Aggressive Therapy for Hypercholesterolemia: Data, Strategy and Outcomes
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Transcript of Aggressive Therapy for Hypercholesterolemia: Data, Strategy and Outcomes
Aggressive Therapy for Aggressive Therapy for Hypercholesterolemia:Hypercholesterolemia:
Data, Strategy and Outcomes Data, Strategy and Outcomes
Aggressive Therapy for Aggressive Therapy for Hypercholesterolemia:Hypercholesterolemia:
Data, Strategy and Outcomes Data, Strategy and Outcomes
Timothy A. Denton, M.D.Timothy A. Denton, M.D.
High Desert Heart InstituteHigh Desert Heart Institute
Victorville, CA Victorville, CA
Can you identify these?
VLDL
B100
CI CIICII CIII
E
IDL B100
E
LDL B100
Chylomicrons
B100
CICII
CIII
E
AI
AII
AIV
B48
Remnants
B48
E
HDL2
AI
AII
AI
AII
HDL3
HDL1
AI
AII
Standard Approachto LDL Management
Event
Diet
Exercise
Diet Drugs
6 months
A Probabilistic Equation
P(success | overall population) =
P(success | ideal population) *
P(compliance | overall population)
1 - Diet2 - Exercise3 - Drugs4 - Partial ileal bypass5 - Portacaval shunting6 - Apheresis
adsorption column (LDL apheresis)plasma exchangedouble membranedextran sulfate precipitationimmunoabsorption
7 - Liver transplantation
Methods for Modifying Cholesterol Levels
Diet
Ornish D, et al. Lancet 1990;336:129
Lifestyle Heart Trial
Changes in Fat Intake
31.5
6.8
30.1 29.5
0
5
10
15
20
25
30
35
40
45
50
Baseline 1 year
Die
tary
Per
cen
t F
at
Ornish D, et al. Lancet 1990;336:129
Lifestyle Heart Trial
Change in Serum Lipids(Intervention Group)
222
168
148
93
38 37
90110
0
50
100
150
200
250
Baseline 1 year
Die
tary
Per
cent
Fat
TCholLDLHDLTG
Ornish D, et al. Lancet 1990;336:129
Lifestyle Heart TrialIntervention group LDL after 1 year
0
5
10
15
20
25
30
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200
Serum LDL Cholesterol (mg/dl)
Mean = 93 mg/dl + 43 mg/dl
NCEP Goal
55.3% 44.7%
Biosphere
•Biosphere 2•“Isolated, confined environment”, 2 years•8 subjects•Green and yellow vegetables•Animal products of 1 egg, 112 g of meat,
500 cc of goat milk per WEEK•All had consistent weight loss for 2 years•Blood samples q 1-2 months
Verdery, et al. Arch Intern Med 1998;158:900
Biosphere2 Dietary Restriction
Change in LDL Cholesterol
105
58
020406080
100120140160180200
Baseline 2 years
LD
L C
ho
lest
ero
l (m
g%
)
Verdery, et al. Arch Intern Med 1998;158:900
Biosphere2 Dietary Restriction
0
5
10
15
20
25
30
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200
Serum LDL Cholesterol (mg/dl)
Mean = 58 + 7 mg/dl
LDL after 2 years
NCEP Goal
Verdery, et al. Arch Intern Med 1998;158:900
Biosphere2 Dietary Restriction
100%0%
Dietary “Success”
Diet % LDLreduction
% achievegoal
AHA Step I 0-4% 0.1% (?)
AHA Step II 6.5-15.5% 0.6%
Diet Altern 13% 1.3%
Pritikin 18.6% 37.6%
Ornish 37% 55.3%
Biosphere 45% 100%
Exercise
Effect of Fitness on Survival
24.6
7.83.1
20.3
7.34.7
64
26.3
20.3
0
10
20
30
40
50
60
70
Unfit Mod Fit Very Fit
Dea
th R
ate
/ 10
,000
CHDCancerAll Cause
Blair JAMA 1989;262:2395
Effect of Fitness on Survival
Blair JAMA 1989;262:2395
Fitness at Two Different Times
122
67.7
39.6
0
20
40
60
80
100
120
140
Unfit-Unfit Unfit-Fit Fit-Fit
Dea
th R
ate
/ 10
,000
Sesso et al. Circ 2000;102:975-980Harvard Alumni Health Study
Adjusted Risk Reduction of First Coronary Event as a Function of Physical Activity
1
0.9
0.81 0.8 0.81
0
0.2
0.4
0.6
0.8
1
1.2
<2100 2100-4199 4200-8399 8400-12599 >12600
kJ per Week
Rel
ativ
e R
isk
4.2 kJ = 1 kcal
500 Cal 500-1000 Cal 1000-2000 Cal 2000-3000 Cal >3000 Cal
Effect of Exercise on Lipids
Kokkinos Arch Int Med 1995:155:415
2906 menage 30-64 yearsexercise treadmill test to exhaustionclassified into 6 groups based on
average miles run per week
Effect of Exercise on Lipids
Kokkinos Arch Int Med 1995:155:415
LDL, TG, HDL versus miles per week
40
45
50
55
60
0-2 mi 3-6 mi 7-10 mi 11-14 mi 15-20 mi 21-60 mi
Miles Run per Week
HD
L m
g%
0
20
40
60
80
100
120
140
LD
L m
g%
Y2
HDLLDLTG
0
5
10
15
20
25
30
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200
Serum LDL Cholesterol (mg/dl)
Mean = 121 + 29 mg/dl
NCEP Goal
Verdery, et al. Arch Intern Med 1998;158:900
Running 21-60 Miles per Week
22.9% 77.1%
Cholesterol-Lowering Drugs
Prescription Non-Prescription
StatinFibrateNiacinResinsOrlistat
Ezetimibe
Fiber (brans)Garlic
Fish OilPlant sterols (Benecol)
Cholesterol Modifying Agents
Achievement of NCEP GoalAchievement of NCEP GoalAchievement of NCEP GoalAchievement of NCEP Goal
Brown, JACC 1998; 32:665
Time Period 0-12 weeks 12-24weeks
24-36weeks
36-48weeks
48-54weeks
Protocol 1 atorva10 mg
atorva20 mg
atorva40 mg
atorva80 mg
atorva 80 +colest 10
Protocol 2 simva10 mg
simva20 mg
simva40 mg
simva 40 +colest 10
simva 40 +colest 20
Protocol 3 lova20 mg
lova40 mg
lova80 mg
lova 80 +colest 10
lova 80 +colest 20
Protocol 4 fluva20 mg
fluva40 mg
fluva 40 +colest 10
fluva 40 +colest 20
fluva 40 +colest 20
atorva = atorvastatin (Lipitor)simva = simvastatin (Zocor)lova = lovastatin (Mevacor)fluva = fluvastatin (Lescol)colest = colestipol (Colestid)
Achievement of NCEP GoalAchievement of NCEP GoalAchievement of NCEP GoalAchievement of NCEP Goal
0102030405060708090
100
0 12 24 36 48 54
Time (weeks)
% R
esp
on
der
s
AtorvFluvaLovaSimva
Brown, JACC 1998; 32:665
P=NS
P=NS
P=NS
Statins
Jones et al. Am J Cardiol2003;92:152
6
-30
-13
6.8
-45.8
-18.2
2.1
-51.1
-28.2
9.6
-55
-26.1
-60
-50
-40
-30
-20
-10
0
10
20
HDL LDL TG
Prava Simva Atorv Rosuva
Lancet 1994;344:1383
4S Survival Curves
MIRACLMIRACL(Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering)
• 122 centers -- Europe, North America, South Africa, Australasia• adults with chest pain x15 min• exclusion
coronary revascularization plannedcholesterol >270 mg%Q-wave MI3 months CABG, 6 months PTCA, 4 weeks MILBBB, CHF III, other drugs, DM, preg
Schwartz JAMA 2001;285:1711
MIRACLMIRACL
P=0.048
Schwartz JAMA 2001;285:1711
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
Ischemic events
MIRACLMIRACL
P=0.02
Schwartz JAMA 2001;285:1711
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
CVA
Pitt, B. et al. N Engl J Med 1999;341:70-76
Cumulative Incidence of First Ischemic Events
• 341 pts• CCS 0,I• PTCA vs MedRx
REVERSALREVERSAL
P=0.02Nissen JAMA 2004;291:1071
Reversal of Atherosclerosis with Aggressive Lipid Lowering
•DB Random atorv v. prava (79 v. 110)•IV US•Atheroma vol
-0.4
2.7
-1
-0.5
0
0.5
1
1.5
2
2.5
3
Atorv Prava
Percen
t C
ha
ng
e
ASCOTT-LLAASCOTT-LLA
P=0.0005
Nissen JAMA 2004;291:1071
Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm
• 19,342 HTN + 3 RF• Tchol < 250• Atorva v placebo• trial stopped 3.3 yrs
100 89
389
178 185154
121
486
247212
0
100
200
300
400
500
600
All Events CVA AllCV All Cor Death
Percen
t C
ha
ng
e
P=0.024
P=0.0005
P=0.0005 P=0.16
ACCESSACCESS
Smith Phamacoeconomics 2003;21:13
Atorvastatin Comparative Cholesterol Efficacy and Safety Study
• 3,387• 54 weeks• Atorva, fluva, lova, prava, simva• titrate to LDL < 100
DrugDrug Total Cost to GoalTotal Cost to Goal
AtorvaAtorva 683.37683.37
fluvafluva +211.35+211.35
lovalova +607.96+607.96
PravaPrava +424.60+424.60
simvasimva +95.74+95.74
Baycol (cerivastatin)Baycol (cerivastatin)Baycol (cerivastatin)Baycol (cerivastatin)
12/1/2000 -- FDA approves 0.8 mg3/30/2001 -- FDA warning about metabolism8/1/01 -- 31 US deaths, 19 lone drug, 12 in combination8/8/2001 -- Bayer removes Baycol from US Market
When should weWhen should we
STARTSTART
therapy?therapy?
When should weWhen should we
STARTSTART
therapy?therapy?
CHAMPCHAMP
Fonarow, AJC 2001;87:819
(Cardiac Hospitalization Atherosclerosis Management Program)
• UCLA• Observational / Interventional• AHA Guidelines• Standard orders, education, DC planning• Phone follow-up
CHAMPCHAMP
Fonarow, AJC 2001;87:819
CHAMPCHAMP
Fonarow, AJC 2001;87:819
When should weWhen should we
STARTSTART
therapy?therapy?
When should weWhen should we
STARTSTART
therapy?therapy?
AS SOON AS POSSIBLE!!!!
But my hospitalized But my hospitalized
patient’s LDL is at goal.patient’s LDL is at goal.
But my hospitalized But my hospitalized
patient’s LDL is at goal.patient’s LDL is at goal.
Change in LDL over time
0
20
40
60
80
100
120
140
160
180
200
PreProc Proc 3-6 mos 6-9 mos
Time
LD
L m
g%
All MIMI no ThrMI w ThrPTCACABG
Brugada, Cardiology 1996;87:194Original paper reports total cholesterolOriginal paper reports total cholesterolConverted to LDL by assuming LDL = 0.67 * total cholesterolConverted to LDL by assuming LDL = 0.67 * total cholesterol
But my hospitalized But my hospitalized
patient’s LDL is at goal.patient’s LDL is at goal.
But my hospitalized But my hospitalized
patient’s LDL is at goal.patient’s LDL is at goal.
Not for long…Not for long…Not for long…Not for long…
Aggressive Approachto LDL Management
Event
Drug therapy
Diet
Exercise
X
The GuidelinesThe Guidelines
Therapy GWTG Goal A Antiplatelet/warfarin Start the Rx B Beta blockers Start the Rx C Cholesterol Start the Rx C ACE Start the Rx D DM Start the Rx C Smoking Counseling E Exercise Counseling W Weight control Counseling H BP control 130-140/80-90
How often do we provide these therapies?How often do we provide these therapies?
Therapy Rate ReferenceSmoking 48% Doescher J Fam Prac 2000;49;543
BP control 25% Berlowitz, NEJM 1998;339:1957Cholesterol 31.7% Fonarow Circ 2001;103:38
Exercise 19.1% MMWR 1998;47:91
Weight control 10.4% MMWR 1998;47:91DM 45% UKPDS AHJ 1999;138:353
Antiplatelet/warfarin 84% Rogers Circ 1994;90:2103ACE 75% (chf) J Gen Int Med 1997;12:563
Beta blockers 17.4% (iv) Rogers Circ 1994;90:2103PTCA (AMI) 30.3% Rogers Circ 1994;90:2103
State StandingsState Standings
State RankCalifornia 41Oklahoma 42West Virginia 43Alabama 44
Texas 45Illinois 46Georgia 47New Jersey 48Louisiana 49Mississippi 50Arkansas 51Puerto Rico 52
Jencks et al. JAMA 2000;284:1670
State RankNew Hampshire 1
Vermont 2Maine 3
Minnesota 4
Massachusetts 5Connecticut 6
North Dakota 7Iowa 8
Colorado 9Oregon 10
Wisconsin 11
Ranked by CV indicators, mammog, immune, etc
Effects of Various Cardiac TherapiesEffects of Various Cardiac Therapies
Therapy Survival QOL MI AdmitsRx A 0
Rx B 0
Rx C
Effects of Various Cardiac TherapiesEffects of Various Cardiac Therapies
Therapy Survival QOL MI Admits PTCA (non-MI) 0 CABG (3v, nl EF, CCS I, II) 0 Statin
Effects of Various Cardiac TherapiesEffects of Various Cardiac TherapiesTherapy Survival QOL MI Admits
PTCA (non-MI) 0
CABG (3v, nl EF, CCS I, II) 0
Exercise
Weight control
Smoking cessation
HTN control
Diabetes control
ASA / coumadin
ACE
Cholesterol lowering
Beta blocker
The End