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