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Program outline

This program highlights the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial—providing an overview of ACE inhibition in patients with preserved left ventricular function, including the following topics:

• The RAAS and its role in atherosclerosis

• The role of ACE inhibition in CV risk reduction

• Update on recent trial data

• ACC/AHA recommendations of the role of ACE inhibition in post-MI patients

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Deleterious effects of angiotensin II

Ang IIAbnormal

vasoconstriction

ActivateSNS

Aldosterone

Vasopressin

Endothelin

PAI-1/thrombosis

Plateletaggregation

Superoxideproduction

CollagenVascular

smooth musclegrowth

Myocytegrowth

Remodeling

Burnier M, Brunner HR. Lancet. 2000;355:637-45.Brown NJ, Vaughn DE. Adv Intern Med. 2000;45:419-29.SNS = Sympathetic nervous system

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Ferrari R. ESC 2004; Munich.

Baseline 1 Year

Apoptosis (%)ecNOS activity (U/mg)

3.5

2.4

3.3

2.5

2.9

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0P < 0.05

1.3

6.8

4.7

7.87.0

0

1

2

3

4

5

6

7

8

9

P < 0.05

Healthy control Perindopril 8 mg Placebo

PERTINENT: ACEI improves endothelial function—Effects on cultivated HUVECs

HUVECs = human umbilical vein endothelial cells

Control Baseline 1 YearControl

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Ferrari R. ESC 2004; Munich.

Baseline 1 Year

18.3

14.817.7

12.4 12.3

0

5

10

15

20P < 0.05

Bradykinin25

Baseline 1 Year

Ang II

10.8

17.1

12.5

15.814.4

02468

1012141618 P < 0.05

Healthy control

Perindopril 8 mg

Placebo

PERTINENT: Effects of ACEI on bradykinin, Ang II, and TNF — Plasma analysis

Baseline 1 Year

TNF-

18.0

27.124.6

27.7 28.9

0

5

10

15

20

25

30

35 P < 0.05

pg/mL

pg/mL pg/mL

Control Control

Control

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Major clinical outcome trials of RAAS manipulationACE inhibitionAngiotensin receptor blockade

GISSI-3

ISIS-4AIRESAVESOLVD-PreventionTRACE

CHARM-Preserved

OPTIMAAL

VALIANT

SOLVD-Treat

CHARM-Added

CHARM-Alternative

ELITE II

Val-HeFT

CONSENSUS

HOPE

EUROPA

PEACE

QUIET

ALLHAT

ANBP2

INVEST

LIFE

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PEACE: Prevention of Events With Angiotensin Converting Enzyme Inhibition

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

Objective: To assess the effect of ACE inhibition added to conventional therapy in patients with stable CAD and normal or slightly reduced LV function

Design: 8290 patients randomized to trandolapril 4 mg or placebo

Follow-up: 4.8 years

PrimaryOutcome: CV death, nonfatal MI, CABG, PCI

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PEACE: Treatment effect on primary outcome

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

Years after randomization

30

20

10

15

5

1 2 3 4 5

25

06

Trandolapril

Placebo

No. at riskTrandolapril 4158 4017 3752 3506 3079 1963 969

Placebo 4132 3990 3719 3486 3027 1929 891

Incidence of primary

outcome (%)

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PEACE: Treatment effect on components of primary outcome and total deaths

Outcome Event rate (%) Hazard ratio (95% CI)

Trandolapril Placebo

Primary* 21.9 22.5 0.96 (0.88–1.06)

CV death 3.5 3.7 0.95 (0.76–1.19)

Nonfatal MI 5.3 5.3 1.00 (0.83–1.20)

CABG 6.5 7.1 0.91 (0.77–1.07)

PCI 12.4 12.0 1.03 (0.91–1.16)

All-cause death 7.2 8.1 0.83 (0.67–1.03)

Non-CV death 3.7 4.4 0.89 (0.76–1.04)

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.*CV death, nonfatal MI, and coronary revascularization

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HOPE, EUROPA: Overview

Study (Follow up) ACE inhibitor Key inclusion criteria Primary outcome

HOPE

N = 9297

(4.5 years)

Ramipril 10 mg Vascular disease* (80% had CAD)

LVEF ≥40%

Age ≥55 years

CV death, MI, stroke

EUROPA

N = 12,218 (4.2 years)

Perindopril 8 mg CAD

No heart failure

Age ≥18 years

CV death, MI, cardiac arrest

HOPE Investigators. N Engl J Med. 2000;342:145-53.EUROPA Investigators. Lancet. 2003;362:782-8.

*CV disease, peripheral artery disease, stroke or diabetes + ≥1 CV risk factor

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HOPE, EUROPA: Treatment benefit on primary and selected secondary outcomes

Event rate (%)

ACEI Placebo 14.0 17.8

8.0 9.9

6.1 8.1

3.5 4.1

9.9 12.3

4.8 6.2

3.4 4.9 1.6 1.7

0.8 1.3

0.1 0.2

Composite outcome

CV mortality

Myocardial infarction

Stroke

Cardiac arrest

FavorsACEI

Favorsplacebo

HOPE

EUROPA

EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

EUROPA = European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery DiseaseHOPE = Heart Outcomes Prevention Evaluation

Hazard ratio 0.5 1.0 1.5

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HOPE, EUROPA, PEACE, QUIET: CV event rate in placebo group

HOPE Investigators. N Engl J Med. 2000;342:145-53.EUROPA Investigators. Lancet. 2003;362:782-8.

PEACE Investigators. N Engl J Med. 2004;351:2058-68.Pitt B. et al. Am J Cardiol. 2001;87:1058-63.

12.3

8.1

4.1

6.2

3.7

5.3

0

2

4

6

8

10

12

14HOPEEUROPAPEACE

CV death Nonfatal MI

Event rate(%)

1.5

4.6

QUIET

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HOPE, EUROPA, PEACE, QUIET: CV therapies at baseline

HOPE EUROPA PEACE QUIET

Antiplatelet agents* (%) 76 92 91 73

-Blockers (%) 40 62 60 26

Lipid-lowering agents (%) 29 58 70 0

Calcium channel blockers (%)

47 32 36 0

Diuretics (%) 15 10 13 NA

HOPE Investigators. N Engl J Med. 2000;342:145-53.EUROPA Investigators. Lancet. 2003;362:782-8.

PEACE Investigators. N Engl J Med. 2004;351:2058-68.Pitt B. et al. Am J Cardiol. 2001;87:1058-63.*Mostly aspirin

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HOPE, EUROPA: Use of lipid-lowering drugs intensified during studies

Yusuf S. Symposium at: AHA 2004; New Orleans.EUROPA Investigators. Lancet. 2003;362:782-8.

*End of study †3 years

29

58

69

49*

0

10

20

30

40

50

60

70

HOPE EUROPA

†Baseline During study

%Patients

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HOPE, EUROPA: Effect of ACEI plus concomitant CV therapy

2.01.0

Added benefit No added benefit

0.6 0.8

Lipid-lowering drugNo lipid-lowering drug

-blockersNo -blockers

HOPE†

EUROPA*

ACE inhibitor

EUROPA Investigators. Lancet. 2003;362:782-8 Dagenais GR et al. Circulation. 2001;104:522-6.

*Perindopril 8 mg

†Ramipril 10 mg

Lipid-lowering drugNo lipid-lowering drug

HOPE†

EUROPA*

-blockersNo -blockers

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HOPE: Dose-dependent effects of ramipril on LV mass and function

8.21 7.86

–3.53–6

–4

–2

0

2

4

6

8

10 5.31

2.9

–1.9–3

–2–1

012345

6

Placebo (n = 151) Ramipril 2.5 mg (n = 149) Ramipril 10 mg (n = 146)

∆ LV mass

(g)

∆ LV end

systolic volume

(mL)

Mean baseline LVEF 58% in all groups

Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.

P Trend = 0.03 P Trend = 0.001

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SECURE: Dose-dependent effect of ramipril on carotid atherosclerosis

Lonn E et al. Circulation. 2001;103:919-925.

0

0.005

0.010

0.015

0.020

0.025

Ramipril 10 mg

Ramipril 2.5 mg

Placebo

0.022

0.018

0.014

NS

37% Reduction

P = 0.028

Slope of the mean

maximum carotid-intima

thickness (mm/y)

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HOPE, EUROPA, PEACE, QUIET: Clinical implications

• Cumulative evidence supports ACE inhibitors for a broad range of CAD patients

• Not all ACE inhibitors can be assumed to have comparable effects on vascular protection

– Medication adherence and dosage are important

• Evidence-based medicine should guide use– Ramipril 10 mg (HOPE)– Perindopril 8 mg (EUROPA)

Pitt B. N Engl J Med. 2004;351:2115-7.

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1-Year survival in post-MI patients according to ACEI Rx at discharge

P < 0.001 for log-rank test

Pilote L et al. Ann Intern Med. 2004;141:102-12.

No. of patientsRamipril

100

90

80

70121086420

Time (months)

Captopril

Ramipril

QuinaprilFosinopril

LisinoprilEnalapril

Perindopril

Cumulativesurvival*

(%)

PerindoprilLisinoprilEnalaprilQuinaprilFosinoprilCaptopril

817215

18942118224713325

905243

22012577276889421

*Unadjusted

N = 7512

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5-Year outcomes after PCI show major impact of disease progression

Target-lesion event

Nontarget-lesion event

1.7

6.7

1

3

5

7

Target-lesionevent

Nontarget-lesion event

%

Cutlip DE et al. Circulation. 2004;110:1226-30.

1228 patients in second-generation coronary stent trials

Average event rate, years 2–5

1.51.32.3 1.6

18.3

6.75.7

7.05.8

12.4

0

5

10

15

20

25

1 2 3 4 5

Event rate (%)

Year

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APRES: Long-term benefit of ACEI started early after PTCA/CABGN = 159, ramipril 10 mg or placebo 1 to 7 days post-revascularization

No. at risk

Ramipril 80 78 78 77 74 55 30

Placebo

79 71 68 67 65 47 23

*APRES = Angiotensin-Converting Enzyme Inhibitor Post-Revascularization Study KjØller-Hansen L et al. Am Heart J. 2004;148:475-80.

0

5

10

15

20

25

Event ratein cardiacdeath/HF

(%)

654321 70

APRES ends

65% P = 0.042

Years

72% P = 0.018

Ramipril

Placebo

Cardiac death/HF

35% P = 0.27

at 5.5 yrs

at 4.3 yrs

at 6.9 yrs

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UA/NSTEMI (1999)* STEMI (2004)†

Class I

ACEIs for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (Level of evidence: A)

Class I

ACEI should be prescribed at discharge for all patients without contraindications after STEMI (Level of evidence: A)

Braunwald E et al.www.acc.org/clinical/guidelines/unstable.pdf

Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.

ACC/AHA recommendations on role of ACEIs in post-MI patients at discharge

*Based on HOPE†Based on HOPE and EUROPANSTEMI = non–ST-elevation MISTEMI = ST-elevation MIUA = unstable angina

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Cumulative impact of 4 CV-protective medication classes in post-MI patients

Medication class RRR (%)5-Year

CV-event risk (%)

None 0 20.0

Aspirin 25 15.0

-Blocker 25 11.3

ACE inhibitor 25 8.4

Lipid lowering 30 5.9

• Cumulative risk reduction if all 4 medication classes are used: 70%

• NNT to prevent 1 major CV event in 5 years: 7

Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):537-46.RRR = relative risk reduction