1. Extension studies show sustained benefits with ACEI TreatmentRamiprilEnalaprilEnalaprilRamipril Follow-up15 mos10 yrs12 yrs7.2 yrs Characteristic Clinical HF,NYHA class IVHF, LV High CV risk, post-MIHFdysfunctionno LV dysfunction no HF Results RRR 36%Overall survivalExtendedReduced major in mortalityprolonged survival CV events and by 50% by 9.4 monew diabetes by 34% SummaryContinue ACEIBeneficial effect Sustained Sustained indefinitely post-MImaintainedimprovementbenefit with several yrsin survivallong-term use AIREXCONSENSUSX-SOLVDHOPE-TOO 1997199920032005 Hall AS et al. Lancet. 1997;349:1493-7. Swedberg K et al. Eur Heart J. 1999;20:136-9. Jong P et al. Lancet. 2003;361:1843-8. HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. Dosage important VBWG

2. HOPE-TOO: Study disposition Ramipril (n = 3393) Placebo (n = 3393) Follow-up ACEI therapy: >90% ramipril “Late” ACEI: Placebo patients from HOPE Open-label ACEI therapy (n = 2211) “Early” ACEI: Ramipril patients from HOPE Open-label ACEI therapy (n = 2317) Primary analysis 174 study centers (n = 6786) HOPE-TOO participants agreed to passive follow-up (n = 4528) Adapted from HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. Inclusion criteria: Age ≥55 years Hx: CAD, stroke, PVD or diabetes + ≥1 CV risk factor Exclusion criteria: CHF, known EF <0.4, Uncontrolled HTN; MI or stroke ≤4 wks; current ACEI, vit E use VBWG

3. HOPE-TOO: Baseline characteristics in extended follow-up Characteristic Ramipril (%) (n = 3393) Placebo (%) (n = 3393) CAD 79.581.2 MI 52.353.5 Stroke 11.111.3 PAD 40.443.2 Hypertension 47.145.0 Diabetes 38.538.2 Elevated total-C 64.866.2 Current cigarette smoking 13.414.2 Medications  -Blockers 39.840.1 Aspirin or other antiplatelet agents 74.877.0 Lipid-lowering drugs 28.529.3 Diuretics 15.615.2 Calcium channel blockers 46.147.3 LV hypertrophy on ECG 7.78.3 Microalbuminuria 19.320.3 VBWG HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

4. HOPE-TOO: Primary outcome (CV death, MI, stroke) HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. 30 RRR = 17% P = 0.0002 0123 45 6 7 0 Placebo Ramipril Years Primary outcome (% HOPE-TOO patients) 25 20 15 10 5 4652 4645 4432 4456 4204 4256 3981 4079 3647 3789 2719 2819 1923 2075 1550 1731 Placebo Ramipril n HOPE-TOO begins Main HOPE study ends VBWG

5. HOPE-TOO: Additional risk reduction in major CV events and new-onset diabetes VBWG HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-41. 19% 34% 16% Revascularization New-onset diabetes MI 0 5 25 15 20 10 30 35 % Reduction with ramipril

6. Benefit of treatment with ACEI Sustained, irreversible, favorable ventricular/vascular remodeling RAAS blockade provides sustainable, favorable effect on glucose homeostasis Benefits are additive to ancillary therapy and extend to all patients, independent of baseline risk “Earlier” rather than later initiation provides longer-term protection HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46. VBWG