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Advances in the Science of Cholesterol Management

Advances in the Science of Cholesterol Management. A Clinical Overview. Slide Contents by Topic. Pathophysiology of Atherosclerosis Risk Factors of CHD Cholesterol and CHD Risk Types of Cholesterol NCEP ATP III Guidelines Treatment Eligibility According to NCEP Attainment of NCEP Goals

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Advances in the Science of Cholesterol Management

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  1. Advances in the Science of Cholesterol Management A Clinical Overview

  2. Slide Contents by Topic • Pathophysiology of Atherosclerosis • Risk Factors of CHD • Cholesterol and CHD Risk • Types of Cholesterol • NCEP ATP III Guidelines • Treatment Eligibility According to NCEP • Attainment of NCEP Goals • Statins and CHD Event Reduction: A Review of Prevention Trials • Benefits of Cholesterol Lowering and Medication Compliance

  3. Normal Arterial Wall Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastic/collagen fibers External elastic membrane

  4. Development of Atherosclerotic Plaques Fatty streak Normal Lipid-rich plaque Foam cells Fibrous cap Lipid core Thrombus

  5. Vulnerable vs Stable Atherosclerotic Plaques Vulnerable Plaque Lumen LipidCore • Thin fibrous cap • Inflammatory cell infiltrates: • proteolytic activity • Lipid-rich plaque FibrousCap Stable Plaque Lumen • Thick fibrous cap • Smooth muscle cells: • more extracellular matrix • Lipid-poor plaque Lipid Core Fibrous Cap Libby P. Circulation. 1995;91:2844-2850.

  6. Thrombosis Influences the Severity of a Cardiovascular Event Nonocclusive thrombus Occlusive thrombus • Unstable angina • Non—Q-wave MI • Q-wave MI • Sudden death Factors limiting thrombosis: Factors favoring thrombosis: • Minor plaque disruption • High flow • Low thrombotic tendency • Major plaque disruption • Low flow or vasospasm • Thrombotic tendency Kullo IJ, et al. Ann Intern Med. 1998;129:1050-1060.

  7. Clinical Manifestations of Atherosclerosis • Coronary heart disease • Stable angina, acute myocardial infarction, sudden death, unstable angina • Cerebrovascular disease • Stroke, TIAs • Peripheral arterial disease • Intermittent claudication, increased risk of death from heart attack and stroke American Heart Association, 2000.

  8. Modifiable Dyslipidemia Raised LDL Low HDL Raised TGs Smoking Hypertension Diabetes mellitus Obesity Dietary factors Thrombogenic factors Sedentary lifestyle Risk Factors for CHD • Nonmodifiable • Age • Sex • Family history of premature CHD Wood D, et al. Atherosclerosis. 1998;140:199-270.

  9. Cholesterol—a Modifiable Risk Factor • In the USA • More than 100 million adults have TC levels 200 mg/dL1 • More than 40 million adults have TC levels 240 mg/dL1 • 10% reduction in TC = 15% reduction in CHD mortality risk and 11% reduction in total mortality risk according to meta-analysis of 38 statin trials2 • LDL-C is the primary target to prevent CHD3 • Intensity of intervention depends on total CV risk3 1. American Heart Association. 2001Heart and Stroke Statistical Update. 2000. 2. Gould AL, et al. Circulation. 1998;97:946-952. 3. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  10. Lower Cholesterol Levels Associated With Lower CHD Risk The Framingham Heart Study 150 125 100 CHD Incidence per 1000 75 50 25 0 265-294  204 205-234 235-264  295 Serum Cholesterol (mg/100 mL) Castelli WP. Am J Med. 1984;76:4-12.

  11. Relation of Serum Cholesterol to CHD Mortality The MRFIT Study 4 3.42 3 Mortality Relative Risk 2 2.21 1.73 1 n = 356,222 (35-57 yrs) 1.29 1 0 < 182 182-202 203-220 221-244 > 244 Serum Cholesterol (mg/dL) Stamler J, et al. JAMA. 1986;256:2823-2828.

  12. Early High TC Levels Associated With Later CHD Events Results After 40 Years 40 35.2 35 30 25 17.5 20 No. of CHD events* 11.5 15 6.9 10 5 0 118-172 173-189 190-208 209-315 TC (mg/dL) *1017 men, average age 22 Adapted from Klag MJ, et al. N Engl J Med. 1993;328:313-318.

  13. Consequences of CHD • Event frequency in 1998 • New or recurrent MI (estimated) = 1,100,0001 • Death prior to hospitalization (estimated) = 220,000 • Total CHD-related deaths = 459,8411 20%1 Rate of post-MI complications* • Death within 1 month of hospitalization 10%2 • Development of heart failure (HF) 33%3 • 1-year death rate for HF patients 21%3 • Recurrent MI within 6 years 18% men1 35% women1 *Numbers vary depending on care 1. American Heart Association. 2001 Heart and Stroke Statistical Update. 2000. 2. Rosamond WD et al. N Engl J Med. 1998;339:861-867. 3. Spencer FA et al. J Am Coll Cardiol. 1999;34:1378-1387.

  14. LDL Cholesterol • Remains the cornerstone of dyslipidemia therapy1 • Strongly associated with atherosclerosis and CHD events1 • 10% increase results in a 20% increase in CHD risk1 • Most patients with elevated LDL untreated • Only 4.5 million out of 28.4 million treated2,3 1. Wood D et al. Atherosclerosis. 1998;140:199-270. 2. National Centre for Health Statistics. National Health and Nutrition Examination Survey (III), 1994. 3. Jacobson TA, et al. ArchInternMed. 2000;160:1361-1369.

  15. Increased Relative Risk of CHD Associated With Increasing LDL Levels ARIC Study Men 4.50 2.85 Relative Risk of CHD 1.80 Adjusted for age and race 12-year follow-up n = 5432 1.15 0.75 2.35 2.85 3.35 3.85 4.35 4.85 (mmol/L) 91 110 130 149 168 188 (mg/dL) LDL Cholesterol Adapted from Sharrett AR, et al. Circulation. 2001;104:1108-1113.

  16. Increased Relative Risk of CHD Associated With Increasing LDL Levels ARIC Study Women 4.50 2.85 Relative Risk of CHD 1.80 Adjusted for age and race 12-year follow-up n = 6907 1.15 0.75 2.15 2.65 3.15 3.65 4.15 4.55 (mmol/L) 84 103 123 142 162 177 (mg/dL) LDL Cholesterol Adapted from Sharrett AR, et al. Circulation. 2001;104:1108-1113.

  17. HDL Cholesterol • Low HDL cholesterol is a strong independent predictor of CHD1 • The lower the HDL cholesterol level the higher the risk for atherosclerosis and CHD2 • Low HDL is defined categorically as a level < 40 mg/dL (a change from < 35 mg/dL in ATP II)1 • HDL cholesterol tends to be low when triglycerides are high2 1. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497. 2. Wood D, et al. Atherosclerosis. 1998;140:199-270.

  18. Triglycerides • Recent data suggest that elevated triglycerides are an independent risk factor for CHD • Normal triglyceride levels: < 150 mg/dL • Borderline-high triglycerides: 150 to 199 mg/dL • High triglycerides: 200 to 499 mg/dL • Very high triglycerides: ( 500 mg/dL) increase pancreatitis risk • Initial aim of therapy is prevention of acute pancreatitis NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  19. Non-HDL Cholesterol • Non-HDL Cholesterol = TC – HDL Cholesterol1 • Secondary target of therapy when serum TG  200 mg/dL1 • New non-HDL-C goal for patients with elevated TG is LDL-C goal + 30 mg/dL1 • Non-HDL-C includes all atherogenic lipoprotein particles including LDL-C, Lp(a), IDL-C, and VLDL-C2 1. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497. 2. Cui Y, et al. Arch Intern Med. 2001;161:1413-1419.

  20. National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) • The National Cholesterol Education Program’s updated clinical guidelines for cholesterol testing and management announced in May 2001 • Establishes goals for patients with varying levels of risk • ATP III builds on previous ATP reports and expands the indications for intensive cholesterol-lowering therapy NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  21. Similarities of NCEP ATP II and ATP III • Continued identification of LDL-C lowering as the primary goal of therapy • Emphasis on intensive LDL-C lowering in people with established CHD • Emphasis on weight loss and physical activity to enhance risk reduction in persons with elevated LDL-C • Identification of 3 categories of risk for different LDL-C goals and intensities of therapy • CHD and CHD risk equivalents • Multiple risk factors (2 or more) • 0 to 1 risk factors NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  22. Similarities of NCEP ATP II and ATP III (cont) • Consideration of high LDL cholesterol ( 160 mg/dL) as a potential target for LDL-lowering drug therapy for • Persons with multiple risk factors whose LDL levels are high after dietary therapy, consideration of drug therapy is recommended • Persons with 0 to 1 risk factors, consideration of drug therapy (after dietary therapy) is optional for LDL 160 to 189 mg/dL and recommended for LDL  190 mg/dL • Identification of subpopulations for detection of high LDL cholesterol and for clinical intervention: • Young adults • Postmenopausal women • Older persons NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  23. New Concepts for ATP III Modified Risk Factor Assessment • Inclusion of more patients in the high-risk category (greater focus on diabetes, noncoronary atherosclerosis, multiple risk factors) • Incorporation of global risk assessment in the guidelines • Complete fasting lipoprotein profile recommended • Definition of low HDL-C is now < 40 mg/dL for males and females • Triglyceride cut points lowered from 200 mg/dL to 150 mg/dL NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  24. New Concepts for ATP III (cont) Modified Treatment Guidelines • LDL-C < 100 mg/dL identified as optimal • LDL-C goal of < 100 mg/dL expanded to include CHD patients and those with CHD risk equivalent NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  25. New Concepts for ATP III (cont) More Intensive Lifestyle Intervention: Therapeutic Lifestyle Changes (TLC) • Therapeutic diet lowers saturated fat (< 7% of total calories) and cholesterol (< 200 mg/d) intakes to levels of previous Step II diet • Adds dietary options to enhance LDL-C lowering • Plant stanols/sterols (2 g/d) • Viscous (soluble) fiber (10-25 g/d) • Increased emphasis on weight management and physical activity NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  26. LDL Cholesterol Goals for Therapeutic Lifestyle Changes (TLC) and Drug Therapy According to NCEP ATP III LDL-C Level for Consideration of Drug Therapy (mg/dL) LDL-C Level for Initiation of TLC (mg/dL) LDL-C Goal (mg/dL) Risk Category CHD or CHD Risk Equivalents (10-y risk > 20%) < 100  100 • 130 (100-129: drug optional) 2 + Risk Factors (10-y risk  20%) < 130  130 10-y risk 10%-20%:  130 10-y risk < 10%:  160 < 160  160  190 (160-189: LDL-C-lowering drug optional) 0-1 Risk Factor NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

  27. NCEP ATP II: Adults Eligible for and Receiving Drug Therapy for Dyslipidemia 25 23 23 20 LDL-C > NCEP goal 15 Drug therapy 14 (clinical judgment) No. of Patients (millions) 11.1 Drug therapy 10 (conservative guidelines) 8.4 7.7 7.7 Receiving drug 4.6 4.6 5 2.1 1.4 1 0 No CHD < 2 RFs No CHD  2 RFs CHD Adapted from Jacobson TA, et al. ArchInternMed. 2000;160:1361-1369.

  28. Millions of Americans Are Under-Treated According to ATP II Population (in millions) CHD  2 RF  2 RF Treatment-eligible 15.7 26.6 8.4 Prescribed diet 5.2 7.0 2.4 Prescribed drug* 0.5 1.6 1.1 RF = Risk factor * Among those who qualify for drug therapy Hoerger TJ, et al. Am J Cardiol. 1998;82:61-65.

  29. Greatest Increase in Individuals Recommended for Drug Therapy Is in Category With CHD or CHD Risk Equivalent 1 2 Millions ATP III LDL Goal: < 100 mg/dL < 130 mg/dL < 160 mg/dL 1. Adapted from Jacobson TA, et al. ArchInternMed. 2000;160:1361-1369. 2. Adapted from NHLBI. Adult Treatment Panel III (ATP III) Guidelines Slide Show. hin.nhlbi.nih.gov/ncep_slds/atpiii/slide101.htm. (accessed 10/25/01).

  30. NCEP-ATP III: Adults Eligible to Receive Treatment for Dyslipidemia TLC Drug Treatment 70 65.3 60 50 40 36.5 No. of US Adults, (x106) 30 24.1 20.7 20 14.6 15.6 10.9 8.3 10 4.7 2.8 0 CHD and CHD risk- equivalents 2+ RFs (10-y risk 10%-20%) 2+ RFs (10-y risk < 10%) 0-1 RF Total Adapted from NHLBI. Adult Treatment Panel III (ATP III) Guidelines Slide Show. hin.nhlbi.nih.gov/ncep_slds/atpiii/slide101.htm. (accessed 10/25/01).

  31. Many Patients Are Not Reaching Their LDL-C Goal 100 90 Diet/exercise (%) 80 Drug therapy* (%) 70 70 59 60 Percent of Patients Achieving Goal 50 40 40 30 21 18 20 8 10 0 Low Risk High Risk CHD n = 282 861 361 1924 108 1352 *Included statins (fluvastatin, lovastatin, pravastatin, simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, or combination drug therapy Adapted from Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

  32. Patients With CHD Achieving LDL-C Targets With Dose Titration: ACCESS At week 54 100 Atorvastatin 10-80 mg 90 Simvastatin 10-40 mg 80 Lovastatin 20-80 mg 70 Fluvastatin 20-80 mg 60 Pravastatin 10-40 mg Patients (%) 50 40 30 20 10 0 LDL-C N = 2543 Adapted from Ballantyne CM, et al. Am J Cardiol. 2001;88:265–269.

  33. Missed Opportunities to Treat CHD Patients In a study of 138,001 patients discharged with acute myocardial infarction from 1470 hospitals during 1998-1999: • Only 31.7% went home on lipid-lowering medication • 41.7% with prior hypercholesterolemia and acute myocardial infarction went home without lipid-lowering medication • Less likely to receive drug therapy: elderly patients, nonteaching hospital patients, patients with high blood pressure or CHF, patients with coronary artery bypass grafting during hospitalization. • More likely to receive drug therapy: past history of coronary artery bypass grafting, smokers receiving counseling, beta-blocker and/or aspirin at discharge. Fonarow GC, et al. Circulation. 2001;103:38-44.

  34. Missed Opportunities to Treat CHD Patients (cont) • The Quality Assurance Program reviewed treatment rates of 48,586 outpatients with CHD from 140 medical practices (80% of which were cardiology practices)1 • Only 39% were treated with lipid-lowering medications1 • Only 25% reached LDL-C levels  100 mg/dL1 • The Swedish Register of Cardiac Intensive Care analyzed the 1-year mortality rate in nearly 20,000 patients2 • 4% mortality rate in patients with initiation of statin therapy prior to hospital discharge2 • 9.3% mortality rate in patients without initiation of statin therapy prior to hospital discharge2 • Early initiation of statin therapy yields a 25% reduction in relative risk for mortality at 1 year (P = .001)3 1. Sueta CA, et al. Am J Card. 1999;83:1301-1307. 2. Stenestrand U, et al. JAMA. 2001;2845:430-436. 3. Fonarow GC, et al. Circulation. 2001;103:2768.

  35. LDL-C Lowering With Statins: Reduced CHD Events Secondary Prevention 4S-PL Primary Prevention 25 LIPID-PL 20 4S-Rx 15 CARE-PL Events (%) CARE-Rx WOSCOPS-PL 10 LIPID-Rx WOSCOPS-Rx 5 AFCAPS-Rx AFCAPS-PL 0 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dL) Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.

  36. West of Scotland Coronary Prevention Study (WOSCOPS) • Study design • Primary prevention of myocardial infarction in 6595 men • Mean baseline LDL: 192 mg/dL • Study intervention • Pravastatin 40 mg or placebo • Primary endpoint • Nonfatal MI and CHD death Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

  37. WOSCOPSNonfatal MI and CHD Death 12 Placebo (n = 3293) 10 Pravastatin (n = 3302) 31% relativerisk reduction P < .001 8 6 Percent With Event 4 2 0 0 1 2 3 4 5 6 Years Adapted from Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

  38. AFCAPS/TexCAPS • Study design • Primary prevention of myocardial infarction in 6605 men and women with average TC and LDL-C levels and below average HDL-C levels • Mean baseline LDL: 150 mg/dL • Study intervention • Lovastatin 20 to 40 mg (to target LDL of 110 mg/dL) or placebo • Primary endpoint • Composite of fatal or nonfatal MI, sudden cardiac death, unstable angina Downs JR, et al. JAMA. 1998;279:1615-1622.

  39. 5 1 2 3 4 >5 AFCAPS/TexCAPS Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina 0.07 Placebo (n = 3301) 37% riskreductionP < .001 Lovastatin (n = 3304) 0.06 0.05 0.04 Cumulative Incidence 0.03 0.02 0.01 0.00 0 Years of Follow-up Adapted Downs JR, et al. JAMA. 1998;279:1615-1622.

  40. Scandinavian Simvastatin Survival Study (4S) • Study design • Secondary prevention in 4444 patients with a history of angina pectoris or acute MI • Mean baseline LDL: 188 mg/dL • Study intervention • Simvastatin 20 to 40 mg (to target TC of 116 to 201 mg/dL) or placebo • Primary endpoint • Total mortality Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.

  41. 1 2 3 6 5 4 4S Total Mortality 1.00 0.95 This improvement in survival is accounted for by the 42% reduction in the risk of coronary death. 0.90 Proportion Alive 0.85 Simvastatin Placebo Log rank P = .0003 0.80 0.00 0.0 Years Since Randomization Adapted from Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.

  42. Cholesterol and Recurrent Events Trial (CARE) • Study design • Secondary prevention in 4159 men and women with average cholesterol levels • Mean baseline LDL: 139 mg/dL • Study intervention • Pravastatin 40 mg or placebo • Primary endpoints • Nonfatal MI or CHD death Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

  43. 1 2 3 4 5 CARENonfatal MI or CHD Death 15 Placebo Change in risk,24% reductionP = .003 Pravastatin 10 Incidence (%) 5 0 0 Years Adapted from Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

  44. High Compliance Results in Reduced Risk WOSCOPS Response to Therapy* 0 -5 High Compliers ( 75% compliance) -10 -15 Entire cohort of patients treated with lipid-lowering drug -20 Relative Risk Reduction (%) -25 -30 -31 -35 -32 -40 -37 -37 -38 -45 -46 -50 CHD death Nonfatal/ fatal MI Need for revascularization *At end of 5-year follow-up (N = 6595) Adapted from WOSCOPS Study Group. Eur Heart J. 1997:18:1718-1724.

  45. Improving Adherence to Cholesterol-Lowering Therapy • Recommendations from the NCEP ATP III guidelines: • Focus on the patient: simplify treatment regimens, effective patient counseling, reinforce and reward adherence, encourage family support • Focus on the provider: teach implementation of guidelines, identify office/patient advocate, develop standardized treatment plan, appointment reminders • Focus on the health system: increase utilization of lipid clinics and nurse case managers, execute critical pathways, collaborate care with pharmacists NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

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