CHOLESTEROL UPDATE 1998

1
CHOLESTEROLUPDATE1998
2
The Impact of Coronary Heart Disease in the
United States

• Heart disease is the leading cause of death in
  the United States in both man and woman
• In 1992 there were 480,170 deaths from Coronary
  Heart Disease
• There are 11.2 million Americans alive today who
  have a history of MI, angina, or both
• Treatment related costs are more than 100
  billion per year

AHA Heart and Stroke Facts 1995 Statistical
Supplement
3
NHANES IIINational Health and Nutrition
Examination Survey

• 13 million adults need treatment for elevated LDL
  cholesterol
• multiple CAD risk factor (6.9 million)
• active CAD (4.4 million)
• elevated LDL-C alone (1.6 million)
• majority need LDL reduction of lt30
• 75 of the women and 88 of the men
• 54 of adults with CAD

Center for Disease and Control 1994
4
Frequently Asked Questions

• Is high serum cholesterol a risk factor for
  Coronary Heart Disease (CHD) ?
• Will lowering serum cholesterol help prevent CHD?
• Will people live longer if serum cholesterol is
  lowered ?
• Does lowering serum cholesterol provide benefit
  if CHD is already present ?

Special Report Circulation 1990 811771-1773
5
Frequently Asked Questions

• Will dietary change effectively lower cholesterol
  levels ?
• Should age or gender change the approach to
  cholesterol management ?
• Are cholesterol interventions cost-effective ?

Special Report Circulation 1990 811771-1773
6
Is high serum cholesterol a risk factor for CHD
?Will lowering serum cholesterol help prevent
CHD ?

• Epidemiologic evidence
• comparisons among various populations
• prospective studies within populations
• individuals with genetic forms of hyperchol
• Animal studies
• monkeys, baboons, rabbits
• Human Clinical Trials

7
Landmark Clinical Trials

• 1971 - Framingham Heart study
• 1981 - Brown and Goldstein - LDL
  receptors
• 1982 - Multiple Risk Factor Intervention
  Trial
• 1984 - Coronary Primary Prevention Trial
• 1987 - Helsinki Heart Study

8
Landmark Clinical Trials

• 1994 - 4S (Scandinavian Simvastatin)
• 1995 - WOSCOP (West of Scotland)
• 1996 - CARE (Chol and Recurrent Event)
• 1997 - Post-CABG Trial
• 1998 - LIPID Trial (long-term intervention)

9
Framingham Heart study

• Started in 1950
• AIM 1971 741-12
• 2282 men
• 2845 women
• followed for 14 years
• TC 150-300 mg/dl
• positive correlation between TC and CHD across
  range

CHD Incidence per 1000/Yr
20
10
0
100
200
300
Total Cholesterol (mg/dl)
10
Meta-analysis of Early Secondary Prevention Trials

• 1960s - 1990s
• therapy of diet and various drugs
• lowered TC by 10-15
• reduced coronary events by 25
• reduced total mortality by 10
• too small to show a definitive result

11
The Multiple Risk Factor Intervention Trial
(MRFIT)

• Primary prevention modifying several coronary
  risk factors
• 12,866 high-risk men, aged 35-57
• CHD mortality begins with serum cholesterol of
  180

Six-year CHD Death Rate / 1000 men
16
14
10
8
6
4
0
140
180
220
260
300
Serum Cholesterol, mg/dl
JAMA 1982 2481465-1477
12
Lipid Research ClinicsCoronary Primary
Prevention Trial

• 3800 middle-aged men
• Placebo vs cholestyramine
• most took lt the 24 g/day prescribed
• Diet reduced TC by 4
• Reduction in coronary events
• 9 ? in TC 19 ? events
• 25 ? in TC 50 ? events

JAMA 1984 251351-364
13
Helsinki Heart study

• Primary prevention trial in men
• gemfibrozile (2,051) vs placebo (2,030)
• lowered TC and LDL-C by 8
• raised HDL-C by 10
• 34 fewer coronary events
• established the additional benefit of raising HDL
  cholesterol

NEJM 1987 3171237-1245
14
Will people live longer if serum cholesterol
levels are lowered ?

• CPPT and Helsinki Heart Study
• demonstrated a reduction in total CHD
• failed to demonstrate ? in TOTAL mortality
• Epidemiologic Evidence
• Seven Countries Study
• Framinghham Heart study

15
Will people live longer if serum cholesterol
levels are lowered ?

• REDUCTION in TOTAL MORTALITY
• The Coronary Drug Project 11
• Osolo Study
• Diet and Anti-smoking 33
• Stockholm
• Ischemic Heart Disease 26

16
Angiographic Trials

• 3 key findings of cholesterol therapy
• therapy delayed lesion progression, and promoted
  regression in some
• the changes in lesion size were small but
  significant - with surprising benefits
• fewer coronary events (unstable angina and
  myocardial infarction)

17
Scandinavian Simvastatin Survival Study
18
4S Objective

• The first randomized, double-blind,
  placebo-controlled mortality study to determine
  whether long-term cholesterol reduction with
  simvastatin will reduce overall mortality in
  post-myocardial infarction (MI) and angina
  patients with hypercholesterolemia

Lancet 1994 3441383-1389
19
4S Study Design

• Randomized, double-blind, placebo-controlled
• 94 centers in 5 countries
• 4,444 men and women with CHD (MI/angina), 35 to
  70 years of age
• Total cholesterol ranged from 212-309 mg/dl at
  patient enrollment
• Followed-up until 440 deaths (5.4 years median
  follow-up period)

Lancet 1994 3441383-1389
20
4S Study Endpoints

• Primary Endpoint - total mortality
• Secondary Endpoints
• coronary deaths
• nonfatal definite or probable MI
• Tertiary Endpoints
• incidence of PTCA/CABG
• death or any atherosclerotic event
• incidence of admission for acute CHD

Lancet 1994 3441383-1389
21
4S Effects of simvastatin 20-40 mg after
6 weeks
8
63 on 20mg
- 28
26 on 40mg
- 38
achieved TC lt200 mg/dl
LDL-C
TC
HDL-C
22
4S Coronary Mortality
189
Coronary Mortality (secondary endpoint) reduced
by 42
42
Cumulative Coronary Deaths
111
Years since randomization
23
4S Fewer Events and Procedures
- 34
Risk Reduction
Secondary and Tertiary endpoints P lt
0.00001
- 37
Major Coronary Events
CABG PTCA
24
4S Conclusions

• Long-term treatment with simvastatin
• was generally well tolerated
• improved survival in CHD patients with elevated
  cholesteroal levels
• Simvastatin reduced
• Total mortality by 30
• Coronary mortality by 42
• Major coronary events by 34
• CABG/PTCA by 37
• LDL-C by 38 at 6 weeks (35 for the study)

Lancet 1994 3441383-1389
25
WOSCOPSWest of ScotlandCoronary Prevention
Study

• Prevention of coronary heart disease with
  pravastatin in men with hypercholesterolemia

NEJM 1995 3331301-1307
26
WOSCOPS

• Primary prevention trial
• 6,595 men with no history of MI
• avg chol 272 mg/dl, follow-up 4.9 yrs
• Pravastatin 40mg reduced
• TC by 20, LDL-C by 26
• coronary events by 31 (174 vs 248)
• risk of death from any cause by 22

NEJM 1995 3331301-1307
27
CARE TrialCholesterol and Recurrent Events

• The effects of pravastatim on coronary events
  after myocardial infarction inpatients with
  average cholesterol level

NEJM 1996 3351001
28
CARE TrialCholesterol and Recurrent Events

• Secondary prevention
• 4159 pts with previous MI, 86 men, 14 women,
  age 21-75, 5yr follow-up
• Baseline Change
• Total-Chol lt240 -20
• LDL-Chol 115-175 -28

NEJM 1996 3351001
29
CARE TrialCholesterol and Recurrent Events

• All cause mortality - 9
• Death from CHD/nonfatal MI - 24
• CHD mortality - 20
• Nonfatal MI - 23
• Fatal MI - 37
• Revascularization - 27

statistically significant
NEJM 1996 3351001
30
Statin in Elderly Patients

• 4S Study
• age 65-70 (1,000 of 4,444 patients)
• significant reduction in events and mortality
• 3,600 / quality-adjusted year of life saved
• 6,000 in the general 4S population
• as cost effective as CABG for left main disease
  or proximal LAD lesion and triple vessel disease

Circulation 1977 96 4211-18
31
Statin in Elderly Patients

• CARE Study
• age 65-75 (1,283 of 4,159 patients)
• risk of nonfatal MI or death reduced by 39
• rate of CABG reduced by 43
• twice the reduction obtained in younger patients

32
CV Disease in Women

• Heart disease is the leading cause of death in
  women (250,000 deaths annually)
• One in two women will eventually die of heart
  disease or stroke 1/25 will eventually die of
  breast cancer
• 63 of women (48 of men) die suddenly from
  coronary heart disease
• 44 of women (27 of men) will die within one
  year after a heart attack

33
Postmenopausal Women with CHD

• Both 4S (827 women) and CARE (567
• women) studies showed siginificant
• reduction in recurrent CHD events
• with LDL-C lowering therapy.

34
Simvastatin Survival StudySubgroup Analysis
Gender - Women vs MenMajor Coronary Events
Coronary death or nonfatal MI
- 34
- 35
of Patients with Events
N531
N372
N91
N59
Women P0.01
Men Plt0.00001
Circulation 1977 96 4211-18
35
Summary of Results

• 4S CARE WOSCOPS
• 
  Secondary Secondary Primary
• Lipid-lowering agent Simvastatin
  Pravastatin Pravastatin
• (mg/day) 20-40 40 40
• Mean follow-up (years) 5.4 5.0 4.9
• Mean LDL-C at entry (mg/dl) 189 139 192
• Change in lipid level ()
• LDL-C -35 -28 -26
• Total cholesterol -25 -20 -20
• HDL-C 8 5 5
• Triglyceride -10 -14 -12

36
Summary of Results

• 4S CARE WOSCOPS
• 
  Secondary Secondary Primary
• Lipid-lowering agent Simvastatin
  Pravastatin Pravastatin
• (mg/day) 20-40 40 40
• Endpoints ( reduction)
• Total deaths 30 9 22
• Death from CAD 35 15 32
• Coronary deaths 42 20 28
• Fatal nonfatal cor events 34 24 31
• Fatal nonfatal strokes 28 31 10

Statistically significantly different from
placebo treatment
37
Lipid Lowering Therapy inSaphenous VeinCoronary
Artery Bypass Grafts

38
Coronary Artery Bypass GraftingNatural History

• 5-10 with recurrent angina
• 15-30 vein grafts stenose in 1 year
• 50 of vein grafts are closed at 10 yrs
• 10-20 of CABG are repeat CABG

39
Saphenous -Vein Diseasethree phases

• Early post-op (1st month)
• technical factor
• thrombotic occlusion
• Intermediate (1st year)
• intimal hyperplasia and thrombosis
• Late (gt one year)
• atherosclerosis and thrombosis

40
Post-CABG Trial 1BACKGROUNG and RATIONALE

• graft occlusion occurs because of atherosclerosis
  and thrombosis
• beneficial effect of colestipol and niacin2 in
  saphenous vein grafts
• ? benefit of lowering LDL-C lt 100 mg/dl? benefit
  of low dose warfarin therapy

1. NEJM 1997 336153-162 2. JAMA 1987
2573233-3240
41
Post-CABG Trial STUDY DESIGN

• To assess the effect of two different intensities
  of lowering LDL-C and the effect of low-dose
  anticoagulation Rx
• Treatment regimens (2x2 design)
• LDL-C 60-85 mg/dl lovastatin 40-80 mg/d
• LDL-C 130-140 mg/dl lovastatin 2.5-5 mg/d
• maintain INR lt 2.0

NEJM 1997 336153-162
42
Post-CABG Trial
43
Post-CABG TrialAngiographic Outcomes
Plt.001
Plt.001
Grafts ()
Plt.001
PNS
44
Post-CABG TrialClinical Outcomes
4-year rate ()
P.03
NS
NS
P.05
NS
45
Post-CABG TrialCONCLUSIONS

• aggressive LDL lowering can reduce
• progression of atherosclerotic narrowing
• occlusion of the grafts
• need for repeat CABG or PTCA
• absence of any benefit from warfarin

NEJM 1997 336153-162
46
LIPID TrialLong-term Intervention with
Pravastatin in Ischemic Disease
47
LIPID Trial

• 9000 patients with TC 155 - 271 mg/dl(3,800 had
  levels lt 215 mg/dl)
• previous history on MI or unstable angina
• Six-year double-blind study
• 87 clinical sites in Australia and New Zeland -
  started in 1989

Am J Cardiol 199576474-478Circulation
1998971784-1790
48
LIPID Trial

• cholesterol lowering on pravastatin
• TC - 18
• LDL-C - 25
• HDL-C - 6

Am J Cardiol 199576474-478Circulation
1998971784-1790
49
LIPID Trial

• Primary endpoint - CHD mortality
• 24 risk reduction
• prevented 19 deaths / 1000 patients treated over
  six years
• Secondary endpoint
• 23 risk reduction in total mortality
• 20-25 reduction in MI, stroke, and coronary
  revascularization

Am J Cardiol 199576474-478Circulation
1998971784-1790
50
AFCAPS / TexCAPSAir Force / Texas Coronary
Atherosclerosis Prevention Study
51
AFCAPS / TexCAPS

• Primary prevention trial
• 6,605 patients, aged 45-73
• no evidence of CAD
• LDL 130-190 mg/dL, HDL lt 50 mg/dL
• lovastatin 20 or 40 mg vs placebo

Am J Cardiol 199780287-293JAMA
19982791615-1622
52
AFCAPS / TexCAPS

• Results
• mean LDL fell from 150 to 114 mg/dL
• primary endpoint (cardiac death, nonfatal MI, or
  unstable angina) was 36 lower over 5 years with
  lovastatin therapy
• benefit was seen only after one year
• Trial was stopped early

Am J Cardiol 199780287-293JAMA
19982791615-1622
53
Statin Prevention Studies

• Primary preventionWOSCOPS Men only with no
  documented MI H (n 6,595)AFCAPS/TexCAPS Men
  and women with no clinical CAD NM (n
  6,605)
• Secondary prevention4S Men and women with
  previous CAD H (n 4,444) CARE Men and
  women with a history of MI NM (n 4,159)
  LIPID Men and women with a history of MI
  NH (n 9,014) and/or unstable angina pectoris

(Total cholesterol Hhigh, NMnormal to mild,
NHnormal to high)
54
Treatment Rates of elevated cholesterol in the
United States

• Majority of Americans who needs
• treatments are not being treated
• only 1 in 4 who need treatment for elevated
  cholesterol receive it
• only 4 of patients were both treated and
  controlled (samples of 4 U.S. communities)

JAMA 1993 2691133-1138 AIM 1995 155 677-684
55
Cholesterol Therapy in Adults
NHLBI Cholesterol Awareness Survey, 1995
56
Treatment of Hyperlipidemia in the Hospital
Setting

• Only 58 of patients admitted for CABG were
  screened for hyperlipidemia by the medical
  service (10 for surgical service)
• Only 56 of patient admitted to a university
  hospital CCU for acute chest pain were screened
  for hyperlipidemia
• Consider initiating drug therapy at discharge if
  LDL cholesterol is gt130 mg/dl

AJC 1995 75736-737 JACC 1995 75716-717 NCEP
Report
57
Lipid Treatment Assessment Project
(L-TAP)Treatment Success in Patient Subgroups

• Surveyed 901 U.S. Primary care providers
• fasting lipids collected on 5,601 patient being
  treated for hypercholesterolemia
• Treatment success was defined by attainment of
  LDL-C goals as defined by the NCEP guidelines

Circulation 1997 96 No. 8
58
Lipid Treatment Assessment Project
(L-TAP)Treatment Success in Patient Subgroups

• Overall, only 38 reached LDL-C goal
• Lower rates of success were observed for
• CHD patients 18 (P lt .001)
• men? 45 vs ? 45 35 vs 54
• women ? 55 vs ? 55 36 vs 52
• high school vs college 32 vs 44
• African-Am vs Caucasian 29 vs 39

Circulation 1997 96 No. 8
59
Lipid Treatment Assessment Project
(L-TAP)Failure to reach LDL-cholesterol levels
AHA 70th Scientific Session Nov. 9-12, 1977.
Orlando Florida
83
63
62
Percent of patients failing to reach NCEP
LDL-cholesteroal target levles
32
? two RF LDL lt130
lt two RF LDL lt160
Known CAD LDL lt100
All patients (4,888)
60
Lipid Treatment Assessment Project
(L-TAP)Failure to reach LDL-cholesterol levels
AHA 70th Scientific Session Nov. 9-12, 1977.
Orlando Florida

• Failure to reach the target LDL level occurred
  despite the fact that 93 of the CAD patients
  were receiving some type of lipid-lowering drug.
• Failure to up-titrate the starting dose
• 40 of patients remained on low-dose combination
  therapy

61
One-Year Discontinuation Rates of
Antihyperlipidemic Drugs

• HMO Clinical Trials
• bile acids 41 31
• niacin 46 4
• gemfibrozil 37 15
• lovastatin 15 15

Reasons 18 adverse effects 10 perceived
lack of efficacy
N Engl J Med 1995 3321125-31
62
ACP Position PaperCholesterol Screening
Guidelines

• RECOMMENDATION
• No Yes / - No
• Men lt35 35-65 65-75 gt75
• Women lt45 45-65 65-75 gt75
• physicians have not embraced the ACP guidelines

63
NCEP Cholesterol Guidelines

• Cholesterol Initial Level Classification
• lt200 mg/dl Desirable (5.2mmol/L)
• 200-239 mg/dl Borderline high
• (5.2-6.2mmol/L)
• ? 240 mg/dl High 6.2mmol/L)

64
NCEP Guidelines for Lipid Management

• Definite Two or more LDL-CAthrosclerosi
  s Risk Factors (mg/dl) Initial
  Goal
• No No gt190 lt160
• No Yes gt160 lt130
• Yes Yes / No gt130 lt100
• coronary, peripheral vascular, and carotid
  disease
• age, FH, smoking, hypertension, HDL-C lt35,
  diabetes

65
Risk Reduction Strategy

• Smoking
• Hypertension - wt, exercise, salt, EtOH
• Physical activity - 30 min 3-4 times / wk
• Weight management
• Pharmacologic agents
• ASA, beta blockers, ACE, estrogens

66
Nonpharmacologic Management

• AHA diet
• caloric restriction
• weight loss
• regular exercise
• teaching in CCU post event or procedure
• coronary risk factor reduction

67
How effective is diet therapy?

• American Heart Association Diet
• Chol Total Fat TC LDL
• Step I 300 8 - 10 8 10
• Step II 200 lt 7 10 15

68
How effective is diet therapy?Diet Diary

• reduce fat intake
• eat more high, soluble fiber
• nuts, whole grains, fish
• low fat milk, eliminate deserts

69
How effective is diet therapy?LCAS Study

• 400 patients with LDL-C gt130 mg/dl
• following 8 weeks of dietary therapy
• 16 had drop in LDL-C of gt30 mg/dl
• only 1.5 achieved NCEP target of an LDL-C of
  lt100 mg/dl
• diet may be 5 to 10 effective

Lipoprotein Coronary atherosclerosis
Study Control Clin Trials 199617550
70
How effective is diet therapy?

• Motivation and Compliance
• 90 compliance in case -management system trial -
  calling monthly post cards
• only 15 to 20 are extremely motivated

71
Diet alone is insufficient

• Current approaches suggest a trial of diet alone,
  followed by drug therapy if diet fails to
  achieve target levels
• changing eating habit takes time
• requires more than simple instructions
• many patients may die before the diet strategy
  works

FJ Pashkow, Cleveland Clinic
72
Are All Statins Created Equal

• HMG-CoA reductase inhibitorsatorvastatin cerivast
  atin fluvastatin lovastatin pravastatin
  simvastatin
• all inhibit the same enzyme
• differences in
• dosing
• potency
• pharmacokinetics

73
Tolerability of Statins

• generally well tolerated
• side effect incidence similar to placebo
• most common (lt5) were minor GI symptoms such as
  dyspepsia and abd pain
• lt2 discontinue meds because of ? LFT
• myopathy (CK gt10 x ULN) lt0.5
• rhabdomyolysis is rare (1in 750,000)

74
Are All Statins Created EqualTriglyceride level

• At high dosages of atorvastatin and simvastatin,
  some VLDL synthesis is blocked, resulting in
  triglyceride lowering
• combination of gemfibrozil and niacin gives more
  triglyceride reduction (by reducing IDL and LDLB)
  and HDL2b increase than the statins - at lower
  cost

75
Are All Statins Created Equal

• Cost
• Ability to achieve LDL-C goal
• need for 30, 40, or 50 reduction
• Convenience and compliance
• Side effects
• sleep disturbance
• myositis

76
CURVES Trial ResultsComparative LDL-C Reductions
-10


-20


Fluvastatin
Mean ?in LDL-C



-30



Pravastatin

-40

Simvastatin

Lovastatin


-50
(40 mg bid)
Atorvastatin

(80 mg qd)
-60
20
40
80
10
Dose range (mg)
. Eur Heart J. 199718371. Abstract.
77
Comparison of LDL Reduction

• LDL Reduction
• Drug (mg) 0.3 10 20 40 80
• cerivastatin 28-30 --- --- ---
  ---
• fluvastatin --- --- 16-18 22-24
  30
• lovastatin --- --- 23-25 30-32 40
• pravastatin --- 18 22-24 30-32 ---
• simvastatin --- 26-28 32-35 39-41 46
• atorvastatin --- 37-40 43-46 50-53 55-60

78
Statin Cost Comparison(cost / month as of 9/97)
79
Are All Statins Created EqualCost and Treatment
Goal

• Statin is the simplest and most effective
  approach
• Statins all come out about the same for cost /
  percentage reduction in LDL
• Treatment goal
• For mild LDL-C reduction (25)fluvastatin may be
  more cost-effective
• For moderate LDL-C reduction (35-50)atorvastati
  n may be most cost-effective

80
Are All Statins Created EqualCompliance

• Even when patients are started on a statin,
  within 6 months as many as half are no longer
  taking it
• Lifestyle change must be reinforced
• diet
• exercise
• smoking cessation