Circulation
`
`JOURNAL OFTHE AMERICAN HEART ASSOCIATION
`
`Associationa
`
`Third Report of the National Cholesterol Education Program (N CEP) Expert Panel on
`Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment
`Panel 111) Final Report
`
`Circulation. 2002;106:3143
`Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
`Copyright @ 2002 American Heart Association, Inc. All rights reserved.
`Print ISSN: 0009-7322. Online ISSN: 1524-4539
`
`The online version of this article, along with updated information and services, is located on the
`World Wide Web at:
`http://circ.ahajournals.org/content/106/25/3143.citation
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`Third Report of the
`National Cholesterol
`Education Program (NCEP)
`Expert Panel on
`
`Detection,
`Evaluation,
`and Treatment
`of High Blood
`Cholesterol
`in Adults
`(Adult Treatment
`Pane|HD
`
`Final Report
`
`National Cholesterol Education Program
`
`National Heart, Lung, and Blood Institute
`
`National Institutes ofHea1th
`
`NIH Publication No. 02-5215
`September 2002
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`Members: Scott M. Grundy, M.D., Ph.D. (Chair
`of the panel), Diane Becker, Sc.D., M.P.H., R.N.,
`Luther T. Clark, M.D., Richard S. Cooper, M.D.,
`Margo A. Denke, M.D., Wm. James Howard, M.D.,
`Donald B. Hunninghake, M.D., D. Roger Illingworth,
`M.D., Ph.D., Russell V. Luepker, M.D., M.S.,
`Patrick McBride, M.D., M.P.H., James M. McKenney,
`Pharm.D., Richard C. Pasternak, M.D., F.A.C.C.,
`Neil J. Stone, M.D., Linda Van Horn, Ph.D., R.D.
`
`Ex-officio Members: H. Bryan Brewer, Jr., M.D.,
`James I. Cleeman, M.D. (Executive Director of the panel),
`Nancy D. Ernst, Ph.D., R.D., David Gordon, M.D.,
`Ph.D., Daniel Levy, M.D., Basil Rifkind, M.D.,
`Jacques E. Rossouw, M.D., Peter Savage, M.D.
`
`Consultants: Steven M. Haffner, M.D.,
`David G. Orloff, M.D., Michael A. Proschan, Ph.D.,
`J. Sanford Schwartz, M.D., Christopher T. Sempos, Ph.D.
`
`Staff: Susan T. Shero, M.S., R.N., Elaine Z. Murray,
`Susan A. Keller, M.P.H., M.S., B.S.N.
`
`Manuscript Preparation: Angela J. Jehle
`
`Mmzmttivta
`
`tmri
`
`Executive Committee Advisor to the Panel:
`Stephen Havas, M.D., M.P.H., M.S.
`
`Reviewers: Eugene Braunwald, M.D., W. Virgil Brown,
`M.D., Alan Chait, M.D., James E. Dalen, M.D.,
`Valentin Fuster, M.D., Ph.D., Henry N. Ginsberg, M.D.,
`Antonio M. Gotto, M.D., D.Phil., Ronald M. Krauss,
`M.D., John C. LaRosa, M.D., F.A.C.P., Thomas H. Lee,
`Jr., M.D., Linda Meyers, Ph.D., Michael Newman, M.D.,
`Thomas Pearson, M.D., Ph.D., Daniel J. Rader, M.D.,
`Frank M. Sacks, M.D., Ernst J. Schaefer, M.D.,
`Sheldon G. Sheps, M.D., Lynn A. Smaha, M.D., Ph.D.,
`Sidney C. Smith, Jr., M.D., Jeremiah Stamler, M.D.,
`Daniel Steinberg, M.D., Ph.D., Nanette K. Wenger, M.D.
`
`The Third Report of the Expert Panel on Detection,
`Evaluation, and Treatment of High Blood Cholesterol
`in Adults was approved by the National Cholesterol
`Education Program Coordinating Committee, which
`comprises the following organizational representatives:
`
`Member Organizations: National Heart, Lung, and
`Blood Institute Claude Lenfant, M.D., (Chair),
`James I. Cleeman, M.D. (Coordinator), American
`Academy of Family Physicians Theodore G. Ganiats,
`M.D., American Academy of Insurance Medicine
`Gary Graham, M.D., American Academy of Pediatrics
`Ronald E. Kleinman, M.D, American Association of
`Occupational Health Nurses Pamela Hixon, B.S.N.,
`R.N., C.O.H.N-S, American College of Cardiology
`Richard C. Pasternak, M.D., F.A.C.C., American College
`of Chest Physicians Gerald T. Gau, M.D., American
`College of Nutrition Harry Preuss, M.D., American
`College of Obstetricians and Gynecologists
`Thomas C. Peng, M.D., American College of
`Occupational and Environmental Medicine
`Ruth Ann Jordan, M.D., American College of Preventive
`Lewis H. Kuller, M.D., Dr.P.H., American
`Medicine
`Diabetes Association, Inc. Alan J. Garber, M.D., Ph.D.,
`Linda Van Horn, Ph.D.,
`American Dietetic Association
`R.D., American Heart Association Scott M. Grundy,
`M.D., Ph.D., American Hospital Association
`Sandra Cornett, Ph.D., R.N., American Medical
`Association Yank D. Coble, Jr., M.D., American Nurses
`Association
`To be named, American Osteopathic
`Association Michael Clearfield, D.O., American
`Pharmaceutical Association James M. McKenney,
`Pharm.D., American Public Health Association
`Stephen Havas, M.D., M.P.H., M.S., American Red
`Cross Donald Vardell, M.S., Association of Black
`Cardiologists Karol Watson, M.D., Ph.D., Association
`of State and Territorial Health Officials Joanne Mitten,
`M.H.E., Citizens for Public Action on Blood Pressure and
`Cholesterol, Inc. Gerald J. Wilson, M.A., M.B.A.,
`National Black Nurses Association, Inc.
`Linda Burnes-Bolton, Dr.P.H., R.N., M.S.N., F.A.A.N.,
`National Medical Association
`Luther T. Clark, M.D.,
`Society for Nutrition Education Darlene Lansing,
`M.P.H., R.D., Society for Public Health Education
`Donald O. Fedder, Dr.P.H., M.P.H.
`
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`3146
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`{?ir:'::.sM?ie:.w
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`;.?&’3::3.3
`
`Associate Member Organization: American Association of
`Office Nurses Joyce Logan.
`
`Federal Agencies: NHLBI Ad Hoc Committee on
`Minority Populations Yvonne L. Bronner, Sc.D., R.D.,
`L.D., Agency for Healthcare Research and Quality
`Francis D. Chesley, Jr., M.D., Centers for Disease Control
`and Prevention Wayne Giles, M.D., M.P.H.,
`Coordinating Committee for the Community
`Thomas M. Lasater, Ph.D.,
`Demonstration Studies
`Department of Agriculture Alanna Moshfegh, M.S.,
`R.D., Department of Defense Col. Robert Dana
`Bradshaw, M.D., M.P.l- ., Food and Drug Administration
`Elizabeth Yetley, Ph.D., Health Resources and Services
`Administration Celia -layes, M.P.H., R.D., National
`Cancer Institute Carolyn Clifford, Ph.D., National
`Center for Health Statistics Clifford Johnson, M.P.H.,
`Office of Disease Prevention and Health Promotion
`Elizabeth Castro, Ph.D., Department of Veterans Affairs
`Pamela Steele, M.D.
`
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`Contents
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`I. Background and Introduction .
`Dcvclopmcnt of an cvidcncc-bascd rcport
`1.
`Fcaturcs of ATP III similar to those of ATP I and II
`New features of ATP III
`Relation of ATP III to .\IcEP's public health approach
`Relation of ATP III to other clinical guidelines
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`ll. Rationale for intervention .
`Basic description of lipids and lipopmleins
`1.
`LDL cholesterol as the primary target of therapy
`2.
`a. Serum LDL cholesterol as a major cause of CHD
`b. Serum LDL cholesterol as target of therapy
`c. Categories and classification of total cholesterol and LDL cholesterol
`Other lipid risk factors
`a. Triglycerides
`1] Elevated serum triglycerides (and triglyceride-rich lipoproteins] as
`a risk factor
`Lipoprotein remnants as atherogenic lipoproteins
`VLDL cholesterol as a marker for remnant lipoproteins
`Causes of elevated serum triglycerides
`Categories of serum triglycerides
`Elevated serum triglycerides and triglyceride-rich lipoproteins
`as targets of therapy
`.\Ion-HDL cholesterol
`1] Non-HDL cholesterol as a risk factor
`2] Non-HDL cholesterol as a secondary target of therapy
`c. High density lipoproteins (HDL)
`1] Low HDL cholesterol as an independent risk factor for CHD
`2] Causes of low HDL cholesterol
`3] Classification of serum HDL cholesterol
`4I Low HDL cholesterol as a potential target of therapy.
`d. Atherogenic dyslipidemia
`1) Atherogenic dyslipidemia as a "risk factor"
`2I Atherogenic dyslipidemia as a target of therapy
`Nonlipid risk factors
`a. Modifiable risk factors
`) Hypertension
`Cigarette smoking
`Diabetes
`Overweight/oh
`Physical inactivity
`6 Athcrogcnic dict
`b. Nnnmodifiable risk factors
`..
`1) Age
`2) Ma1cscx..
`3) Family history ofprcmaturc CHD
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`3.
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`4I
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`b.
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`contents
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`:1 41
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`5. Emerging risk factors
`a. Emerging lipid risk factors
`1) Triglycerides
`2)
`-ipoprotein remnants
`(a)
`3)
`4) Small LDL particles
`{ D L subspecies
`5)
`6) Apolipoproteins
`a) Apo ipoprotein B
`3) Apo ipoprotein A-1
`7) Total c qolesterol/HDL-cholesterol ratio
`b. Emerging nonlipid risk factors
`1) domocysteine
`2) Thromoogenic/hemostatic factors
`3) nflammatory markers
`4) mpaired fasting glucose
`c. Subclinica atherosclerotic disease
`1) Ankle-3rachial blood pressure index (AB1)
`2) Tests for myocardial ischemia
`3) Tests for atherosclerotic plaque burden
`a) Carotid intimal medial thickening
`b) Coronary calcium
`6. Metabolic syndrome
`a. Metabolic syndrome as multiple, interrelated factors that raise risk
`b. Diagnosis of metabolic syndrome
`c. Metabolic syndrome as a target of therapy
`7. Primary prevention: persons without established CHD
`a. Scope of primary prevention
`b. Clinical strategy in primary prevention effort
`c. Concepts of short-term and long-term prevention
`d. Role of LDL lowering in short-term and long-term primary prevention
`e. Risk assessment in primary prevention
`f. Primary prevention with lifestyle changes
`1) Basis for lifestyle recommendations for primary prevention
`2) Dietary clinical trials of cholesterol lowering
`3) Linkage of public health approach and clinical approach in
`primary prevention
`g. Effectiveness of LDL-lowering drugs in primary prevention
`h. Selection of persons for short-term risk reduction with LDL-lowering drugs
`i. Selection of older persons for short-term, primary prevention
`j. Selection of persons for long-term primary prevention in the clinical setting
`k. LDL goals in primary prevention
`8. Secondary prevention: persons with CHD
`a. Secondary prevention of recurrent CHD
`b. Effects of lipid-lowering therapy on stroke
`9. Total mortality considerations and therapeutic safety
`10. Magnitude of reduction in CHD risk
`11. CHD as a risk indicator
`12. Concept of CHD risk equivalents
`a. Other forms of clinical atherosclerotic disease
`1) Peripheral arterial disease (PAD)
`2) Carotid artery disease
`3) Abdominal aortic aneurysm (AAA)
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`3182
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`b. Diabetes as a CHD risk equivalent
`c. High-risk persons with multiple risk factors
`13. Models for clinical intervention: role of multidisciplinary team
`14. Cost-effectiveness issues
`a. Purpose of cost-effectiveness analysis of LDL-lowering therapy
`b. Approaches to estimating cost-effectiveness of cholesterol-lowering therapies
`c. Criteria for cost-effectiveness therapies
`d. Cost-effectiveness analysis for LDL lowering for secondary prevention
`(persons with established CHD)
`e. Cost-effectiveness analysis in persons with CHD risk equivalents
`f. Cost-effectiveness of primary prevention
`1) Cost-effectiveness of dietary therapy for primary prevention
`2) Cost-effectiveness of drug therapy for short-term primary prevention
`3) Cost-effectiveness for primary prevention based on WOSCOPS results
`4) Cost-effectiveness of primary prevention based on the
`AFCAPS/TexCAPS trial
`5) Cost-effectiveness in long-term primary prevention
`g. Summary
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`55%.
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`1.
`
`Identification of risk categories for setting of LDL-cholesterol goals
`Identification of persons with CHD and CHD risk equivalents
`a.
`b. Risk assessment in persons without CHD or CHD risk equivalents
`(starting with risk factor counting)
`Identification of persons with multiple (2+) risk factors
`1)
`2) Calculation of 10-year CHD risk
`2. Determination and classification of LDL cholesterol
`a. Who should be tested for cholesterol and lipoproteins?
`b. Procedures of measurement
`c. Classification of lipid and lipoprotein levels
`d. Secondary dyslipidemias (see Section VII)
`3. Atherogenic dyslipidemia and the metabolic syndrome
`a. Atherogenic dyslipidemia and classification of serum triglycerides
`b. Diagnosis of the metabolic syndrome
`4. Role of emerging risk factors in risk assessment
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`mm:
`
`31 49
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`3212
`3216
`3216
`3216
`3217
`3217
`3219
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`3219
`3220
`3220
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`3220
`3220
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`3221
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`3227
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`Distributions of Total Cho esterol, LDL Cholesterol,
`HDL Cholesterol, and Triglycerides in the U.S. Adult
`Population, NHANES III Data (1988-1994) (Serum)
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`3237
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`:=fsM.Ti%
`3243
`3244
`3244
`3244
`3244
`3245
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`W.
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`1. Therapeutic goals for -DL cholesterol
`2. Management of LDL Cholesterol
`a. CHD and CHD risk equivalents
`1) Baseline LDL cqolesterol 2130 mg/dL
`2) Baseline LDL cqolesterol 100-129 mg/dL
`3) Baseline LDL cqolesterol <100 mg/dL
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`b. Multiple (2+) risk factors
`1) Multiple risk factors, and 10-year risk >20 percent
`2) Multiple risk factors, and 10-year risk 10-20 percent
`3) Multiple risk factors, 10-year risk <10 percent
`c. Zero to one risk factor
`d. Management of LDL cholesterol when risk assessment begins with
`Framingham scoring
`e. Recommendations for persons whose LDL cholesterol levels are
`below goal
`f. LDL-lowering therapy in older persons
`3. Management of atherogenic dyslipidemia and the metabolic syndrome
`a. Atherogenic dyslipidemia
`b. Metabolic syndrome
`
`vi
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`1. Population approach: promoting a base of healthy life habits
`2. General approach to therapeutic lifestyle changes (TLC)
`3. Components of the TLC Diet
`a. Major nutrient components
`1) Saturated fatty acids
`2) Trans fatty acids
`3) Dietary cholesterol
`4) Monounsaturated fatty acids
`5) Polyunsaturated fatty acids
`6) Total fat
`7) Carbohydrate
`8) Protein
`b. Additional dietary options for LDL lowering
`Increasing viscous fiber in the diet
`1)
`2) Plant stanols/sterols
`3) Soy protein
`c. Other dietary factors that may reduce baseline risk for CHD
`1) n-3 (omega-3) polyunsaturated fatty acids
`2) Vitamins/antioxidants
`a) Folic acid and vitamins B5 and B12
`b) Antioxidants
`3) Moderate intakes of alcohol
`4) Dietary sodium, potassium, and calcium
`5) Herbal or botanical dietary supplements
`6) High protein, high total fat and saturated fat weight loss regimens
`4. Management of the metabolic syndrome through life habit changes
`a. Weight control
`lncreased regular physical activity
`b.
`5. Practical approach to life habit changes
`a. Role of the physician
`1) Visit 1: Risk assessment, diet assessment, and initiation of
`therapeutic lifestyle change
`2) Visit 2: lntensifying the TLC diet for LDL cholesterol lowering
`3) Visit 3: Decision about drug therapy; initiating management
`of the metabolic syndrome
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`321 5
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`321 6
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`321 7
`321 7
`321 7
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`3253
`3254
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`4) Visit N: Long-term follow-up and monitoring adherence to
`therapeutic lifestyle changes (TLC)
`b. Role of nurses, physician assistants, and pharmacists
`c. Specific role of registered dietitians and other qualified nutrition
`professionals
`1) Role of the nutrition professional in LDL-lowering therapy
`a) First: dietary assessment
`b) Dietary guidance on adopting the TLC diet
`c) Specific foods and preparation techniques
`d) Recommendations by food group
`e) Other eating tips
`2) Role of the dietitian in management of the metabolic syndrome
`Improving patient adherence to life habit changes
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`6.
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`3274
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`E
`
`E
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`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
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`E
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`
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`
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`
`E
`
`E
`
`Sample Dietary Assessment Questionaire MEDFICTS
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
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`
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`
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`
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`
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`
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`
`E
`
`E
`
`E
`
`TLC Sample Menus: Traditional American Cuisine: Male, 25-49 Years
`Traditional American Cuisine: Female, 25-49 Years
`Lacto Ovo Vegetarian Cuisine: Male, 25-49 Years
`Lacto Ovo Vegetarian Cuisine: Female, 25-49 Years
`Southern Cuisine: Male, 25-49 Years
`Southern Cuisine: Female, 25-49 Years
`Asian Cuisine: Male, 25-49 Years
`Asian Cuisine: Female, 25-49 Years
`Mexican-American Cuisine: Male, 25-49 Years
`Mexican-American Cuisine: Female, 25-49 Years
`
`:=fs$3i$%f=:%
`3283
`
`E 3287
`3287
`3288
`3289
`3290
`3291
`3292
`3293
`3294
`3295
`3296
`
`E:}l%i%%T
`Saturated Fat, Total Fat, Cholesterol, and Omega-3 Content of Meat,
`Fish, and Poultry in 3-Ounce Portions Cooked Without Added Fat
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
`E
`
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`
`E
`
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`
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`
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`
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`
`E
`
`E
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`
`E
`
`E
`
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`
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`
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`
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`
`3299
`
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`
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`
`WE
`
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`
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`
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`
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`
`E
`
`1. Thresholds and goals for drug treatment
`a. Drug therapy to achieve treatment goals: overview
`b. Cholesterol management in persons with CHD or CHD risk equivalents
`1) Baseline LDL cholesterol 2130 mg/dL
`2) On-treatment LDL cholesterol 100-129 mg/dL
`3) Baseline LDL cholesterol 100-129 mg/dL
`4) Baseline LDL cholesterol <100 mg/dL
`Initiating cholesterol-lowering drugs in hospitalized patients
`5)
`6) Special considerations for drug therapy in CHD patients
`c. General principles of primary prevention with drug therapy
`d. Drug considerations for persons with multiple (2+) risk factors
`1) 10-year risk >20 percent
`2) 10-year risk 10-20 percent
`3) 10-year risk <10 percent
`e. Drug considerations for persons with 0-1 risk factor,
`10-year risk <10 percent
`2. Available drug therapies
`a. Overview and general approach
`
`:=fsEE*a&T;%:=.%
`3303
`3303
`3304
`3305
`3305
`3305
`3306
`3306
`3307
`3307
`3307
`3307
`3307
`3308
`
`3308
`3308
`3308
`
`Downloaded from http://circ.ahaj0urnals.0rg/ by guest on November 13, 2014
`
`AMRNOO289924
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 10 of 280
`
`

`

`3152
`
`Eil:era:c:=wr:E:~m’
`
`Sm, ;mm
`
`b. Major drugs
`1) HMG CoA reductase inhibitors (statins)-lovastatin,
`pravastatin, simvastatin, fluvastatin, atorvastatin
`2) Bile acid sequestrants-cholestyramine, colestipol, colesevelam
`3) Nicotinic acid
`4) Fibric acid derivatives (fibrates): gemfibrozil, fenofibrate, clofibrate
`c. Other drugs
`d. n-3 (omega) fatty acids
`e. Hormone replacement therapy (HRT)
`1) Selective estrogen receptor modulators (SERM)-Raloxifene
`f. Miscellaneous drugs and therapeutic approaches
`lnvestigational drugs
`1)
`2) Other approaches
`3. Selection of drugs for elevated LDL cholesterol
`a. Practical advice on combined drug therapy
`1) Statin-bile acid sequestrant combination
`2) Statin-fibrate combination therapy
`3) Statin-nicotinic acid combination therapy
`4) Fibrate-nicotinic acid combination therapy
`lnitiation, monitoring and followup of drug treatment
`Initiation of LDL-lowering drug therapy
`a.
`b. Baseline measurements
`Interval of follow up
`c.
`d. Followup treatment decisions
`
`4.
`
`WE.
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`ail?’
`1. Very high LDL cholesterol
`a. Familial hypercholesterolemia (FH)
`b. Familial defective apolipoprotein B-100 (FDB)
`c. Polygenic hypercholesterolemia
`2. Elevated triglycerides
`a. Classification, causation, and clinical significance
`1) Classification of serum triglycerides
`2) Causes of elevated triglycerides
`3) Relation of elevated triglycerides to CHD and other conditions
`b. Therapeutic considerations for persons with elevated triglycerides
`1) Non-HDL cholesterol: secondary target for persons with
`elevated triglycerides
`2) Changes in life habits are primary therapy for elevated triglycerides
`3) Special treatment considerations for different triglyceride categories
`3. Low HDL cholesterol (without hypertriglyceridemia)
`a. Definition, causes and relationship to CHD
`b. Therapeutic considerations in persons with low HDL cholesterol
`1) Clinical trial evidence
`2) Recommendations for low HDL cholesterol in persons with
`CHD or CHD risk equivalents, 10-year risk >20 percent
`3) Considerations for persons with low HDL cholesterol in
`other risk categories, 10-year risk S20 percent
`4. Diabetic dyslipidemia
`a. Definition of diabetic dyslipidemia
`
`3309
`
`3309
`3311
`3313
`3315
`3318
`3318
`3318
`3320
`3320
`3320
`3320
`3320
`3322
`3322
`3322
`3323
`3324
`3324
`3324
`3324
`3324
`3325
`
`:i*sf;*a$fi%E%
`3329
`3330
`3330
`3330
`3331
`3331
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`3333
`
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`3334
`3334
`3336
`3336
`3337
`3337
`
`3338
`
`3338
`3338
`3338
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`Downloaded from http://circ.ahaj0urnals.0rg/ by guest on November 13, 2014
`
`AMRNOO289925
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 11 of 280
`
`

`

`b. Role of elevated LDL and other risk factors in causation of CHD in
`persons with diabetes
`c. Therapeutic recommendations for lipoprotein disorders in persons
`with diabetes
`1) Special therapeutic considerations according to
`LDL-cholesterol level
`2) Comments on specific drug classes used in management of lipid
`disorders in persons with diabetes
`5. Other secondary dyslipidemias
`6. Persons with high blood cholesterol and concomitant hypertension
`a. Therapeutic considerations
`b. Effects of antihypertensive agents on serum lipids
`c. Selection of antihypertensive therapy
`d. Selection of lipid-lowering therapy
`e. Compliance with therapy
`
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`WEE.
`
`l’T&s"e:mg:m .
`
`l. Middle-aged men
`2. Women
`3. Older persons (men 265 years; women 275 years)
`4. Younger adults (men 20-35 years; women 20-45 years)
`5. Racial and ethnic groups
`a. African Americans
`b. Hispanic Americans
`c. Native Americans (American Indians)
`d. Asian and Pacific Islanders
`e. South Asians
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`1. Recurrent themes and perspectives
`Interventions to improve adherence
`2.
`Interventions focused on the patient
`a.
`1) Simplify medication regimens
`2) Provide explicit patient instruction and use good counseling techniques
`to teach the patient how to follow the prescribed treatment
`3) Encourage the use of prompts to help persons remember treatment
`regimens
`4) Use systems to reinforce adherence and maintain contact with
`the patient
`5) Encourage the support of family and friends
`6) Reinforce and reward adherence
`Increase patient visits for persons unable to achieve treatment goal
`7)
`Increase the convenience and access to care
`8)
`Involve patients in their care through self-monitoring
`9)
`Interventions focused on the physician and medical office
`1) Teach physicians to implement lipid treatment guidelines
`2) Use reminders to prompt physicians to attend to lipid management
`Identify a patient advocate in the office to help deliver or prompt care
`3)
`4) Use patients to prompt preventive care
`5) Develop a standardized treatment plan to structure care
`
`mm:
`
`31 53
`
`3339
`
`331 0
`
`331 0
`
`331 2
`331 2
`331 3
`331 3
`331 3
`331 4
`331 4
`331 4
`
`331 9
`3350
`3350
`3351
`3353
`3353
`3354
`3355
`3356
`3356
`
`3359
`3360
`3360
`3361
`
`3361
`
`3361
`
`3361
`3362
`3362
`3362
`3362
`3362
`3362
`3363
`3363
`3363
`3363
`3363
`
`Downloaded from http://circ.ahaj0urnals.0rg/ by guest on November 13, 2014
`
`AMRNOO289926
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 12 of 280
`
`

`

`3154
`
`Cnclildtilrn
`
`December 17/24. 2002
`
`.
`
`6) Use feedback from past performance to foster change in future care
`7) Remind patients of appointments and follow up missed appointments
`Interventions focused on the health delivery system
`1) Provide lipid management through a lipid clinic
`2) Utilize case management by nurses
`3) Deploy telemedicine
`4) Utilize the collaborative care of pharmacists
`5) Execute critical care pathways in hospitals
`
`.
`
`.
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`.
`
`3363
`3364
`3364
`3364
`3364
`3365
`3365
`3365
`
`3369
`
`3373
`
`List of Studies
`
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`References
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`Downloaded emm http'//cir<:.al1ajou|'nals.org/ hy guest on November 13, 2014
`
`AMRN00289927
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 13 of 280
`
`

`

`-
`
`I. Background and
`Introduction
`
`I
`
`I
`
`Downloaded from http://circ.ahnjoun1als.ory by guest on November 13, 2014
`
`AMRNOO289928
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 14 of 280
`
`

`

`Downloaded from http://circ.ahajourna1s.org/ by guest on November 13, 2014
`
`AMRNOO289929
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 15 of 280
`
`

`

`3157
`
`The Third Report of the Expert Panel on Detection,
`Evaluation, and Treatment of High Blood Cholesterol
`in Adults (Adult Treatment Panel III, or ATP Ill)
`presents the National Cholesterol Education Programs
`(NCEP’s) updated recommendations for cholesterol
`testing and management. It is similar to Adult
`Treatment Panel ll (ATP H)12 in general outline and
`fundamental approach to therapy. It focuses on the
`role of the clinical approach to prevention of coronary
`heart disease (CHD).* This report continues to identify
`low-density lipoprotein (LDL) as the primary target of
`cholesterol-lowering therapy. Since ATP H, a number
`of controlled clinical trials with newer cholesterol-
`lowering drugs have been reported. These trials
`demonstrated remarkable reductions in risk for CHD,
`in both primary and secondary prevention. Their
`results enrich the evidence base upon which the new
`guidelines are founded.
`
`*2.
`
`M W
`
`W}ig3lti.Wii.
`
`The ATP lll panel extensively analyzed the results of
`recent clinical trials whose findings strongly influenced
`the development of the new guidelines. The panel’s
`major goals were to review the literature objectively
`and to document and display the scientific evidence for
`ATP lll recommendations. Prior to the appointment of
`the ATP lll panel, the NCEP Coordinating Committee
`developed a list of important issues for the panels
`consideration. This list was presented to the panel,
`discussed, and modified appropriately. The literature
`pertaining to each defined issue was identified by the
`panel members and by a l\/IEDLINE search. Panel
`members produced a series of issue papers that careful-
`ly reviewed the literature; these issue papers became
`the foundation for writing the first draft of the report.
`Modifications of drafts were made following review
`and discussion of additional evidence arising from the
`literature search. ATP lll contains both evidence state-
`ments and specific recommendations based on these
`statements. Each evidence statement is qualified
`according to category of evidence (A-D) and strength
`of evidence (1-3), as follows:
`
`in ATP lll, CHD is defined as symptomatic ischemic heart disease, including
`myocardial
`infarction, stable or unstable angina, demonstrated myocardial
`ischemia by noninvasive testing, and history of coronary artery procedures.
`
`Category of Type
`of Evidence
`
`Description of Type of Evidence
`
`A
`
`B
`
`C
`
`D
`
`Major randomized controlled clinical
`trials (RCTS)
`
`Smaller RCTS and meta-analyses of
`other clinical trials
`
`Observational and metabolic studies
`
`Clinical experience
`
`Category of Strength
`of Evidence
`
`Description of Strength
`of Evidence
`
`1
`
`2
`
`3
`
`Very strong evidence
`
`Moderately strong evidence
`Strong trend
`
`Empirical data provide the foundation for recommen-
`dations; but research in the cholesterol field, as in
`almost any other, generally has addressed large ques-
`tions and has not necessarily provided answers to every
`specific question of clinical intervention. Thus, in the
`panel’s view, the general evidence (including type and
`strength) often fails to carry a one-to-one correspon-
`dence with needed specific recommendations.
`Consequently, ATP lll recommendations are based on
`the panel’s best interpretation of the relation between
`empirical evidence and issues of clinical intervention.
`The recommendations are crafted in language that best
`links general evidence to specific issues; they are not
`qualified quantitatively according to category and
`strength of evidence, which is implicit in the language
`of the recommendation. Finally, for complex issues,
`several evidence statements or recommendations may
`be grouped together.
`
`Downloaded from http://circ.ahaj0urnals.0rg/ by guest on November 13, 2014
`
`AMRNOO28993O
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1008, p. 16 of 280
`
`

`

`3158
`
`{?irg::.s.%a?iw:s
`
`5;i%e>e:l%r;*iExe>r'
`
`;.?t’3::3.3
`
`This evidence-based report should not be viewed as a
`standard of practice. Evidence derived from empirical
`data can lead to generalities for guiding practice, but
`such guidance need not hold for individual patients.
`Clinical judgment applied to individuals can always
`take precedence over general management principles.
`Recommendations of ATP lll thus represent general
`guidance that can assist in shaping clinical decisions,
`but they should not override a clinician’s considered
`judgment in the management of individuals.
`
`The ATP lll panel played four important roles in
`forging this evidence-based report. First, it systemati-
`cally reviewed the literature and judged which reports
`provided relevant information. Second, it synthesized
`the existing literature into a series of evidence state-
`ments. This synthesis also required a judgment as to
`the category and strength of evidence. Third, the panel
`developed recommendations based on the evidence
`statements; these recommendations represent a
`consensus judgment about the clinical significance of
`each evidence statement. Lastly, the panel created an
`integrated set of recommendations and guidelines
`based on individual recommendations.
`
`l?lmt:l.,mals
`
`AW 21% sil:rlilm:
`
`tilrlme.~
`
`AW E amlti El
`
`ATP lll represents an update of recommendations for
`clinical management of high blood cholesterol and
`related abnormalities. It is constructed on the founda-
`tion of previous reports, ATP I34 and ATP ll.1v2 The
`NCEP periodically produces ATP clinical updates as
`warranted by advances in the science of cholesterol
`management. Each report has a major thrust. ATP I
`outlined a strategy for primary prevention of CHD
`in persons with high LDL cholesterol (3160 mg/dL)
`or in those with borderline-high LDL cholesterol
`(l30-l59 mg/dL) and multiple (2+) other risk factors.
`ATP ll affirmed the importance of this approach and
`added a new feature: the intensive management of LDL
`cholesterol in persons with established CHD. For CHD
`patients, ATP ll set a new, lower LDL-cholesterol goal
`of 5100 mg/dL. ATP lll maintains continuity with ATP
`I and ATP ll. Before considering the