Advances in the Science of Cholesterol Management

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
Lipid Core

• Thin fibrous cap
• Inflammatory cell infiltrates
• proteolytic activity
• Lipid-rich plaque

Fibrous Cap
Stable Plaque
Lumen

• Thick fibrous cap
• Smooth muscle cells
• more extracellular matrix
• Lipid-poor plaque

Lipid Core
Fibrous Cap
Libby P. Circulation. 1995912844-2850.
6
Thrombosis Influences the Severity of a
Cardiovascular Event
Nonocclusive thrombus
Occlusive thrombus

• Unstable angina
• NonQ-wave MI

• Q-wave MI
• Sudden death

Factors favoring thrombosis
Factors limiting 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.
19981291050-1060.
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
Risk Factors for CHD

• Modifiable
• Dyslipidemia
• Raised LDL
• Low HDL
• Raised TGs
• Smoking
• Hypertension
• Diabetes mellitus
• Obesity
• Dietary factors
• Thrombogenic factors
• Sedentary lifestyle

• Nonmodifiable
• Age
• Sex
• Family history of premature CHD

Wood D, et al. Atherosclerosis. 1998140199-270.
9
Cholesterola 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. 2001 Heart and
Stroke Statistical Update. 2000. 2. Gould AL, et
al. Circulation. 199897946-952. 3. NCEP, Adult
Treatment Panel III. JAMA. 20012852486-2497.
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. 1984764-12.
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
lt 182
182-202
203-220
221-244
gt 244
Serum Cholesterol (mg/dL)
Stamler J, et al. JAMA. 19862562823-2828.
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.
1993328313-318.
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
  

201
Rate of post-MI complications

• Death within 1 month of hospitalization

102
333

• Development of heart failure (HF)

213

• 1-year death rate for HF patients

18 men1

• Recurrent MI within 6 years

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. 1998339861-867. 3. Spencer
FA et al. J Am Coll Cardiol. 1999341378-1387.
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.
1998140199-270. 2. National Centre for Health
Statistics. National Health and Nutrition
Examination Survey (III), 1994. 3. Jacobson TA,
et al. Arch Intern Med. 20001601361-1369.
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.
20011041108-1113.
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.
20011041108-1113.
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 lt 40
  mg/dL (a change from lt 35 mg/dL in ATP II)1
• HDL cholesterol tends to be low when
  triglycerides are high2

1. NCEP, Adult Treatment Panel III. JAMA.
20012852486-2497. 2. Wood D, et al.
Atherosclerosis. 1998140199-270.
18
Triglycerides

• Recent data suggest that elevated triglycerides
  are an independent risk factor for CHD
• Normal triglyceride levels lt 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.
20012852486-2497.
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.
20012852486-2497. 2. Cui Y, et al. Arch
Intern Med. 20011611413-1419.
20
National Cholesterol Education Program, Adult
Treatment Panel III (NCEP ATP III)

• The National Cholesterol Education Programs
  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.
20012852486-2497.
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.
20012852486-2497.
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.
20012852486-2497.
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 lt 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.
20012852486-2497.
24
New Concepts for ATP III (cont)

• Modified Treatment Guidelines
• LDL-C lt 100 mg/dL identified as optimal
• LDL-C goal of lt 100 mg/dL expanded to include CHD
  patients and those with CHD risk equivalent

NCEP, Adult Treatment Panel III. JAMA.
20012852486-2497.
25
New Concepts for ATP III (cont)

• More Intensive Lifestyle Intervention
• Therapeutic Lifestyle Changes (TLC)
• Therapeutic diet lowers saturated fat (lt 7 of
  total calories) and cholesterol (lt 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.
20012852486-2497.
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 gt 20)
lt 100
? 100

• 130
• (100-129 drug optional)

2 Risk Factors (10-y risk ? 20)
lt 130
? 130
10-y risk 10-20 ? 130 10-y risk lt 10 ? 160
lt 160
? 160
? 190 (160-189 LDL-C-lowering drug optional)
0-1 Risk Factor
NCEP, Adult Treatment Panel III. JAMA.
20012852486-2497.
27
NCEP ATP II Adults Eligible for and Receiving
Drug Therapy for Dyslipidemia
25
23
23
20
LDL-C gt NCEP goal
15
Drug therapy
14
No. of Patients (millions)
(clinical judgment)
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 lt 2 RFs
CHD
Adapted from Jacobson TA, et al. Arch Intern Med.
20001601361-1369.
28
Millions of Americans Are Under-Treated
According to ATP II
Population (in millions)
? 2 RF
CHD
? 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. 19988261-65.
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
lt 100 mg/dL
lt 130 mg/dL
lt 160 mg/dL
1. Adapted from Jacobson TA, et al. Arch Intern
Med. 20001601361-1369. 2. Adapted from NHLBI.
Adult Treatment Panel III (ATP III) Guidelines
Slide Show. hin.nhlbi.nih.gov/ncep_slds/atpiii/sli
de101.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
0-1 RF
Total
CHD and CHD risk- equivalents
2 RFs (10-y risk 10-20)
2 RFs (10-y risk lt 10)
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

282
861
361
1924
108
1352
n
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.
2000160459-467.
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.
200188265269.
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. 200110338-44.
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. 1999831301-1307.
2. Stenestrand U, et al. JAMA. 20012845430-436.
3. Fonarow GC, et al. Circulation. 20011032768.
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.
20008423-42.
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.
19953331301-1307.
37
WOSCOPSNonfatal MI and CHD Death
12
Placebo (n 3293)
10
Pravastatin (n 3302)
31 relativerisk reduction P lt .001
8
6
Percent With Event
4
2
0
1
2
3
4
5
6
0
Years
Adapted from Shepherd J, et al. N Engl J Med.
19953331301-1307.
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. 19982791615-1622.
39
AFCAPS/TexCAPS Fatal/Nonfatal MI, Sudden Cardiac
Death, Unstable Angina
0.07
Placebo (n 3301)
37 riskreductionP lt .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. 19982791615-1622.
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. 19943441383-1389.
41
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. 19943441383-1389.
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. 19963351001-1009.
43
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.
19963351001-1009.
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
-32
-35
-37
-37
-40
-38
-45
-46
-50
CHD death
Need for revascularization
Nonfatal/ fatal MI
At end of 5-year follow-up (N 6595) Adapted
from WOSCOPS Study Group. Eur Heart J.
1997181718-1724.
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.
20012852486-2497.