1. HOPE: Diabetes and Cardiovascular Disease Songsak Kiatchoosakun Cardiology, Medicine Khon Kaen University

2. More than 115 million people worldwide suffered form diabetes 65% of people with diabetes die from cardiovascular disease (CVD) Cardiovascular mortality in type 2 diabetes increases 2-4 fold Diabetes & Cardiovascular Risks

3. Patients with Diabetes at Similar Risk to No Diabetes with MI Haffner SM et al. N Engl J Med 1998;339:229-234. p<0.001 No diabetes (n=1373) Diabetes (n=1059) ns n=1304n=890n=69n=169

4. Medical Management of Atherosclerotic in Diabetes Treating hyperglycemic and insulin resistance Lipid goal Without CVD: LDL < 100 mg/dl With CVD LDL < 70 mg/dl Antiplatelet therapy Age > 40, additional risk factors of CAD Smoking cessation Hypertension and blood pressure control Blood pressure goal < 130/80 mmHg Prevention of cardiovascular disease (CVD)

5. Prevention of CVD & Modifying known risk factors (diabetes, dyslipidemia,hypertension, smoking) does not fully reduce CVD risk & Atherosclerosis progression - precursor of clinical CVD & Evidence that renin-angiotensin system activation and lipid oxidation have important roles in atherosclerosis progression

6. Angiotensin II and Progression of Vascular Disease LDLDMHTSmoking Oxidative Stress Endothelial dysfunction/ Smooth muscle activation NO Local mediators Tissue ACE, Angiotensin II Platelet aggregation, VCAM/ICAM cytokines, Inflammation, Growth factor VasoconstrictionThrombosisInflammationPlaque rupture

7. Renin Angiotensin System and Role of Angiotensin Converting Enzyme Inhibitor in Coronary Artery Disease

8. Renin Angiotensin System

9. Secondary Prevention of CAD - Role of ACE Inhibition ANGIOTENSIN SYSTEM Angiotensinogen renin Ang I Ang II vasoconstriction Potentiation of sympathetic activity + ACE (enzyme) BRADYKININ SYSTEM kallikrein kininogen Bradykinin Endothelium Prostaglandin NO  platelet aggregation  SMC mitogenesis Vasodilation Inactive peptide + + ACE inhibitor impact ACE inhibitor impact FGF PDGF

10. ACE Inhibition and Anti- atherosclerotic Effect (A) Control Candido R et al. Circulation. 2002;106:246-253. (B) Diabetic apoE-deficient mice (C) Diabetic apoE-deficient mice ACE inhibition treated

11. ACE Inhibition for Secondary Prevention of CAD Rationale Anti-atherosclerotic effects Improvement in vascular endothelial function Vasodilation:reduce preload and afterload LV hypertrophy reduction Blood pressure lowering Angiotensin II reduction / bradykinin increase

12. Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–1263 Cardiovascular Death Risk factors Diabetes Hypertension Smoking Dyslipidemia End-Stage Heart Disease Atherosclerosis Chain of Events Leading to End Stage Heart Disease: Congestive Heart Failure Ventricular Dilation/ Dysfunction Remodelling Myocardial Infarction

13. Major Clinical Outcome Trials of RAAS Manipulation ACE inhibition Angiotensin receptor blockade GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT CONSENSUS ALLHAT ANBP2 INVEST LIFE

14. Survival and Ventricular Enlargement Trial (SAVE) 19% reduction in all causes mortality Pfeffer MA. SAVE Trial. N Engl J Med 1992;327:669

15. Major Clinical Outcome Trials of RAAS Manipulation ACE inhibition Angiotensin receptor blockade GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT CONSENSUS HOPE EUROPA ALLHAT ANBP2 INVEST LIFE

16. The Heart Outcomes Prevention Evaluation Study: HOPE Study Aim: Effect of Ramipril (up to 10mg/d) or Vitamin E (400 IU/d) vs its placebo on CV death, MI or stroke (primary) Design:Randomized double blind, 2x2 factorial, Wide entry criteria, large, simple trial Size: 9541 patients followed for 4 to 6 years Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

17. Key Inclusion / Exclusion Criteria Inclusion Criteria Patients (age >55) at high risk for CV events because of: previous CV disease (CHD, stroke, PVD) DM + one other CV risk factor BP>160/90 or on Rx- smoker- microalbuminuria Cholesterol > 5.2- HDL<=0.9- previous CVD Exclusion Criteria Heart failure or low EF Dipstick + proteinuria (>=1+) On ACE-I or Vitamin E Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

18. HOPE Study Population: “Typical” Office Practice Patients Patients did not have heart failure Patients had normal or controlled blood pressure (53% normal) Patients were 55 years or older CV events 11% had previous stroke 80% had history of CAD 42% had history of PVD Diabetes 39% had diabetes + 1 or more CVD risk factors The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

19. HOPE: Assessment of Outcomes Primary outcome Composite of myocardial infarction, stroke or cardiovascular death Secondary outcomes Unstable angina, heart failure, hospitalization, revascularization Microalbuminuria, overt nephropathy, retinopathy, cataract Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

20. HOPE: Primary Outcome Reductions in MI, Stroke, or Cardiovascular Death Note: Trial halted early due to the highly significant risk reductions seen with Ramipril 0.20 0.15 0.10 0.05 0 050010001500 22% Reduction in Events P=.0001* Days of Follow-up % of Patients Reaching Endpoints Placebo Ramipril 15% Reduction in Events at 1 year

21. Relative Risk Reduction in Cardiovascular Endpoints Combined cardiovascular endpoints Cardiovascular mortality Myocardial Infarction Stroke -22%, p<0.01 -26%, p<0.001 -20%, p<0.001 -32%, p<0.001

22. HOPE – Secondary Endpoints RevascularizationDMComplications New diagnosis of Diabetes Mellitus 16% Risk Reduction P<0.001 16% Risk Reduction P=0.03 23% Risk Reduction P<0.001 HFHospitalization Heart Failure N Engl J Med. January 20, 2000 13% Risk Reduction P=0.19 32% Risk Reduction P=0.002

23. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. Aspirin Diuretics  -blockade Other antiplatelets Lipid-lowering agents Calcium channel blockade + Ramipril 10 mg *P = 0.0001 † P = 0.005 HOPE: Additive Risk Reduction with Ramipril 10 mg Effects beyond baseline therapy VBWG

24. Ramipril (%) Placebo (%) Ramipril vs Placebo RR95% CIp No.Rand 46454652 2  Outcomes Unstable Angina 11.9 12.1 0.98 0.87-1.10 0.68 with ECG changes 3.9 4.0 0.96 0.79-1.18 0.72 Heart failure 9.011.5 0.77 0.67-0.87<0.001 Revascularization 16.0 18.3 0.85 0.77-0.94 0.002 Secondary Adjudicated Events

26. 732 patients Mean F/U 4.5 years

27. HOPE: Compliance HOPE Study. N engl J Med 2002;342:145-153.

28. MicroHOPE: Outcomes in Diabetics With Ramipril Study Parameters Substudy of HOPE 3577 Patients with diabetes + previous CV event or 1 other CV risk factor Exclusion Proteinuria Heart failure ACE inhibitor therapy Low EF (<40%) Duration: 4.5 years Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet. 2000;355:253-259.

29. MicroHOPE: CV Events in Diabetic Patients PlaceboRamipril Heart Outcomes Prevention Study Investigators. Lancet. 2000;355:253-259. 0.16 0.12 0.08 0.04 0 Total Mortality 0.16 0.12 0.08 0.04 0 0500100020001500 Myocardial Infarction Stroke 0.08 0.06 0.04 0.02 0 0500100020001500 Duration of Follow-up (Days) RR reduction: 24% RR reduction: 33% RR reduction: 22% 5001000200015000 Heart Failure 0 2 4 6 8 10 12 14 RamiprilPlacebo

30. Bosch J. European Society of Cardiology Congress 2003. Aug 30–Sep 3, 2003. Vienna, Austria HOPE/HOPE-TOO: Primary outcome Hazard Years 1234567 Ramipril Placebo 0.0 0.05 0.10 0.15 0.20 0.25 0.30 1234567 Ramipril Placebo Ramipril: CV Death/MI/Stroke - Extended Follow-up ALL: RR: 0.81, CI: (0.74-0.88) CONT: RR: 0.83, CI: (0.75-0.91)  HOPE Study Ends

31. HOPE:Conclusions  In people with high risk for CVD, addition of ramipril to other effective therapies prevents: CV death, strokes and MI Total mortality Revascularization Diabetic nephropathy  The benefit is independent of the effect on BP (3/2 mmHg)  The only adverse event is a 5% excess of cough

32. HOPE: Implications for CHD ACE-I with ramipril reduced events in most groups Treating 1,000 patients with ramipril for four years prevents about 150 events in approximately 70 patients HOPE suggests ACE-I should be used like aspirin, for prevention of vascular events in high risk subjects Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

33. Major Clinical Outcome Trials of RAAS Manipulation ACE inhibition Angiotensin receptor blockade GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT CONSENSUS HOPE EUROPA ALLHAT ANBP2 INVEST LIFE

34. EUROPA Study Hypothesis In selected patient groups (high CV risk or LV dysfunction), ACE-I results in secondary prevention of coronary disease However, the multiple ways by which ACE inhibition affects the atherosclerotic process, suggest that it might occur in all patients with coronary disease EROPA Study. Lancet 2003;362:782

35. Selection Criteria Male or female > 18 years of age Documented coronary disease Not scheduled for revascularisation No clinical signs of heart failure EUROPA Study. Lancet 2003;362:782

36. Primary Endpoint % CV death, MI or cardiac arrest Placebo annual event rate: 2.4% Perindopril Placebo p = 0.0003 RRR: 20% Years 0 2 4 6 8 10 12 14 0 1 2345 EUROPA Study. Lancet 2003;362:782

37. 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 Favors ACEI Favors placebo 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 Disease HOPE = Heart Outcomes Prevention Evaluation Hazard ratio 0.51.01.5

38. New Approach to the Classification of Heart Failure Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) Refractory end-stage HF D Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Symptomatic HF C Previous MI LV systolic dysfunction Asymptomatic valvular disease Asymptomatic HF B Hypertension CAD Diabetes mellitus Family history of cardiomyopathy High risk for developing heart failure (HF) A Patient DescriptionStage Carvedilol is indicated for use in patients with mild to severe chronic HF and in patients with HTN. Hunt SA et al. J Am Coll Cardiol. 2001;38:2101 – 2113.

39. Treatment Approach for the Patient with Heart Failure Stage A At high risk, no structural disease Stage B Structural heart disease, asymptomatic Stage D Refractory HF requiring specialized interventions Therapy Treat HypertensionTreat Hypertension Treat lipid disordersTreat lipid disorders Encourage regular exerciseEncourage regular exercise Discourage alcohol intakeDiscourage alcohol intake ACE inhibition for vascular disease or diabetesACE inhibition for vascular disease or diabetesTherapy All measures under stage AAll measures under stage A ACE inhibitors in appropriate patientsACE inhibitors in appropriate patients Beta-blockers in appropriate patientsBeta-blockers in appropriate patientsTherapy All measures under stage AAll measures under stage ADrugs: DiureticsDiuretics ACE inhibitorsACE inhibitors Beta-blockersBeta-blockers DigitalisDigitalis Aldosterone antagonistAldosterone antagonistTherapy All measures under stages A,B, and CAll measures under stages A,B, and C Mechanical assist devicesMechanical assist devices Heart transplantationHeart transplantation Continuous (not intermittent) IV inotropic infusions for palliationContinuous (not intermittent) IV inotropic infusions for palliation Hospice careHospice care Stage C Structural heart disease with prior/current symptoms of HF Abraham WT,et al. ACC/AHA Guidelines CHF, 2005.

40. Conclusions The relationship between RAAS and diabetic vascular disease is well established 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 ACE inhibition (ramipril 10 mg) in patients with diabetes and vascular disease Pitt B. N Engl J Med. 2004;351:2115-7.

42. Bosch J. European Society of Cardiology Congress 2003. Aug 30 – Sep 3, 2003. Vienna, Austria HOPE/HOPE-TOO: Development of diabetes 0.0 0.02 0.06 0.10 1234567 Ramipril Placebo Ramipril: New Diabetes - All Patients Hazard ALL: RR: 0.69, CI: (0.57-0.83)  HOPE Study Ends Years 0.12 0.08 0.04 7.3% 10.3 30% reduction

43. 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 0 1 2 3 4 5 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

44. Heart Outcomes Prevention Evaluation Study – The Ongoing Outcomes HOPE-TOO VBWG

45. HOPE-TOO: Study questions 1. Are the cardiovascular benefits from ramipril seen at the end of the HOPE study sustained over time? 2. Does prolonged treatment (+2.6 yrs) with vitamin E prevent cancer?

46. CV events: 174 continuing centers Ramipril N (%)Placebo N (%)RR (95% CI) MI HOPE339 (10.0)412 (12.1)0.81 (0.71-0.94) Extension145 (5.1)169 (6.1)0.81 (0.65-1.01) Overall484 (14.3)581 (17.1)0.81 (0.72-0.92) Stroke HOPE115 (3.4)159 (4.7)0.72 (0.56-0.91) Extension 59 (2.0) 55 (1.9)1.02 (0.71-1.48) Overall174 (5.1)214 (6.3)0.80 (0.65-0.97) CV Death HOPE194 (5.7)248 (7.3)0.78 (0.71-0.94) Extension 133 (5.1) 126 (5.1)1.02 (0.65-1.01) Overall327 (14.3)374 (17.1)0.86 (0.72-0.92) Bosch J. European Society of Cardiology Congress 2003. Aug 30 – Sep 3, 2003. Vienna, Austria

47. HOPE-TOO: Conclusions Bosch J. European Society of Cardiology Congress 2003. Aug 30–Sep 3, 2003. Vienna, Austria Benefits of ramipril seen in HOPE are sustained with an additional 2.5 years of follow-up Apparent incremental benefit on prevention of myocardial infarction and diabetes