Transcript Document

Advances in the Science of
Cholesterol Management
A Clinical Overview
Slide Contents by Topic
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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
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
Development of Atherosclerotic
Plaques
Fatty streak
Normal
Lipid-rich plaque
Foam cells
Fibrous cap
Thrombus
Lipid core
Vulnerable vs Stable
Atherosclerotic Plaques
Vulnerable Plaque
Lumen
Fibrous Cap
Lipid
Core
• Thin fibrous cap
• Inflammatory cell infiltrates:
proteolytic activity
• Lipid-rich plaque
Stable Plaque
Lumen
Lipid
Core
Fibrous Cap
Libby P. Circulation. 1995;91:2844-2850.
• Thick fibrous cap
• Smooth muscle cells:
more extracellular matrix
• Lipid-poor plaque
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.
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.
Risk Factors for CHD
• Modifiable
• Nonmodifiable
– Dyslipidemia
– Age
 Raised LDL
– Sex
 Low HDL
– Family history of premature CHD
 Raised TGs
– Smoking
– Hypertension
– Diabetes mellitus
– Obesity
– Dietary factors
– Thrombogenic factors
– Sedentary lifestyle
Wood D, et al. Atherosclerosis. 1998;140:199-270.
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. 2001 Heart 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.
Lower Cholesterol Levels Associated
With Lower CHD Risk
The Framingham Heart Study
CHD Incidence per 1000
150
125
100
75
50
25
0
 204
205-234
235-264 265-294
 295
Serum Cholesterol (mg/100 mL)
Castelli WP. Am J Med. 1984;76:4-12.
Relation of Serum Cholesterol to
CHD Mortality
The MRFIT Study
Mortality Relative Risk
4
3.42
3
2
2.21
1.73
1
1
n = 356,222
(35-57 yrs)
1.29
0
< 182
182-202
203-220 221-244
Serum Cholesterol (mg/dL)
Stamler J, et al. JAMA. 1986;256:2823-2828.
> 244
Early High TC Levels Associated
With Later CHD Events
Results After 40 Years
No. of CHD events*
40
35.2
35
30
25
17.5
20
11.5
15
10
6.9
5
0
118-172
*1017 men, average age 22
173-189
190-208
TC (mg/dL)
Adapted from Klag MJ, et al. N Engl J Med. 1993;328:313-318.
209-315
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
*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.
35% women1
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. Arch Intern Med. 2000;160:1361-1369.
Relative Risk of CHD
Increased Relative Risk of CHD
Associated With Increasing LDL Levels
ARIC Study
Men
4.50
2.85
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.
Relative Risk of CHD
Increased Relative Risk of CHD
Associated With Increasing LDL Levels
ARIC Study
Women
4.50
2.85
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
LDL Cholesterol Goals for Therapeutic
Lifestyle Changes (TLC) and Drug Therapy
According to NCEP ATP III
Risk Category
LDL-C Goal
(mg/dL)
LDL-C Level for
Initiation of TLC
(mg/dL)
LDL-C Level for
Consideration of
Drug Therapy
(mg/dL)
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
0-1 Risk Factor
< 160
 160
 190
(160-189: LDL-C-lowering
drug optional)
NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.
NCEP ATP II: Adults Eligible for and Receiving
Drug Therapy for Dyslipidemia
No. of Patients (millions)
25
23 23
20
LDL-C > NCEP goal
15
Drug therapy
(clinical judgment)
Drug therapy
(conservative guidelines)
Receiving drug
14
11.1
10
5
8.4
7.7 7.7
4.6
1.4
0
No CHD
< 2 RFs
4.6
2.1
No CHD
 2 RFs
1
CHD
Adapted from Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369.
Millions of Americans Are
Under-Treated According to ATP II
Population
(in millions)
 2 RF
 2 RF
15.7
26.6
8.4
Prescribed diet
5.2
7.0
2.4
Prescribed drug*
0.5
1.6
1.1
Treatment-eligible
RF = Risk factor
* Among those who qualify for drug therapy
Hoerger TJ, et al. Am J Cardiol. 1998;82:61-65.
CHD
Greatest Increase in Individuals
Recommended for Drug Therapy Is in
Category With CHD or CHD Risk Equivalent
25
ATP II 1
ATP III 2
Millions
20
15
10
5
0
CHD or
equivalent
ATP III LDL Goal: < 100 mg/dL
2+ risk factors
<2 risk factors
< 130 mg/dL
< 160 mg/dL
1. Adapted from Jacobson TA, et al. Arch Intern Med. 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).
NCEP-ATP III: Adults Eligible to Receive
Treatment for Dyslipidemia
No. of US Adults, (x106)
TLC
Drug Treatment
70
65.3
60
50
40
30
20
10
0
36.5
24.1
20.7
10.9
8.3
14.6
15.6
2.8
CHD and
2+ RFs
2+ RFs
CHD risk(10-y risk (10-y risk
equivalents 10%-20%) < 10%)
4.7
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).
Many Patients Are Not Reaching
Their LDL-C Goal
Percent of Patients
Achieving Goal
100
90
80
70
60
Diet/exercise (%)
Drug therapy* (%)
70
59
50
40
40
30
20
10
0
n=
21
18
8
Low Risk
282
861
High Risk
CHD
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.
Patients (%)
Patients With CHD Achieving LDL-C Targets
With Dose Titration: ACCESS
100
90
80
70
60
50
40
30
20
10
0
At week 54
Atorvastatin 10-80 mg
Simvastatin 10-40 mg
Lovastatin 20-80 mg
Fluvastatin 20-80 mg
Pravastatin 10-40 mg
LDL-C
N = 2543
Adapted from Ballantyne CM, et al. Am J Cardiol. 2001;88:265–269.
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.
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.
LDL-C Lowering With Statins:
Reduced CHD Events
Secondary Prevention
4S-PL
Primary Prevention
25
LIPID-PL
20
4S-Rx
15
CARE-PL
CARE-Rx
10
LIPID-Rx
5
WOSCOPS-Rx
WOSCOPS-PL
AFCAPS-Rx
AFCAPS-PL
0
50
70
90
110
130
150
170
LDL Cholesterol (mg/dL)
Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.
190
210
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.
WOSCOPS
Nonfatal MI and CHD Death
12
Placebo (n = 3293)
Pravastatin (n = 3302)
10
31%
relative
risk
reduction
P < .001
8
6
4
2
0
0
1
2
3
4
5
Years
Adapted from Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.
6
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.
Cumulative Incidence
AFCAPS/TexCAPS Fatal/Nonfatal MI, Sudden
Cardiac Death, Unstable Angina
0.07
Placebo (n = 3301)
Lovastatin (n = 3304)
0.06
37% risk
reduction
P < .001
0.05
0.04
0.03
0.02
0.01
0.00
0
1
2
3
4
Years of Follow-up
Adapted Downs JR, et al. JAMA. 1998;279:1615-1622.
5
>5
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.
4S
Total Mortality
Proportion Alive
1.00
0.95
This
improvement in
survival is
accounted for
by the 42%
reduction in the
risk of coronary
death.
0.90
0.85
Simvastatin
Placebo
0.80
Log rank P = .0003
0.00
0.0
1
2
3
4
5
6
Years Since Randomization
Adapted from Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
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.
CARE
Nonfatal MI or CHD Death
15
Placebo
Change in risk,
24% reduction
P = .003
Incidence (%)
Pravastatin
10
5
0
0
1
2
3
4
5
Years
Adapted from Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
High Compliance Results in
Reduced Risk
Relative Risk Reduction (%)
WOSCOPS Response to Therapy*
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
-50
High Compliers
( 75% compliance)
Entire cohort of patients
treated with lipid-lowering
drug
-31
-32
-37
-37
-38
-46
CHD death
Need for
Nonfatal/
revascularization
fatal MI
*At end of 5-year follow-up (N = 6595)
Adapted from WOSCOPS Study Group. Eur Heart J. 1997:18:1718-1724.
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.