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HOPE: Diabetes and Cardiovascular Disease

HOPE: Diabetes and Cardiovascular Disease. Songsak Kiatchoosakun Cardiology, Medicine Khon Kaen University. Diabetes & Cardiovascular Risks. More than 115 million people worldwide suffered form diabetes 65% of people with diabetes die from cardiovascular disease (CVD)

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HOPE: Diabetes and Cardiovascular Disease

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

  2. Diabetes & Cardiovascular Risks • 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

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

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

  6. Angiotensin II and Progression of Vascular Disease LDL DM HT Smoking Oxidative Stress Endothelial dysfunction/ Smooth muscle activation NO Local mediators Tissue ACE, Angiotensin II Platelet aggregation, VCAM/ICAM cytokines, Inflammation, Growth factor Vasoconstriction Thrombosis Inflammation Plaque rupture

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

  8. Renin Angiotensin System

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

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

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

  13. 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 SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT ALLHAT ANBP2 INVEST LIFE CONSENSUS

  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 GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT Angiotensin receptor blockade HOPEEUROPA SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT ALLHAT ANBP2 INVEST LIFE CONSENSUS

  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. 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 HOPE Study Population: “Typical” Office Practice Patients 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. 22% Reductionin Events P=.0001* HOPE: Primary Outcome Reductions in MI, Stroke, or Cardiovascular Death 0.20 Placebo 0.15 Ramipril % of Patients Reaching Endpoints 0.10 15% Reduction in Events at 1 year 0.05 0 0 500 1000 1500 Days of Follow-up Note: Trial halted early due to the highly significant risk reductions seen with Ramipril

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

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

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

  24. Ramipril Placebo Ramipril vs Placebo (%) (%) RR 95% CI p No. Rand 4645 4652 ° 2 Outcomes Unstable Angina 11.9 12.1 0.98 0.87-1.10 0.68 with ECG 3.9 4.0 0.96 0.79-1.18 0.72 changes Heart failure 9.0 11.5 0.77 0.67-0.87 <0.001 Revascularization 16.0 18.3 0.85 0.77-0.94 0.002 Secondary Adjudicated Events

  25. 732 patients • Mean F/U 4.5 years

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

  27. MicroHOPE: Outcomesin Diabetics With Ramipril • Study Parameters • Substudy of HOPE • 3577 Patients with diabetes + previous CV eventor 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.

  28. Total Mortality Stroke 0.16 0.08 0.12 0.06 0.08 0.04 RR reduction: 33% 0.04 0.02 RR reduction: 24% 0 0 0 500 1000 1500 2000 0 500 1000 1500 2000 Duration of Follow-up (Days) Duration of Follow-up (Days) Heart Failure Myocardial Infarction 14 0.16 12 0.12 10 8 0.08 6 0.04 4 RR reduction: 22% 2 0 0 500 1000 1500 2000 0 Ramipril Placebo Duration of Follow-up (Days) MicroHOPE: CV Eventsin Diabetic Patients Placebo Ramipril Heart Outcomes Prevention Study Investigators. Lancet. 2000;355:253-259.

  29. HOPE/HOPE-TOO: Primary outcome Ramipril: CV Death/MI/Stroke - Extended Follow-up 0.30 HOPE Study Ends Ramipril Ramipril 0.25 Placebo Placebo 0.20 Hazard 0.15 0.10 0.05 ALL: RR: 0.81, CI: (0.74-0.88) CONT: RR: 0.83, CI: (0.75-0.91) 0.0 Years 1 1 2 2 3 3 4 4 5 5 6 6 7 7 Bosch J. European Society of Cardiology Congress 2003. Aug 30–Sep 3, 2003. Vienna, Austria

  30. 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

  31. HOPE: Implications for CHD Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145. 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

  32. 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 HOPEEUROPA SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT ALLHAT ANBP2 INVEST LIFE CONSENSUS

  33. 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

  34. 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

  35. 14 12 10 8 6 RRR: 20% 4 p = 0.0003 2 0 1 0 2 3 4 5 Years Primary Endpoint % CV death, MI or cardiac arrest Placebo Perindopril Placebo annual event rate: 2.4% EUROPA Study. Lancet 2003;362:782

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

  37. New Approach to the Classificationof Heart Failure Stage Patient Description A High risk for developing heart failure (HF) • Hypertension • CAD • Diabetes mellitus • Family history of cardiomyopathy Asymptomatic HF B • Previous MI • LV systolic dysfunction • Asymptomatic valvular disease C Symptomatic HF • Known structural heart disease • Shortness of breath and fatigue • Reduced exercise tolerance D Refractory end-stage HF • 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) 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.

  38. Treatment Approach for the Patient with Heart Failure Stage A At high risk, no structural disease Stage B Structural heart disease, asymptomatic Stage C Structural heart disease with prior/current symptoms of HF Stage D Refractory HF requiring specialized interventions • Therapy • Treat Hypertension • Treat lipid disorders • Encourage regular exercise • Discourage alcohol intake • ACE inhibition for vascular disease or diabetes • Therapy • All measures under stage A • ACE inhibitors in appropriate patients • Beta-blockers in appropriate patients • Therapy • All measures under stage A • Drugs: • Diuretics • ACE inhibitors • Beta-blockers • Digitalis • Aldosterone antagonist • Therapy • All measures under stages A,B, and C • Mechanical assist devices • Heart transplantation • Continuous (not intermittent) IV inotropic infusions for palliation • Hospice care Abraham WT,et al. ACC/AHA Guidelines CHF, 2005.

  39. 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.

  40. HOPE/HOPE-TOO: Development of diabetes Ramipril: New Diabetes - All Patients HOPE Study Ends 0.12 Ramipril 10.3 0.10 Placebo 30% reduction 0.08 7.3% Hazard 0.06 0.04 ALL: RR: 0.69, CI: (0.57-0.83) 0.02 0.0 Years 1 2 3 4 5 6 7 Bosch J. European Society of Cardiology Congress 2003. Aug 30–Sep 3, 2003. Vienna, Austria

  41. 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 5 8 8.21 7.86 ∆ LV end systolic volume (mL) 4 6 ∆ LV mass (g) 2.9 3 4 2 2 1 0 0 –2 –1 –2 –4 –3.53 –1.9 –3 –6 P Trend = 0.03 P Trend = 0.001 Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.

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