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Arshed A. Quyyumi MD Professor of Medicine

Current management of stable coronary artery disease. Atlanta. Arshed A. Quyyumi MD Professor of Medicine Division of Cardiology Emory University School of Medicine Atlanta, Georgia, USA. Stable CAD: Multiple treatment options. Beta blockers Calcium antagonists Nitrates

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Arshed A. Quyyumi MD Professor of Medicine

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  1. Current management of stable coronary artery disease Atlanta Arshed A. Quyyumi MD Professor of Medicine Division of CardiologyEmory University School of Medicine Atlanta, Georgia, USA

  2. Stable CAD: Multiple treatment options Beta blockers Calcium antagonists Nitrates Ranolazine Lifestyle Interevntion Aspirin Lipid lowering ACE inhibitors ARBs Rx Insulin resistance Lifestyle intervention Medicaltherapy Reduce symptomsTreat underlying disease CABG PCI

  3. Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture) • Vulnerable plaque • Minor obstruction • Eccentric plaque • Lipid pool • Thin cap • Severe fibrotic plaque • Severe obstruction • No lipid • Fibrosis, Ca2+ • Plaque rupture • Acute MI • Unstable angina • Sudden death • Exertional angina • (+) ETT Revascularization Anti-anginal Rx Pharmacologic stabilization Early identification of high-risk? Courtesy of PH Stone, MD.

  4. Components of Secondary Prevention AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2006 Update

  5. Landmark Statin Trials 4S WOSCOPS CARE AFCAPS/TexCAPS LIPID • Early trials proved relative risk reduction in morbidity and mortality vs placebo 1994 1995 1996 1998 MIRACLHPSPROSPER ALLHAT-LLT ASCOT CARDS ALLIANCE PROVE IT A to Z • Focus on other high-risk groups: • ACS, elderly, diabetes, hypertension 2001 2002 2003 2004 • Comparisons beyond placebo • Versus usual care (ALLIANCE, ALLHAT-LLT) • Active comparator (PROVE IT, A to Z) TNT IDEAL SPARCL • Focus on the value of intensive statin treatment in: • Higher-risk patients with CHD • Patients with prior stroke or TIA without established CHD 2005 2006

  6. STATINS • Goal of therapy • Mechanisms of action of statins • Regression of atherosclerosis? • Non-lipid lowering effects

  7. Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis JAMA, March 3, 2004—Vol 291, No. 9 1071

  8. Effect of 13 weeks of statin therapy on carotid plaque composition MMP-2 TIMP-1 control pravastatin Circulation 2001;102:928

  9. Pleiotropic effects of statins  Coagulation  Endothelial progenitor cells  Platelet activation  Endothelial function Effects on collagen  NO bioactivity Statins  Reactive oxygen species  MMPs  AT1 receptor  VSMC proliferation  Macrophages  Inflammation  Immunomodulation  Endothelin MMPs = matrix metalloproteinases Liao JK. Am J Cardiol. 2005;96(suppl 1):24F-33F.

  10. Should “low” cholesterol be lowered in the high risk patient? What is the goal for statin therapy?

  11. Elevated Cholesterol Levels AssociatedWith High Risk of CHD Multiple Risk Factor Intervention Trial (MRFIT) (N=361,662) Framingham Study(N=5209) 18 150 16 125 14 100 12 10 6-Year CHD Incidence per 1000 Men Age-Adjusted 6-Year CHD Mortality per 1000 Men 75 8 50 6 4 25 2 0 0 140 160 180 200 220 240 260 280 300 320 204 205–234 235–264 265–294 295 Total Cholesterol (mg/dL) Total Cholesterol (mg/dL) Each 1% reduction in total cholesterol resulted in a 2% decrease in CHD risk Each 1% increase in total cholesterol associated with a 2% increase in CHD risk Adapted from Martin MJ, et al. Lancet. 1986;2:933-936, with permission Reproduced from Castelli WP. Am J Med. 1984;76:4-12, with permission

  12. 30 4S Statin Placebo 25 4S 20 15 LIPID LIPID CARE CARE 10 HPS HPS TNT (10 mg atorvastatin) 5 TNT (80 mg atorvastatin) 0 70 90 110 130 150 170 190 210 0 LDL cholesterol (mg/dL) HMG-CoA Reductase Inhibitor: Secondary Prevention Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD Event(%) LaRosa JC et al. N Engl J Med. 2005;352.

  13. Statin benefit independent of baseline lipids: Meta-analysis of 14 trials Events (%) Groups Treatment(45,054) Control(45,002) Controlbetter Treatment better Total-C (mg/dL) ≤201 13.5 16.6 0.76 0.79 13.9 17.4 >201-251 >251 15.2 19.7 0.80 LDL-C (mg/dL) 0.76 16.7 13.4 ≤135 0.79 17.6 14.2 >135-174 20.4 0.81 15.8 >174 HDL-C (mg/dL) 0.78 22.7 ≤35 18.2 >35-43 18.2 0.79 14.3 >43 14.2 11.4 0.79 TG (mg/dL) 0.79 ≤124 13.4 16.8 0.78 13.8 18.0 >124-177 0.80 15.3 >177 18.8 Overall 14.1 17.8 0.79 0.5 1.0 1.5 Relative risk CHD death, MI, stroke, coronary revascularizationCholesterol Treatment Trialists’ Collaboration CTT Collaborators. Lancet. 2005;366:1267-78.

  14. Components of Secondary Prevention

  15. Exercise Evidence: Mortality Risk Observational study of self-reported physical activity in 772 men with established coronary heart disease Light or moderate exercise is associated with lower risk Wannamethee SG et al. Circulation 2000;102:1358-1363

  16. Adiposity predicts mortality National Institutes of Health-AARP Diet and Health Study 527,265 men and women age 50-71 years 3.0 2.5 2.0 Relative risk of 1.5 death 1.0 0 0 20 25 30 35 40 45 Current BMI (kg/m2) All men (n = 313,047; 42,173 deaths)All women (n = 214,218; 19,144 deaths) Adams KF et al. New Engl J Med. 2006;355:763-78.

  17. Weight Management Recommendations Goal: BMI 18.5 to 24.9 kg/m2 Waist Circumference: Men: < 40 inches (< 35.4’ or 90cm SA) Women: < 35 inches (< 31.5” or 90cm SA) Assess BMI and/or waist circumference on each visit encourage weight maintenance physical activity, caloric intake, behavioral programs If waist circumference high: lifestyle changes and consider treatment strategies for metabolic syndrome. Goal: reduce body weight by 10 percent *BMI is calculated as the weight in kilograms divided by the body surface area in meters2. Overweight state is defined by BMI=25-30 kg/m2. Obesity is defined by a BMI >30 kg/m2.

  18. Diet reduces mortality in primary prevention trials 2002 Physician’s Health Study(N = 20,551)* 2003 Cardiovascular Health Study(N = 5,201)* 2002 Nurses’ Health Study(N = 84,688) 2003 European Prospective Investigation into Cancer and Nutrition–Greek cohort (N = 22,043)† 2005 European Prospective Investigation into Cancer and Nutrition–elderly cohort (N = 74,607)† 2004 The Healthy Aging: A Longitudinal Study in Europe (N = 2339) Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87. Trichopoulou A et al. BMJ. 2005;330:991-7. Knoops KTB et al. JAMA. 2004;292:1433-9. *Blood levels of n-3 fatty acids inversely related to death †Greater adherence associated with lower mortality

  19. Nine Main Components of the Mediterranean diet: 1) Abundance of plant food • whole grain breads, pastas, cereals, • Fruits and Vegetables • Beans • Nuts/Seeds 2) Minimally Processed Fresh Foods 3) Desserts composed mainly of fresh fruits with rare sweets containing refined sugars or honey 4) Olive Oil as principal source of fat 5) Daily Dairy product (cheese or yogurt) in low to moderate amounts 6) Fish and Poultry in low to moderate amounts 7) Up to four eggs weekly 8) Rare Red Meat 9) Wine in low to moderate amounts with meals

  20. Components of Secondary Prevention

  21. Odds Ratio for Vascular Events Aspirin Dose No. of Trials (%) 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 P<.0001 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse Aspirin Evidence: Dose and Efficacy Indirect Comparisons of Aspirin Doses on Vascular Events in High-Risk Patients Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86

  22. Renin-Angiotensin-Aldosterone System Blockers Recommendations

  23. CV and renal continuum: RAAS as a mediator of pathophysiology Atherothrombosis & progressive CVD Tissue injury (MI, stroke,renal insufficiency, PAD) Early tissue dysfunction Pathological remodeling RAAS Oxidative & mechanical stress inflammation Target organ damage Vasoconstriction/Na/H2Oretention (High BP) End-organ failure (CHF, ESRD) Risk factors Death ESRD = end-stage renal disease. Adapted from Dzau V et al. Circulation. 2006;114:2850-70.

  24. EUROPA, HOPE, PEACE, QUIET: Effect of ACEIs on CV endpoints EUROPA CV death/MI/cardiac arrest* HOPECV death/MI/stroke* Placebo 15 20 Placebo 20% RRR HR 0.80 (0.71–0.91) P = 0.0003 22% RRR HR 0.78 (0.70–0.86) P < 0.001 15 10 10 Ramipril 10 mg Perindopril 8 mg 5 5 0 0 0 1 2 3 4 5 0 1 2 3 4 Patients (%) PEACECV death/MI/CABG/PCI* QUIETCV death/MI/cardiac arrest† Placebo 8 30 Placebo 5 4% RRR HR 0.96 (0.88–1.06) P = 0.43 13% RRR HR 0.87 (0.59–1.29) 20 Trandolapril 4 mg 3 10 Quinapril 20 mg 1 0 0 0 1 2 3 1 2 3 4 5 6 Time (years) Fox KM et al; EUROPA study. Lancet. 2003;362:782-8. Yusuf S et al; HOPE study. N Engl J Med. 2000;342:145-53. Braunwald E et al; PEACE trial. N Engl J Med. 2004;351:2058-68. Pitt B et al; QUIET study. Am J Cardiol. 2001;87:1058-63. *Primary endpoint†Secondary endpoint

  25. VALIANT: ACEI and ARB show similar effects in post-MI patients with LV dysfunction Death from any cause Combined CV endpoint* 0.4 0.4 0.3 0.3 Probability of event 0.2 0.2 0.1 0.1 0.0 0.0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months Valsartann = 4909 Valsartan/captopriln = 4885 Captopril n = 4909 *CV death, reinfarction, or hospitalization for HF. Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.

  26. ONTARGET: Time to primary outcome N = 25,620 with vascular disease or high-risk diabetes 0.20 0.15 Cumulative hazard ratio 0.10 0.05 0.00 0 1 2 3 4 5 Follow-up (years) Ramipril Telmisartan Telmisartan plus ramipril ONTARGET Investigators. N Engl J Med. 2008;358:1547-59.

  27. Use indefinitely in all patients with LVEF ≤40% and in those with HTN, T2DM, or chronic kidney disease unless contraindicated LOE I (A) Consider in all other (high- risk) patients LOE I (B) Use in ACEI-intolerant patients with HF and in post-MI patients with LVEF ≤40% LOE I (A) Consider in other ACEI-intolerant patients LOE I (B) AHA/ACC guidelines for secondary CVD prevention—2006 Update: ACEI and ARB ACEI ARB LOE = level of evidence Smith SC Jr et al. J Am Coll Cardiol. 2006;47:2130-9.

  28. What is the definitive role of PCI in chronic angina and stable CAD? • PCI improves angina and short-term exercise capacity • However, compared to optimal medical therapy, does PCI • Prolong survival? • Reduce risk of subsequent MI? • Reduce hospitalization for unstable angina? • Decrease need for subsequent CABG? • Improve quality of life? Courtesy of WE Boden, MD.

  29. COURAGE: Defining optimal care Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Intensive lifestyle intervention Intensive medicaltherapy Reduce symptomsTreat underlying disease Revascularization?

  30. COURAGE: Study design AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia (or ≥80% stenosis + CCS class III angina without provocation testing) Optimal medical therapy* + PCI (n = 1149) Optimal medical therapy*(n = 1138) Randomized Primary outcomes: All-cause mortality, nonfatal MI Secondary outcomes: Death, MI, stroke; ACS hospitalization Follow-up: Median 4.6 years *Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

  31. COURAGE: Baseline angiographic data *Patients who underwent previous CABG†P = 0.01 Boden WE et al. N Engl J Med. 2007;356:1503-16.

  32. COURAGE: Treatment effect on primary outcome All-cause death, MI 1.0 0.9 0.8 Survival free of primary outcome HR 1.05 (0.87-1.27) P = 0.62* 0.7 0.6 0.5 0 0 1 2 3 4 5 6 7 Years Medical therapy PCI + medical therapy No. at risk Medical therapy 1138 1017 959 834 638 408 192 30 PCI 1149 1013 952 833 637 417 200 35 *Unadjusted, log-rank Boden WE et al. N Engl J Med. 2007;356:1503-16.

  33. COURAGE: Treatment effect on angina NS P = 0.02 P < 0.001 Angina-free(%) NS Years Boden WE et al. N Engl J Med. 2007;356:1503-16.

  34. COURAGE: Summary and implications • PCI added to optimal medical therapy did not reduce risk of death, MI, or other major CV events compared with optimal medical therapy alone • Findings reinforce existing clinical practice guidelines • Optimal medical therapy and aggressive management of multiple treatment targets without initial PCI can be implemented safely in the majority of patients with chronic stable angina, even those with objective evidence of ischemia and significant multivessel CAD Boden WE et al. N Engl J Med. 2007;356:1503-16.

  35. Pfisterer and Gersh Lancet 2010

  36. BARI 2D: Study design

  37. BARI 2D: Enrollment, randomization, and treatments

  38. BARI 2D: Death, MI, stroke for medical therapy vs type of revascularization

  39. BARI 2D: All-cause death by type of insulin therapy

  40. BARI 2D: Conclusions

  41. BARI 2D: Implications

  42. Stable CAD: Multiple treatment options Aspirin Beta blockers Calcium antagonists Ranolazine Lipid lowering ACE inhibitors ARBs Lifestyle intervention Medicaltherapy Reduce symptomsTreat underlying disease CABG PCI Thank you

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