPA: Benefit of ACEI on primary and secondary outcomes
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EUROPA: Benefit of ACEI on primary and secondary outcomes
N = 12,218
Perindopril (%)
(n = 6110)
Placebo (%)
(n = 6108)
Favors
perindopril
Favors
placebo
CV mortality, MI, cardiac arrest
Total mortality, MI, UA, cardiac arrest
CV mortality, MI
Total mortality
CV mortality
Fatal/nonfatal MI
8.0
14.8
7.9
6.1
3.5
5.2
9.9
17.1
9.8
6.9
4.1
6.8
Perindopril was associated with reductions in the primary and all secondary endpoints, although the outcomes did not reach statistical significance for some endpoints.1
In particular, the perindopril group had a 14% reduction (95% CI, 6%–21%; P = ) in total mortality, nonfatal MI, unstable angina, and cardiac arrest, which was the original primary endpoint of the study.
Perindopril significantly reduced fatal and nonfatal MI.
0.5
1.0
2.0
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

9. EUROPA: Benefit of ACEI on selected secondary outcomes
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EUROPA: Benefit of ACEI on selected secondary outcomes
N = 12,218
Perindopril (%)
(n = 6110)
Placebo (%)
(n = 6108)
Favors
perindopril
Favors
placebo
Unstable angina
Cardiac arrest
Stroke
Revascularization
HF w/hospital admission
5.6
0.1
1.6
9.4
1.0
6.0
0.2
1.7
9.8
Revascularizations, stroke, and heart failure were infrequent in both groups.1
The fact that revascularizations were not reduced significantly might be explained by the low rate of either percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG) among patients, as is expected in a low-risk population.
As noted earlier, the risk of hospitalizations for heart failure was significantly reduced by 39% (95% CI, 17%–56%; P = 0.002).
0.5
1.0
2.0
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

10. EUROPA: Consistent benefits in predefined subgroups
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EUROPA: Consistent benefits in predefined subgroups
N = 12,218
Primary events (%)
Perindopril (n = 6110)
Placebo (n = 6108)
Favors
perindopril
Favors
placebo n
Male Female ≤ –65 ≥66
10,
Benefits of perindopril on the primary endpoint were consistent for all patients, across all predefined subgroups.1
Outcome was improved in both men and women and in all age groups, including younger patients (age ≤55 years).
Age (years)
0.5
1.0
2.0
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

11. EUROPA: Consistent benefits in predefined subgroups (continued)
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EUROPA: Consistent benefits in predefined subgroups (continued)
Primary events (%)
Previous MI No previous MI
Previous revascularization No previous revascularization
Hypertension No hypertension
Diabetes mellitus No diabetes mellitus
,716
Perindopril (n = 6110)
Placebo (n = 6108)
Favors
perindopril
Favors
placebo n
Results in prespecified subgroups indicate a benefit of treatment in a broad population of patients with stable CAD and no evidence of heart failure.1
Outcome was improved among patients with and without hypertension, diabetes, or previous MI, and in those who had or had not undergone previous revascularization.
0.5
1.0
2.0
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

12. EUROPA: Benefit of perindopril was on top of recommended medications
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EUROPA: Benefit of perindopril was on top of recommended medications
Primary events (%)
Favors
perindopril
Favors
placebo
Perindopril (n = 6110)
Placebo (n = 6108)
Lipid-lowering drug No lipid-lowering drug
-blockers No -blockers
Calcium channel blockers No calcium channel blockers
Perindopril showed additional benefits for patients on (recommended) concomitant therapy, including lipid-lowering drugs and beta-blockers.1
More than 90% of patients in EUROPA were on antiplatelet therapy, which was mostly recorded as aspirin.
0.5
1.0
2.0
EUROPA Investigators. Lancet. 2003;362:782-8.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:

13. VBWG
EUROPA: Risk reduction with perindopril stratified by baseline systolic BP level
N = 12,218
Baseline SBP (mm Hg)
<120
120 to <140
140
EUROPA investigators evaluated whether the CV benefits in perindopril-treated patients were related to baseline BP and its subsequent reduction.1
The mean systolic/diastolic BP reduction was 5/2 mm Hg lower in the perindopril group compared with placebo (see slide).
There was no interaction between treatment effect and systolic BP reduction.
Prevention of CV events with perindopril 8 mg did not depend on the patient’s BP, although the benefit tended to be greater in the group with the lowest baseline systolic BP. 5 10
Primary endpoint relative risk reduction with perindopril (%) 15 20 17 18 25
No interaction between treatment and SBP: P = 0.464 30 35 40 39
Remme WJ. Circulation. 2004;110(suppl):III-628.
1. Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary disease does not depend on blood pressure and its reduction: Results from the EUROPA study. Circulation. 2004;110(suppl):III-628. Abstract 2919.

14. VBWG
EUROPA: Systolic BP reduction during run-in did not affect risk reduction during trial
N = 12,218
RRR 20%
RRR 18% 12
n = 1841 10
n = 4263
n = 1804
Prior to randomization, all 12,218 patients in the EUROPA study participated in a 4-week run-in period in which they received perindopril 8 mg. This enabled investigators to evaluate the effect of BP lowering on subsequent CV events during the study.1
Systolic BP remained unchanged during the run-in period in 3645 patients, whereas it decreased in 8566 patients. There was no difference in the incidence of primary outcome between groups, which indicates that outcomes were not influenced by either baseline BP or subsequent BP reduction.
This suggests that other mechanisms, including direct antiatherosclerotic effects of ACE inhibitors, may be implicated. 8
n = 4303
Primary event (%) 6 4 2
SBP decrease
during run-in
No SBP decrease
during run-in
Placebo
Perindopril
Run in = 4 weeks when all patients received perindopril 8 mg
Remme WJ. Circulation. 2004;110(suppl):III-628.
1. Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary disease does not depend on blood pressure and its reduction: Results from the EUROPA study. Circulation. 2004;110(suppl):III-628. Abstract 2919.

15. EUROPA vs HOPE: Inclusion criteria
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EUROPA
Age ≥18 years
Females: 15%
No clinical HF
Documented CAD including
Previous MI, PCI/CABG
Angiographic evidence of CAD with/without previous coronary event
Positive stress test (men)
HOPE
Age ≥55 years
Females: 27%
No HF or LV dysfunction
High-risk of CV events with history of
CAD, stroke, or peripheral vascular disease
Diabetes + ≥1 CV risk factor (hypertension, dyslipidemia, smoking, microalbuminuria)
EUROPA and the HOPE (Heart Outcomes Prevention Evaluation) study were the first randomized prospective trials aimed at determining the effects of ACE inhibitors on CV events in patients with stable CAD but without overt heart failure.1,2
The findings of EUROPA extend the observations of the HOPE study, in which CV events were reduced in high-risk patients with or at risk for vascular disease.
As the slide shows, HOPE patients were at higher risk than EUROPA (discussed elsewhere in this kit).
HOPE recruited patients age ≥55 years whereas EUROPA recruited patients age ≥18 years.
HOPE patients had CV disease or diabetes plus ≥1 other CV risk factor whereas EUROPA patients were recruited based on angiographic evidence of CAD with/without a previous coronary event. Men with chest pain who had a positive stress test were eligible to enroll in EUROPA.
HOPE patients were at higher risk than EUROPA
EUROPA Investigators. Lancet. 2003;362: HOPE Study Investigators. N Engl J Med. 2000;342:
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
2. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:

16. EUROPA vs HOPE: Study populations
VBWG
EUROPA
HOPE
Age, mean (yrs) 60 66
BP (mm Hg)
137/82
139/79
Known CAD (%)
MI (%)
PVD (%)
Stroke/TIA (%)
Revascularization (%)
Diabetes (%)
Hypertension (%)
Hypercholesterolemia (%)
100 65 7 3 58 12 27 63 80 53 43 11 44 39 47
EUROPA and HOPE were both conducted in patients at risk for CV events, but due to key differences in baseline risk factors, the HOPE population was a higher-risk group.1,2
EUROPA patients were younger than HOPE patients (60 vs 66 years). One third of EUROPA patients were <55 years old.
Fewer EUROPA patients had diabetes (12% vs 39%) or hypertension (27% vs 47%).
More EUROPA patients had undergone revascularization (58% vs 44%).
Differences in baseline characteristics suggest that HOPE participants were at higher risk for CV events than the EUROPA population.
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled multicentre trial (the EUROPA study). Lancet. 2003;362: Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin- converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:

17. 80% higher annual rate of CV and total mortality in HOPE
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EUROPA vs HOPE: Event rates in placebo groups reflect differences in baseline risk
3.0
2.7
2.5
2.0
1.8
Annualized
event rate
in placebo groups
(%)
The lower risk level in EUROPA patients is clearly indicated by the higher rates of adverse events in the HOPE placebo group.1,2
Annualized event rates in the placebo groups for both trials are shown on the slide.
The annual rate of major adverse events was 40% to 80% higher in HOPE compared with EUROPA.
1.5
1.5
1.0
1.0
0.5
0.0
CV mortality
Total mortality
EUROPA
HOPE
80% higher annual rate of CV and total mortality in HOPE
EUROPA Investigators. Lancet. 2003;362: HOPE Study Investigators. N Engl J Med. 2000;342:
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
2. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:

18. EUROPA vs HOPE: Treatment more intensive in EUROPA than in HOPE
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EUROPA vs HOPE: Treatment more intensive in EUROPA than in HOPE
Baseline medication
100 92 80 75 62
The rate of concomitant therapy in EUROPA, including antiplatelet drugs (mostly aspirin), beta-blockers, and lipid-lowering drugs, was higher than in the HOPE study.1,2 57 60 % 39 40 28 20
Antiplatelet drugs*
Beta- blockers
Lipid- lowering drugs
EUROPA
HOPE
EUROPA Investigators. Lancet. 2003;362: HOPE Study Investigators. N Engl J Med. 2000;342:
*Mostly aspirin
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
2. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:

19. EUROPA: Clinical implications
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EUROPA: Clinical implications
In optimally treated CAD patients, perindopril 8 mg significantly reduced
CV mortality + nonfatal MI + cardiac arrest: 20%
CV mortality + nonfatal MI: 19%
Fatal + nonfatal MI: 24%
Heart failure hospitalization: 39%
Benefits exhibited on top of recommended therapy (aspirin, -blockers, lipid-lowering agents)
Benefits consistent across all predefined subgroups
Baseline BP and changes in BP had no significant impact on outcome
The results of the EUROPA study showed that in a broad population of CAD patients without heart failure, treatment with perindopril 8 mg reduced the primary outcome (CV mortality, nonfatal MI, and resuscitated cardiac arrest) by 20%.1
CV mortality and nonfatal MI were reduced by 19%.
Heart failure hospitalizations were reduced by 39%.
These benefits were seen in persons receiving a high rate of preventive therapy, including aspirin, beta-blockers, and lipid-lowering drugs, and were consistent among all patients in the perindopril arm.
Baseline BP and changes in BP had no significant impact on the primary outcome.2
Overall, the results suggest that treatment with perindopril should be considered in all CAD patients, including patients who are at low risk.
Treatment with perindopril should be considered in all CAD patients, including patients at low risk
EUROPA Investigators. Lancet. 2003;362: Remme WJ. Circulation. 2004;110(suppl):III-628.
EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
Remme WJ. Prevention of cardiovascular events by perindopril in patients with stable coronary disease does not depend on blood pressure and its reduction: Results from the EUROPA study. Circulation. 2004;110(suppl):III-628. Abstract 2919.

20. VBWG
PEACE: Prevention of Events with Angiotensin Converting Enzyme inhibition
Objective: Assess effect of ACEI in patients with stable CAD and normal/slightly reduced LV function
Design: N = 8290 randomized
Treatment: Trandolapril 4 mg or placebo
Follow-up: 4.8 years
Primary
outcome: CV death, nonfatal MI, CABG, PCI
The PEACE (Prevention of Events With Angiotensin Converting Enzyme Inhibition) trial studied the effects of ACE inhibitors in patients with stable CAD and normal or slightly reduced LV function who were receiving conventional therapy.1
PEACE patients were similar to the patient population in EUROPA.
The study randomized 8290 patients to trandolapril 4 mg or placebo; mean follow-up was 4.8 years.
The primary outcome was CV death, nonfatal MI, and revascularization for PCI or CABG.
PEACE Trial Investigators. N Engl J Med. 2004;351:
1. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:

21. PEACE: Primary outcome
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PEACE: Primary outcome
CV death, MI, CABG/PCI; N = 8290 30
4% Risk reduction
HR 0.96 (0.88–1.06)
P = 0.43
Placebo
Treatment with trandolapril 4 mg/day had a neutral effect on the primary outcome (CV death, MI, or coronary revascularization).1
The incidence of the primary outcome was 21.9% in the trandolapril group vs 22.5% in the placebo group, yielding a 4% relative risk reduction in the trandolapril group (hazard ratio [HR] 0.96; 95% CI, 0.88–1.06), but it was not statistically significant (P = 0.43).
Although the PEACE and EUROPA populations were similar, the outcomes with the two ACE inhibitors were not.
PEACE results contrast with HOPE and EUROPA, which both show comparable and consistent benefits of treatment. 25
Trandolapril
4 mg 20
Patients (%) 15 10 5 1 2 3 4 5 6
Time (years)
PEACE Trial Investigators. N Engl J Med. 2004;351:
1. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:

22. EUROPA vs PEACE: Differences in compliance
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EUROPA vs PEACE: Differences in compliance
3 Years
100 93 81 80
74.5
68.6
Adherence with the study medication in the PEACE trial was lower than in EUROPA.
At 3 years, 81% of EUROPA patients assigned to perindopril continued the drug compared with only 74.5% of PEACE patients assigned to trandolapril.1,2
At 3 years, 93% of EUROPA patients in the perindopril group were on the target dose (8 mg) compared with only 68.6% of PEACE patients who were on the target dose for trandolapril (4 mg).
This data suggests that the ACE inhibitor arm in the PEACE study was undertreated.
Patients
(%) 60 40 20
On study ACEI
At target ACEI dose
EUROPA (perindopril 8 mg)
PEACE (trandolapril 4 mg)
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
2. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:

23. ACEI trials in CAD without HF: Primary outcomes
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ACEI trials in CAD without HF: Primary outcomes
EUROPA
CV death/MI/cardiac arrest
HOPE CV death/MI/stroke 14 20
Placebo 12
Placebo 10 15
20% Risk reduction
HR 0.80 (0.71–0.91)
P =
22% Risk reduction
HR 0.78 (0.70–0.86)
P < 0.001
Ramipril 10 mg % 8 % 6 10
Perindopril 8 mg 4 5 2
Four major trials have studied the effect of long-term ACE inhibition in CAD patients with normal LV function.
EUROPA: Perindopril 8 mg demonstrated a 20% reduction in the primary outcome (CV death, MI, and cardiac arrest) in relatively low-risk patients.1
HOPE: Ramipril 10 mg demonstrated a 22% reduction in the primary outcome (CV death, MI, and stroke) in high-risk patients.2
EUROPA and HOPE achieved comparable benefits, even though EUROPA patients were at lower risk and more intensively treated.
PEACE: In contrast, trandolapril 4 mg demonstrated a neutral effect on the primary outcome (CV death, MI, and revascularization) in lower-risk patients.3
QUIET: This trial also demonstrated a neutral effect of ACE inhibition on a composite of all major CV outcomes. Quinapril 20 mg was administered to 1750 patients who had undergone coronary angioplasty or atherectomy. Subjects were randomized to treatment or placebo and followed for a mean of 27 months.4
The proposed reasons for the differences among the trial findings include: a low-risk population; the drug or dosage; too brief a study period (QUIET); or underpowered (PEACE) to demonstrate a reduction in MI and CV death.4,5 1 2 3 4 5 1 2 3 4
Time (years)
Time (years)
PEACE CV death/MI/CABG/PCI
QUIET All CV events
Placebo 30 50
Quinapril 20 mg 25 40
4% Risk increase
HR 1.04 (0.89–1.22)
P = 0.6 20
4% Risk reduction
HR 0.96 (0.88–1.06)
P = 0.43 30 %
Trandolapril
4 mg % 15
Placebo 20 10 10 5 1 2 3 4 5 6 1 2 3
Time (years)
Time (years)
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:
HOPE Study Investigators. N Engl J Med. 2000;342:
Pitt B et al. Am J Cardiol. 2001;87:
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular high-risk patients. N Engl J Med. 2000;342: PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351: Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87: Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction–May they rest in PEACE? N Engl J Med. 2004;351:

24. ACEI trials in CAD patients without HF: Key baseline characteristics
VBWG
ACEI trials in CAD patients without HF: Key baseline characteristics
EUROPA HOPE PEACE QUIET
N 12,
Follow-up (yrs)
ACEI/dose (mg) P R T Q-20
Age (yrs)
Men (%)
CAD/Cor rev (%) / / / /100
Diabetes (%)
Hypertension (%)
Prior MI (%)
Ejection fraction (%) NA NA
PVD (%) NA NA
All four trials were conducted in at-risk patients, but there were important differences in baseline risk factors.1-4
More patients in HOPE had diabetes.
More patients in PEACE, QUIET, and EUROPA had undergone coronary revascularization.
HOPE patients were older.
These differences in baseline characteristics suggest that patients in EUROPA, PEACE, and QUIET had similar risk levels compared with HOPE participants, who were at higher risk.
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:
PEACE Trial Investigators. N Engl J Med. 2004;351:
Pitt B et al. Am J Cardiol. 2001;87:
EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:
PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:
Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:

25. EUROPA, HOPE, PEACE, QUIET: Totality of trial evidence
VBWG
EUROPA, HOPE, PEACE, QUIET: Totality of trial evidence
Event rate (%) P
ACEI
Placebo
Favors ACEI
Favors placebo
All-cause death
7.5
8.9
0.0004
Combined analyses of the data from EUROPA, HOPE, PEACE, and QUIET show that treatment with ACE inhibition reduced the risk of total mortality in CAD patients without heart failure.1-5
There was an overall relative risk reduction in total mortality of 14% (P < ).
MI, stroke, and revascularizations were also significantly reduced.
This analysis confirms the clear benefits of ACE inhibitors in patients with vascular disease and no LV dysfunction.
0.86
6.4
7.7
0.0004 MI
0.86
2.1
2.7
0.0004
Stroke
0.77
Revascularization
15.5
16.3
0.025
0.93
0.5
0.75 1
1.25
Odds ratio
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).
EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:
PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:
Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:
Pepine CJ, Probstfield JL. A HOPE for PEACE? Update on the role of ACE inhibition in CAD patients. In: Vascular Biology in Clinical Practice: A CME monograph. University of Florida College of Medicine: Gainesville, Fla: 2004;6(3).

26. EUROPA, HOPE, PEACE, QUIET: CV therapies at entry/during study
VBWG
EUROPA, HOPE, PEACE, QUIET: CV therapies at entry/during study
EUROPA
HOPE
PEACE
QUIET
Antiplatelet agents (%) 92 76 91 73
-Blockers (%) 62 40 60 26
Lipid-lowering agents (%)
58/69*
29/49† 70
0/14†
Calcium antagonists (%) 31 47 36
0/7†
Diuretics (%) 9 15 13 NA
Patients in all four trials were treated with ACE inhibitors in addition to other recommended cardioprotective therapies, including antiplatelet agents (mostly aspirin), beta-blockers, lipid-lowering agents, and antihypertensive agents.1-4
However, patients in EUROPA and PEACE were more aggressively treated, reflecting changes in clinical practice at the time these trials were initiated.
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:
PEACE Trial Investigators. N Engl J Med. 2004;351:
Pitt B et al. Am J Cardiol. 2001;87:
*at 3 yrs
†at study end
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342: PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351: Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:

27. VBWG
ACEI outcome trials in CAD patients without HF: BP at entry/during study
BP (mm Hg)
EUROPA
HOPE
PEACE
QUIET
At entry
137/82
139/79
133/78
123/74
BP in ACEI group
128/78*
136/76†
129/74‡ NA
Difference in mean BP during follow-up (ACEI vs placebo)
5/2
3.3/1.2
3/1.2
Average baseline BP in EUROPA and HOPE were similar, and both were higher than in PEACE and QUIET (see slide).1-4
During the run-in period in EUROPA (when all patients received perindopril), BP was lowered to 128/78 mm Hg and maintained in the perindopril group. The average BP difference between the treated and placebo groups was 5/2 mm Hg.1
HOPE reported a mean BP of 136/76 mm Hg in the ramipril group at the end of the study. The average BP difference between the treated and placebo groups was 3.3/1.2 mm Hg.2
In PEACE, mean BP after 36 months was 129/74 mm Hg; the mean BP difference between the treated and placebo groups was 3/1.2 mm Hg.3
Changes in BP were not reported in QUIET.4
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:
PEACE Trial Investigators. N Engl J Med. 2004;351:
Pitt B et al. Am J Cardiol. 2001;87:
*Run-in BP maintained during study †at study end
‡at 3 years
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342: PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351: Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:

28. HOPE, EUROPA, PEACE, QUIET: Differences in baseline CV risk
VBWG
HOPE, EUROPA, PEACE, QUIET: Differences in baseline CV risk
3.0
2.7
2.0
2.0
1.8
Annualized event rate in placebo group
(%/yr)
The differences in baseline risk in the four studies is evident in the annual rate of fatal and nonfatal CV events in the respective placebo groups.1-4
Annualized rates of CV death and nonfatal MI were lower (and roughly similar) in the placebo groups of PEACE, EUROPA, and QUIET.1,3,4
Patients in the placebo arm of HOPE had the highest annualized rate of CV death and nonfatal MI, reflecting the high-risk population.2
1.5
1.1
1.0
1.0
0.8
0.7
0.0
CV death Nonfatal MI
HOPE Study Investigators. N Engl J Med. 2000;342:
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE Trial Investigators. N Engl J Med. 2004;351:
Pitt B et al. Am J Cardiol. 2001;87:
HOPE
EUROPA
PEACE
QUIET
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342: PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351: Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:

29. EUROPA, HOPE: Consistent benefit of ACEI on CV outcomes
VBWG
EUROPA, HOPE: Consistent benefit of ACEI on CV outcomes
Event rate (%)
Favors
ACE inhibitor
Favors
Placebo
ACEI
Placebo
Composite outcome
CV mortality
Myocardial infarction
Stroke
Cardiac arrest
EUROPA and HOPE showed consistent benefits with ACE inhibition in a broad population of stable CAD patients without heart failure.1,2
Treatment significantly reduced the primary composite outcomes of CV death, MI, and resuscitated cardiac arrest in EUROPA, and CV mortality, nonfatal MI, and stroke in HOPE. – In both studies, treatment reduced the individual outcomes of MI and CV mortality.
Significant reductions in stroke and cardiac arrest were seen in HOPE and showed favorable trends in EUROPA. The failure to reach statistical significance reflects the lower-risk EUROPA population and the low incidence of these events.
HOPE (ramipril 10 mg)
EUROPA (perindopril 8 mg)
0.5
1.0
1.5
Hazard ratio
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:
EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:

30. VBWG
Should all patients with stable CAD without HF receive an ACEI? Interpreting evidence
Totality of clinical trial evidence supports ACEI for treatment of stable CAD patients with/without HF
Benefits have been shown in patients at all levels of risk
All ACEIs may not have comparable effects for all indications
Consider evidence and guidelines in selection of an ACEI and dose.
Both ramipril and perindopril reduce risk of CV events in stable CAD patients without HF
– Ramipril 10 mg has proven efficacy in CAD patients ≥55 yrs
– Perindopril 8 mg has proven efficacy in CAD patients ≥18 yrs
Pooled data from EUROPA, HOPE, PEACE, and QUIET support the use of ACE inhibition in stable patients with CAD and without clinical signs of heart failure, including those at low risk.1-4
The cardioprotective findings seen in the EUROPA and HOPE studies do not necessarily indicate a cardioprotective class effect of ACE inhibitors. Dose, as well as lipophilicity, tissue penetration, or other features of individual agents, may be important determinants of efficacy.1
While the decision of which agent to use is based on the physician’s judgment, evidence-based medicine and current guidelines are important considerations in forming treatment decisions.
Perindopril 8 mg and ramipril 10 mg have each shown significant benefits in CAD patients without heart failure. Ramipril 10 mg was studied in high-risk CAD patients compared with perindopril 8 mg, which was studied in a broader population with CAD, but not necessarily at high risk.
Pitt B. N Engl J Med. 2004;351:
EUROPA Investigators. Lancet. 2003;362:782-8.
HOPE Study Investigators. N Engl J Med. 2000;342:
PEACE Trial Investigators. N Engl J Med. 2004;351:
1. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction–May they rest in PEACE? N Engl J Med. 2004;351:
2. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:
3. HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:
4. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:

31. VBWG
Evidence-based medicine: Updated guide-lines for ACEI in CAD patients without HF
“ACE inhibitors should be used as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease.” R.J. Gibbons et al.
“The HOPE trial…confirms that the ACE inhibitor ramipril reduced CV death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence of heart failure.” R.J. Gibbons et al.
EUROPA “showed that an ACE inhibitor can have a vasculoprotective effect in patients at lower risk than those enrolled in the HOPE study.” V. Snow et al.
The updated ACC/AHA [American College of Cardiology and the American Heart Association] guidelines advise the routine use of ACE inhibitors in CAD patients without heart failure. This update is based on the HOPE study, which showed benefits in patients who were at high risk for, or had, vascular disease without heart failure.1
In 2004, following publication of the EUROPA study, the American College of Physicians (ACP) recognized that EUROPA had extended the results of HOPE to lower-risk patients than those enrolled in the HOPE study.2
The ACP guidelines mention that the EUROPA study enrolled a group of patients similar to HOPE, but also included those with positive stress test results.2
Gibbons RJ et al ACC/AHA Practice Guidelines. July 2005.
Snow V et al. Ann Intern Med. 2004;141:562-7.
1. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al; American College of Cardiology/American Heart Association Task Force on practice guidelines. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—Summary article: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Committee on the Management of Patients With Chronic Stable Angina. J Am Coll Cardiol. 2003;41: Full report available at: Accessed June 2005.
2. Snow V, Barry P, Fihn SD, Gibbons RJ, Owens DK, Williams SV, et al; American College of Physicians/American College of Cardiology Chronic Stable Angina Panel. Primary care management of chronic stable angina and asymptomatic suspected or known coronary artery disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004;141:

32. ACP guidelines for ACEI in chronic stable angina or asymptomatic CAD
VBWG
ACP guidelines for ACEI in chronic stable angina or asymptomatic CAD
Symptomatic patients with chronic stable angina (Level of evidence: A)
Asymptomatic patients – CAD with systolic dysfunction (Level of evidence: A) – Diabetes with CAD (Level of evidence: A) – Diabetes without CAD (Level of evidence: B)
The ACP recommendations for ACE inhibitors (based on ACC/AHA guidelines), are summarized on the slide.1
Use of ACE inhibitors is recommended in all symptomatic patients.
The ACP guidelines also recommend ACE inhibitors for asymptomatic patients with CAD and systolic dysfunction, and in patients with diabetes both with and without CAD.
Snow V et al. Ann Intern Med. 2004;141:562-7.
1. Snow V, Barry P, Fihn SD, Gibbons RJ, Owens DK, Williams SV, et al, for the American College of Physicians/American College of Cardiology Chronic Stable Angina Panel. Primary care management of chronic stable angina and asymptomatic suspected or known coronary artery disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004;141:

33. VBWG
PERSUADE: PERindorpil SUbstudy of coronary Artery disease and DiabEtes: The diabetic substudy of EUROPA
Objective: Investigate the effect of long-term treatment with perindopril added to standard therapy on CV events in diabetic patients with CAD and without heart failure
Population: N = 1502 with known diabetes at randomization
Treatment: Perindopril 8 mg (n = 721) or placebo (n = 781)
Follow-up: years
PERSUADE, a substudy of EUROPA, investigated the effect of perindopril on CV mortality, nonfatal MI, and cardiac arrest in diabetic patients with CAD but without heart failure.1
In EUROPA, 1502 (12%) patients had an established diagnosis of diabetes at baseline. These patients form the population in the PERSUADE study. (Although PERSUADE was a preplanned substudy of EUROPA, there was no attempt to achieve a prespecified target proportion of diabetic patients.)
Patients were randomized to perindopril 8 mg once daily (n = 721) or placebo (n = 781) and followed for a median of 4.2 years.
Daly CA et al. Eur Heart J. 2005;26:
1. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2004;26:

34. PERSUADE: Primary outcome
VBWG
PERSUADE: Primary outcome
CV death, MI, cardiac arrest 20
RRR: 19%
95% CI: –7% to 38%
P = 0.13
Placebo 16
The primary endpoint of CV death, nonfatal MI, and resuscitated cardiac arrest occurred in 91 (12.6%) patients in the perindopril group vs 121 (15.5%) patients in the placebo group, with a relative risk reduction of 19% (95% CI, –7% to 38%; P = 0.13).1
Kaplan–Meier curves indicate that, at ~3 years, the cumulative incidence of the primary endpoint in the perindopril group began to decrease in comparison to the placebo group, and persisted to the end of the study.
The 19% risk reduction in PERSUADE was of similar relative magnitude to the 20% risk reduction observed in the main EUROPA population. However, the absolute effect was greater because of a higher event rate in the diabetic subgroup than in the overall EUROPA population.
Perindopril 8 mg 12
Cumulative frequency
(%) 8 4 1 2 3 4 5
Years from randomization
Daly CA et al. Eur Heart J. 2005;26:
1. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J. 2004;26:

35. PERSUADE and EUROPA: Comparable outcomes
VBWG
PERSUADE and EUROPA: Comparable outcomes
Perindopril n = 6110
n = 721
Placebo n = 6108
n = 781 
RRR (%)
EUROPA
PERSUADE
Favors
perindopril
Favors
placebo
CV mortality, nonfatal MI, cardiac arrest
488
603 20 91
121 19
375
420 11
Total mortality 73 93 15
The effects of treatment with perindopril on secondary outcomes in the diabetic population of PERSUADE and the overall EUROPA population are comparable.1
The primary outcome and individual secondary outcomes in PERSUADE showed trends in favor of treatment that were similar to EUROPA.
The incidence of non–Q-wave MI was lowered significantly by 34% (95% CI, 0.1%–56%; P = 0.048) in PERSUADE. The relative risk reductions in MI (23%) and hospitalizations for heart failure (46%) closely match observations in EUROPA.
Given the relatively small subgroup of patients in PERSUADE, the study did not show statistical significance, but there was no heterogeneity observed between EUROPA and PERSUADE, indicating that the benefit of perindopril in diabetic patients was similar to the entire EUROPA population.2
215
249 14
CV mortality 47 60 16
320
418 24
Fatal and nonfatal MI 56 78 23
212
273 23
Non–Q-wave infarction 37 60 34
Stroke 98
102 4 18 23 15 63
103 39
Heart failure 13 26 46
0.5
1.0
2.0
EUROPA
PERSUADE
Daly CA et al. Eur Heart J. 2005;26:
1. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2004;26:
2. Verma S, Leiter LA, Lonn EM, Strauss MH. Perindopril in diabetes: Perspective from the EUROPA substudy, PERSUADE. Eur Heart J. 2005;26:

36. PERSUADE and MICRO-HOPE: Consistency of benefit
VBWG
PERSUADE and MICRO-HOPE: Consistency of benefit
Favors ACEI
Favors placebo
Primary outcome
PERSUADE results indicated a consistent trend toward benefit across primary and secondary outcomes in the perindopril 8-mg group.1
The confidence intervals overlapped with unity, indicating that the results did not reach statistical significance.
However, as shown, the results are consistent with those of the diabetic substudy of HOPE, MICRO-HOPE, which enrolled 3577 patients with diabetes (38%).1,2
Total mortality
MICRO-HOPE
(N = 3577)
CV mortality
PERSUADE
(N = 1502)
All MI
Stroke
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Relative risk (95% CI)
Daly CA et al. Eur Heart J. 2005;26:
HOPE Study Investigators. Lancet. 2000;355:253-9.
1. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2004;26:
2. HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:

37. PERSUADE: Clinical implications
VBWG
PERSUADE: Clinical implications
Perindopril 8 mg once daily reduced CV events in patients with CAD and diabetes
Relative risk reduction in primary and secondary outcomes with perindopril was similar to EUROPA
Results extend the benefit of ACEI shown in MICRO-HOPE to a lower-risk population with diabetes and CAD
Long-term treatment with perindopril 8 mg daily reduced CV events in patients with CAD and diabetes.1
The trend towards a reduction in CV events in the PERSUADE population was similar to the benefit shown in the overall EUROPA population as well as in previous trials of ACE inhibition in diabetic patients.1
The PERSUADE findings extend the benefit of ACE inhibitors shown in MICRO-HOPE to a lower-risk population with diabetes and CAD; the trend toward a reduction in risk was observed beyond the consistent use of other secondary-preventive therapies.
The PERSUADE results along with the well-established MICRO-HOPE data underscore the important role of ACE inhibition for vascular protection in the clinical management of high-risk patients with diabetes.2
Daly CA et al. Eur Heart J. 2005;26:
1. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2004;26:
2. Verma S, Leiter LA, Lonn EM, Strauss MH. Perindopril in diabetes: Perspective from the EUROPA substudy, PERSUADE. Eur Heart J. 2005;26:

38. Are all ACEIs the same? Survival 1-year post-MI by ACEI at discharge
VBWG
Are all ACEIs the same? Survival year post-MI by ACEI at discharge
N = 7512, Canadian pharmacy database
100
Pilote et al conducted a retrospective observational study using a Canadian pharmacy database to determine whether all ACE inhibitors have a similar effect in reducing mortality among elderly survivors of MI.1
The study participants (N = 7512) were age ≥65 years who had a recent MI, filled a prescription for an ACE inhibitor within 30 days of discharge, and continued to receive the same drug for at least 1 year.
Perindopril and ramipril were associated with lower mortality over 1 year compared with several other ACE inhibitors (see slide).
Results suggest that not all ACE inhibitors within the same class should be considered to have the same effect.1
Given that this was a retrospective, observational study of an administrative database, a large randomized clinical trial or prospective study would be necessary to confirm these results. 90
Unadjusted
cumulative survival (%)
Ramipril
n = 905
Perindopril
n = 243
Lisinopril
n = 2201 80
Enalapril
n = 2577
Quinapril
n = 276
Fosinopril
n = 889
Captopril
n = 421
P < log-rank 2 4 6 8 10 12
Months
Reference = ramipril
Pilote L et al. Ann Intern Med. 2004;141:
1. Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: A class effect? Ann Intern Med. 2004;141:

39. Multiple mechanisms of ACEI in atherosclerotic CVD
VBWG
Multiple mechanisms of ACEI in atherosclerotic CVD
Blood pressure lowering
Cardioprotective effects
 Preload and afterload
 LV mass
 Sympathetic stimulation
 Reperfusion injury
Improved myocardial remodeling
Vasculoprotective effects
Direct antiatherogenic
Enhance endogenous fibrinolysis
Inhibit platelet aggregation
Antimigratory for mononuclear cells
 Matrix formation
Improve endothelial function
Antioxidant
Anti-inflammatory
Protection from plaque rupture
Improved arterial compliance and tone
• Current experimental evidence and mechanistic studies in humans suggests that ACE inhibitors reduce the risk associated with CV disease through multiple cardiac and vascular protective actions.
These protective actions are a result of decreased Ang II formation, prevented breakdown of bradykinin, and, possibly, the modulating action of other peptides.1
In addition to their effect on BP, ACE inhibitors exert specific cardioprotective effects related to reductions in preload and afterload, in LV mass, in sympathetic stimulation, and in reperfusion injury, as well as a restoration of the balance between oxygen supply and demand.
• The vascular protective effects of ACE inhibitors are directly related to antiproliferative effects and antiatherogenic properties, and to favorable effects on thrombotic mechanisms, arterial compliance, and tone.
ACE inhibitors are lipid neutral and improve glucose metabolism.
Metabolic syndrome
Lipid neutral
Improved glucose metabolism
Lonn E et al. Eur Heart J. 2003;5(suppl):A43-8.
1. Lonn E, Gerstein HC, Smieja M, Mann JFE, Yusuf S. Mechanisms of cardiovascular risk reduction with ramipril: Insights from HOPE and HOPE substudies. Eur Heart J. 2003;5(suppl):A43-A48.

40. Clinical trials of ARBs: CV outcomes
VBWG
Clinical trials of ARBs: CV outcomes
Trial (year)
Patients
(Follow-up)
Treatment BP
CV outcomes
LIFE (2002)
VALUE (2004)
Essential HTN
N = 9193
(4.8 years)
Essential HTN, high CV risk
N = 15,245
(4.3 years)
Losartan vs atenolol
Valsartan vs amlodipine
Similar 
Greater  with amlodipine (2.0/1.6 mm Hg)
13%  in primary outcome (CV death, MI, stroke) with ARB (P = 0.021) driven by 25%  in stroke (P = 0.001)
No difference in CV death/MI
The LIFE (Losartan Intervention For Endpoint reduction) study was a double-blind study comparing the effects of losartan with atenolol in hypertensive patients with LV hypertrophy (N = 9193). Mean follow-up was 4.8 years.1
BP reductions were similar in the losartan and atenolol groups (-30.2/16.6 mm Hg vs -29.1/16.8 mm Hg, respectively).
Compared with atenolol, the losartan group had a 13% reduction in primary outcome (CV death, MI, and stroke) (P = ), which was driven by a 25% reduction in stroke.
Rates of CV death and MI were similar in the losartan and atenolol groups.
The VALUE (Valsartan Antihypertensive Long-term Use Evaluation) study tested the hypothesis that in hypertensive patients at high CV risk (N = 15,425) and with the same level of BP control, a valsartan-based regimen would reduce cardiac mortality and morbidity more than an amlodipine-based regimen. Mean follow-up was 4.2 years.2
– BP control was more pronounced with amlodipine, especially in the early months of the study.
– For the primary outcome (composite of CV mortality and morbidity), there was no difference between the two treatment groups, but the trend favored amlodipine at 3 and 6 months.
Primary outcome similar at study end
Trend favors amlodipine at 3 and 6 months
Difficult to interpret due to BP difference
Dahlöf B et al. Lancet. 2002;359: Julius S et al. Lancet. 2004;363:
HTN = hypertension
1. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:
2. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet. 2004;363:

41. LIFE: Effects of ARB vs -blockade on primary outcome and components
VBWG
LIFE: Effects of ARB vs -blockade on primary outcome and components
N = 9193 with hypertension and ECG-LVH
Primary composite endpoint (CV death/MI/stroke)
Primary outcome components
(Losartan vs atenolol) 16
Results of the LIFE study show an adjusted risk reduction of 13.0% in the primary composite endpoint (CV death, MI and stroke) in the losartan group (P = 0.021).1
In comparing individual outcomes, losartan-based therapy reduced the risk of stroke by 25% compared with atenolol, despite almost identical BP control.
There were no significant differences between losartan and atenolol on CV mortality and fatal and nonfatal MI.
Adjusted RR 13.0%
P = 0.021
(losartan vs atenolol) 10 MI
Risk increase (%) 5 12
CV death
Stroke
Proportion of patients with first event (%)
Atenolol
P = 0.491 8
Losartan 5 10
Risk reduction (%) 4
P = 0.206 15 20 6 18 30 42 54 66 25
P = 0.001
Time (months)
LIFE = Losartan Intervention for Endpoint Reduction in Hypertension
Dahlöf B et al. Lancet. 2002;359:
1. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:

42. VALUE: Similar treatment effects on primary outcome at study end
VBWG
VALUE: Similar treatment effects on primary outcome at study end 14
Valsartan-based regimen 12 10
In the VALUE trial, Kaplan-Meier curves for the primary outcome of CV mortality and morbidity show there was no difference between treatment groups at study end.1
Proportion of patients with first event (%) 8 6
Amlodipine-based regimen 4 2
HR = 1.03; 95% CI 0.94–1.14; P = 0.49 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Julius S et al. Lancet. 2004;363:
1. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet. 2004;363:

43. VALUE: SBP and outcome differences during consecutive time periods
VBWG
VALUE: SBP and outcome differences during consecutive time periods
Primary outcome
Myocardial infarction
Time interval (mos)
∆ SBP (mm Hg)
Favors valsartan
Favors amlodipine
Favors valsartan
Favors amlodipine
In the VALUE trial, the primary outcomes of fatal and nonfatal cardiac disease at study end were similar in high-risk hypertensive patients treated with valsartan or amlodipine. But at 3 and 6 months, when BP control was substantially better in the amlodipine group, trends favored amlodipine.1
The disparity in BP control in the comparator groups makes it difficult to interpret the results. However, unequal BP reductions might account for the differences between groups in cause-specific outcomes such as MI.
The findings in VALUE emphasize how important it is to control BP as soon as possible in high-risk hypertensive patients—within weeks rather than months.
All study
2.2
0–3
3.8
3–6
2.3
6–12
2.0
12–24
1.8
24–36
1.6
36–48
1.4
Study end
1.7
0.5
1.0
2.0
4.0
0.5
1.0
2.0
4.0
Odds ratio
Odds ratio
VALUE = Valsartan Antihypertensive Long-Term Use Evaluation
Julius S et al. Lancet. 2004;363:
1. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet. 2004;363:

44. Evidence of benefit: ACEI vs ARB
VBWG
High risk condition
ACE inhibitor
ARB
Heart failure √
Post-MI
High CAD risk
Diabetes
Chronic kidney disease
Recurrent stroke prevention
Evidence from clinical trials supports the benefit of ACEIs in a wider range of patients with high risk conditions than for ARBs.1
ACEIs have the broadest impact of any class of drugs in CV medicine, reducing the risk of heart failure, MI, stroke, diabetes, and renal impairment.
In the JNC 7 hypertension guidelines, ACEIs are the only class of drugs for which all of the high-risk conditions listed here are recognized as compelling indications (ie, conditions for which there is substantial evidence of benefit).1
Evidence from clinical trials supports the use of ACEIs vs ARBs in a broader range of high-risk conditions
JNC 7. JAMA. 2003;289:
1. JNC 7. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA. 2003;289: