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Coronary Artery Disease (CAD): The Diagnosis Often Comes Too Late

Coronary Artery Disease (CAD): The Diagnosis Often Comes Too Late. (Adapted from Levy et al.) Levy D et al in Textbook of Cardiovascular Medicine , 1998. Vascular Disease: Scope of the Problem.

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Coronary Artery Disease (CAD): The Diagnosis Often Comes Too Late

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  1. Coronary Artery Disease (CAD):The Diagnosis Often Comes Too Late (Adapted from Levy et al.) Levy D et al in Textbook of Cardiovascular Medicine, 1998.

  2. Vascular Disease: Scope of the Problem • Vascular disease—and CAD in particular—is the leading cause of death in the US and other Western nations • By 2020, cardiovascular disease will become the most common cause of death worldwide • Due to the high initial mortality of vascular disease, the target of clinical practice must be aggressive risk factor management • American Heart Association, 2000 Heart and Stroke Statistical Update, 1999; Braunwald E, N Engl J Med, 1997;Kannel WB in Atherosclerosis and Coronary Artery Disease, 1996.

  3. Atherosclerosis: A Systemic Disease From a prospective analysis of 1886 patients aged 62 years, 810 patients were diagnosed with CAD as defined by a documented clinical history of MI, ECG evidence of Q-wave MI, or typical angina without previous MI. (Adapted from Aronow et al.) • Aronow WS et al, Am J Cardiol, 1994.

  4. Carotid IMT Predicts Coronary Events (Adapted from Salonen.) Salonen R in Risk Factors for Ultrasonographically Assessed Common Carotid Atherosclerosis, 1991.

  5. Major Risk Factors for CAD Grundy SM et al, Circulation, 1998; Grundy SM, Circulation, 1999.

  6. CAD Risk Is Incremental (Adapted from Neaton et al.) • Neaton JD et al, Arch Intern Med, 1992.

  7. Most Myocardial Infarctions Are Causedby Low-Grade Stenoses Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.(Adapted from Falk et al.) • Falk E et al, Circulation, 1995.

  8. Lesion Severity: A PoorPredictor of Survival From the Coronary Artery Surgery Study (CASS) as reported by Little et al. Little WC et al, Clin Cardiol, 1991.

  9. Angiography: Significant Limitations in Atheroma Assessment • Angiography reflects a planar, 2-dimensionalsilhouette of the lumen • Remodeling • Because angiography does not visualize thevessel wall, it cannot account for positive ornegative remodeling • Composition • Becauseangiography does not assess plaque composition, it cannot differentiate lipid-rich, more vulnerable plaques • Postprocedure • Due to plaque fissuring, angiography overestimatesthe degree of postintervention lumen expansion Nissen SE et al in Restenosis After Intervention With New Mechanical Devices, 1992; Yamashita T et al, Progress in CardiovascularDiseases, 1999; Topol EJ et al, Circulation, 1995.

  10. Coronary Remodeling Progression Expansion overcome: lumen narrows Compensatory expansion maintains constant lumen Normal vessel Minimal CAD Moderate CAD Severe CAD (Adapted from Glagov et al.) Glagov et al, N Engl J Med, 1987.

  11. 3.1 mm Angiography Cannot Account forCoronary Remodeling 3.1 mm

  12. Atheroma Morphology by Ultrasound “Soft” Lipid-Laden Plaque “Hard” Fibrous Plaque

  13. Angiography Masks Complicated Lesions LAO RAO

  14. Angiography Underestimates Diffuse Disease

  15. What Is the Culprit Lesion? • 58-year-old male with chronic stable angina • Positive stress test with small reversible ischemic defecton nuclear scintigraphy • Medical Rx, but 6 weeks later… • 3-day history of unstableangina, including30 minutes of rest pain • Medically “cooled off”followed by angiography • Case provided by the McLaren Heart and Vascular Center, Flint, Michigan; used with permission.

  16. Absence of Correlation Between Angiographic Results and Clinical Outcomes (Adapted from Brown et al.) Brown BG et al, Circulation, 1993.

  17. Same Lumen Size: Different Atheromas Thin Cap With Lipid Core Thick Stable Fibrotic Cap

  18. Assessing Volumetric Atheroma Changes • Trial performed at Kobe General Hospital (Kobe, Japan) • Hypothesis: patients with angiographically normal arteries receiving statin therapy will show reduced progression of coronary plaque as measured by IVUS Takagi T et al, Am J Cardiol, 1997.

  19. IVUS: Changes in Atheroma Volume • Statin reduced TC and LDL-C; no change in HDL-C or TG Results for 25 patients (13 in the pravastatin group, 12 in the control group) who completed the study. These patients were similarat baseline with regard to dyslipidemia (LDL-C 200-260 mg/dL) and IVUS. Mean plaque index at baseline was 41.2%. Qualifying arteries had not undergone a procedure and were angiographically normal (<25% lumen reduction). (Adapted from Takagi et al.) Takagi T et al, Am J Cardiol, 1997.

  20. Ongoing Statin Trials Utilizing IVUS: REVERSAL Primary hypothesis • A large (vs moderate) reduction in LDL-C will cause a greater decrease in the total atherosclerotic burden in patients with established CAD measured by IVUS Secondary hypothesis • The reduction in plaque burden as assessed by IVUS will be evident despite the absence of any angiographically apparent improvement Data on file, Pfizer Inc., New York, NY.

  21. REVERSAL: Study Design • International, prospective, randomized, multicenter, double-blind • Projected completion: 2002 Data on file, Pfizer Inc., New York, NY.

  22. Interventions Beyond Lipid Reduction Lichtlen PR et al, Lancet, 1990; Waters D et al, Circulation, 1990; Borhani NO et al, JAMA, 1996.

  23. CCB Imaging Trials: Results • INTACT–CCB showed significantly lower rate of new lesions; neutral effect on existing lesions • Montreal Heart Study–CCB showed significantly less progression of early lesions; neutral effect on existing lesions overall • MIDAS–CCB showed initial effect on IMT; but there was no subsequent difference • Although these trials were not powered for clinical end points, the shorter-acting CCBs exerted neutral effects overall; nonsignificant trends suggested poorer outcomes in at least one study Lichtlen PR et al, Lancet, 1990; Waters D et al, Circulation, 1990; Borhani NO et al, JAMA, 1996.

  24. Ongoing IVUS/Calcium Channel Blocker Trial: CAMELOT/NORMALISE CAMELOT hypothesis • Whether amlodipine will reduce major cardiacend points in patients with CAD compared with enalapril and placebo NORMALISE (substudy) hypothesis • Whether amlodipine will reduce the progression of coronary atherosclerosis as measured by IVUS(vs QCA) Data on file, Pfizer Inc., New York, NY.

  25. CAMELOT/NORMALISE: Study Design • International, prospective, randomized, multicenter, double-blind • Projected completion: 2003 Data on file, Pfizer Inc., New York, NY.

  26. IVUS: An Invaluable Research Tool • Correlates more closely with clinical end points than angiography, which is insensitive until lesions are relatively advanced • Reveals direct effects on plaque of treatmentsfor atherosclerosis as well as modifications of its predisposing risks • Used in conjunction with angiography, IVUS is uncovering new data about vascular responseand atherogenesis Nissen SE et al in Textbook of Cardiovascular Medicine, 1998; Yamashita T et al, Progress in Cardiovascular Diseases, 1999;Topol EJ et al, Circulation, 1995.

  27. Atherosclerosis Begins in Childhood (Adapted from Berenson et al.) Berenson GS et al, N Engl J Med, 1998.

  28. One in Six Teenagers Has Atheromas (Adapted from Tuzcu et al.) Tuzcu EM et al, in press.

  29. Consistent Evidence of Early Atherosclerosis (Adapted from Berenson et al and Tuzcu et al.) Berenson GS et al, N Engl J Med, 1998; Tuzcu EM et al, in press.

  30. CAD: Silent Disease Necessitates Aggressive Risk Factor Management • IVUS corroborates necroscopy studies, proving that atherosclerosis begins in youth • CAD progresses silently; the initial presentation is usually MI or sudden death • Most atheromas are extraluminal, rendering them angiographically silent • The only reasonable approach is early and aggressive risk factor management Berenson GS et al, N Engl J Med, 1998; Tuzcu EM et al, in press; Levy D et al in Textbook of Cardiovascular Medicine, 1998;Yamashita T et al, Progress in Cardiovascular Diseases, 1999; Topol EJ et al, Circulation, 1995. Kannel WB in Atherosclerosis and Coronary Artery Disease, 1996.

  31. The Correlation Between Atherosclerosis and Risk Factors Begins Early (Adapted from Berenson et al.) • Berenson GS et al, N Engl J Med, 1998.

  32. Small Increases in Cholesterol Lead to Dramatic Increases in CAD Death (Adapted from Neaton et al.) • Neaton JD et al, Arch Intern Med, 1992.

  33. CAD: Not Just a Lipid Disease • Half of all MIs occur in normolipidemic patients • SmokingAccounts for 200,000 cardiovascular deaths annually • DiabetesAffects 16 million Americans—and is growing • HypertensionConfers as much risk for MI as smoking or dyslipidemia • Systolic hypertension is an even greater indicator of CAD risk than diastolic hypertension Braunwald E, N Engl J Med, 1997; Grundy SM et al, Circulation, 1998; The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the National High Blood Pressure Education Program Coordinating Committee, Arch Intern Med, 1997.

  34. Systolic BP Confers Incremental RiskEven Within “Normal” Levels (Adapted from Neaton et al.) Neaton JD et al, Arch Intern Med, 1992.

  35. CAD Risk Factors: Minimal and Optimal Grundy SM, Circulation, 1999; American Heart Association Consensus Panel, Circulation, 1995; The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the National High Blood Pressure Education Program Coordinating Committee, Arch Intern Med, 1997.

  36. Conclusions: Critical Lessonsin Understanding Atherogenesis • CAD is a ubiquitous, systemic disease that requires a systemic solution • Most patients progress to MI or sudden death before a diagnosis of CAD is ever considered • IVUS demonstrates that remodeling causes angiography to underestimate the extent of disease • Extraluminal, angiographically silent atheromas are responsible for most acute coronary events, including sudden death Aronow WS et al, Am J Cardiol, 1994; Levy D et al in Textbook of Cardiovascular Medicine, 1998; Nissen SE et al in Textbook of Cardiovascular Medicine, 1998; Falk E et al, Circulation, 1995.

  37. Conclusions: Risk Factor Management • Atherosclerosis begins in childhood and is strongly associated with major CAD risk factors from the youngest ages • Hypertension (particularly systolic), diabetes, and smoking—in addition to dyslipidemia—confer comparable risks • The effect of these risk factors is continuous, extending even into the “normal” range • Therefore, aggressive risk factor modification is the most effective strategy for reducing the consequences of CAD Berenson GS et al, N Engl J Med, 1998; Braunwald E, N Engl J Med, 1997; Neaton JD et al, Arch Intern Med, 1992; Kannel WB inAtherosclerosis and Coronary Artery Disease, 1996.

  38. “Awaiting overt signs and symptoms of coronary diseasebefore treatment is no longer justified.” • “In some respects, the occurrence of symptoms may be regarded more properly as a medical failure than as the initial indication for treatment.” • —William B. Kannel, MDDepartment of MedicineBoston University Medical Center Kannel WB in Atherosclerosis and Coronary Artery Disease, 1996.

  39. Supplemental Slides

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