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

Deleterious effects of angiotensin II PAI-1/ thrombosis Abnormal vasoconstriction Ang II Platelet aggregation Activate SNS Superoxide production Vascular smooth muscle growth Aldosterone Myocyte growth Collagen Vasopressin Endothelin 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

PERTINENT: ACEI improves endothelial function—Effects on cultivated HUVECs Healthy control Perindopril 8 mg Placebo ecNOS activity (U/mg) Apoptosis (%) 4.0 9 P < 0.05 3.5 8 7.8 P < 0.05 3.5 3.3 7.0 7 6.8 3.0 2.9 2.5 6 2.5 2.4 5 4.7 2.0 4 1.5 3 1.0 2 1.3 0.5 1 Control Baseline 1 Year Control Baseline 1 Year HUVECs = human umbilical vein endothelial cells Ferrari R. ESC 2004; Munich.

PERTINENT: Effects of ACEI on bradykinin, Ang II, and TNF — Plasma analysis 25 18 17.1 P < 0.05 P < 0.05 15.8 16 20 14.4 18.3 17.7 14 12.5 14.8 12 10.8 15 12.4 pg/mL 12.3 pg/mL 10 10 8 6 5 4 2 Control Baseline 1 Year Control Baseline 1 Year 35 TNF- P < 0.05 30 28.9 27.1 27.7 25 24.6 Healthy control 20 pg/mL 18.0 Perindopril 8 mg 15 Placebo 10 5 Control Baseline 1 Year Ferrari R. ESC 2004; Munich.

Major clinical outcome trials of RAAS manipulation ACE inhibition GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT Angiotensin receptor blockade HOPE EUROPA PEACE QUIET SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT ALLHAT ANBP2 INVEST LIFE CONSENSUS

PEACE: Prevention of Events With Angiotensin Converting Enzyme Inhibition 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 Primary Outcome: CV death, nonfatal MI, CABG, PCI PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

PEACE: Treatment effect on primary outcome Placebo 30 25 Trandolapril 20 Incidence of primary outcome (%) 15 10 5 1 2 3 4 5 6 Years after randomization No. at risk Trandolapril 4158 4017 3752 3506 3079 1963 969 Placebo 4132 3990 3719 3486 3027 1929 891 PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

PEACE: Treatment effect on components of primary outcome and total deaths 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 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 4.4 0.89 (0.76–1.04) *CV death, nonfatal MI, and coronary revascularization PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

HOPE, EUROPA: Overview HOPE N = 9297 (4.5 years) Ramipril 10 mg 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 *CV disease, peripheral artery disease, stroke or diabetes + ≥1 CV risk factor HOPE Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8.

HOPE, EUROPA: Treatment benefit on primary and selected secondary outcomes Favors ACEI Favors placebo 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 HOPE EUROPA 0.5 1.0 1.5 EUROPA = European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease HOPE = Heart Outcomes Prevention Evaluation Hazard ratio EUROPA Investigators. Lancet. 2003;362:782-8. HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

HOPE, EUROPA, PEACE, QUIET: CV event rate in placebo group 14 12.3 HOPE 12 EUROPA PEACE 10 QUIET 8.1 Event rate (%) 8 6.2 6 5.3 4.6 4.1 3.7 4 2 1.5 CV death Nonfatal MI 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.

CV therapies at baseline 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 Calcium channel blockers (%) 47 32 36 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

HOPE, EUROPA: Use of lipid-lowering drugs intensified during studies Baseline During study † 69 70 58 60 49* 50 % Patients 40 29 30 20 10 HOPE EUROPA *End of study †3 years Yusuf S. Symposium at: AHA 2004; New Orleans. EUROPA Investigators. Lancet. 2003;362:782-8.

HOPE, EUROPA: Effect of ACEI plus concomitant CV therapy ACE inhibitor Added benefit No added benefit EUROPA* Lipid-lowering drug No lipid-lowering drug HOPE† Lipid-lowering drug No lipid-lowering drug EUROPA* -blockers No -blockers HOPE† -blockers No -blockers 0.6 0.8 1.0 2.0 *Perindopril 8 mg †Ramipril 10 mg EUROPA Investigators. Lancet. 2003;362:782-8 Dagenais GR et al. Circulation. 2001;104:522-6.

HOPE: Dose-dependent effects of ramipril on LV mass and function Mean baseline LVEF 58% in all groups Placebo (n = 151) Ramipril 2.5 mg (n = 149) Ramipril 10 mg (n = 146) 10 6 5.31 8 5 8.21 7.86 ∆ LV end systolic volume (mL) 4 6 ∆ LV mass (g) 3 2.9 4 2 2 1 –2 –1 –4 –2 –3.53 –1.9 –6 –3 P Trend = 0.03 P Trend = 0.001 Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.

Slope of the mean maximum carotid-intima thickness (mm/y) SECURE: Dose-dependent effect of ramipril on carotid atherosclerosis 0.025 P = 0.028 0.022 NS 0.020 Slope of the mean maximum carotid-intima thickness (mm/y) 0.018 0.015 37% Reduction 0.014 0.010 0.005 Placebo Ramipril 2.5 mg Ramipril 10 mg Lonn E et al. Circulation. 2001;103:919-925.

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.

Cumulative survival* (%) 1-Year survival in post-MI patients according to ACEI Rx at discharge N = 7512 100 90 Cumulative survival* (%) Ramipril Perindopril 80 Lisinopril Enalapril Quinapril Fosinopril P < 0.001 for log-rank test Captopril 70 2 4 6 8 10 12 No. of patients Time (months) Ramipril 905 817 Perindopril 243 215 Lisinopril 2201 1894 Enalapril 2577 2118 Quinapril 276 224 Fosinopril 889 713 Captopril 421 325 *Unadjusted Pilote L et al. Ann Intern Med. 2004;141:102-12.

5-Year outcomes after PCI show major impact of disease progression 1228 patients in second-generation coronary stent trials Target-lesion event 25 Nontarget-lesion event Average event rate, years 2–5 20 7 6.7 18.3 Event rate (%) 15 5 12.4 % 10 7.0 3 6.7 5.8 5.7 1.7 5 2.3 1.3 1.5 1.6 1 1 2 3 4 5 Target-lesion event Nontarget- lesion event Year Cutlip DE et al. Circulation. 2004;110:1226-30.

APRES: Long-term benefit of ACEI started early after PTCA/CABG N = 159, ramipril 10 mg or placebo 1 to 7 days post-revascularization 25 APRES ends Cardiac death/HF 20 72% P = 0.018 at 4.3 yrs Placebo Event rate in cardiac death/HF (%) 15 Ramipril at 5.5 yrs 10 65% P = 0.042 5 at 6.9 yrs 35% P = 0.27 1 2 3 4 5 6 7 Years No. at risk Ramipril 80 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.

ACC/AHA recommendations on role of ACEIs in post-MI patients at discharge UA/NSTEMI (1999)* STEMI (2004)† Class I ACEIs for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (Level of evidence: A) ACEI should be prescribed at discharge for all patients without contraindications after STEMI (Level of evidence: A) *Based on HOPE †Based on HOPE and EUROPA NSTEMI = non–ST-elevation MI STEMI = ST-elevation MI UA = unstable angina Braunwald E et al. www.acc.org/clinical/guidelines/unstable.pdf Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.

5-Year CV-event risk (%) Cumulative impact of 4 CV-protective medication classes in post-MI patients Medication class RRR (%) 5-Year CV-event risk (%) None 20.0 Aspirin 25 15.0 -Blocker 11.3 ACE inhibitor 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 RRR = relative risk reduction Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):537-46.