4 acc prevention cholesterol

88
The Evidence for Current Cardiovascular Disease Prevention Guidelines: Cholesterol Management Evidence and Guidelines American College of Cardiology Best Practice Quality Initiative Subcommittee and Prevention Committee

Upload: turgun-hamit

Post on 07-May-2015

895 views

Category:

Health & Medicine


4 download

DESCRIPTION

prevention cholesterol

TRANSCRIPT

Page 1: 4 acc prevention cholesterol

The Evidence for Current Cardiovascular Disease

Prevention Guidelines:

Cholesterol Management Evidence and Guidelines

American College of Cardiology Best Practice Quality Initiative Subcommittee

and Prevention Committee

Page 2: 4 acc prevention cholesterol

Classification of Classification of Recommendations and Levels Recommendations and Levels of Evidenceof Evidence

*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.

†In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.

Page 3: 4 acc prevention cholesterol

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

Icons Representing the Classification and Icons Representing the Classification and Evidence Levels for RecommendationsEvidence Levels for Recommendations

Page 4: 4 acc prevention cholesterol

Cholesterol, Cholesterol Therapies, Cholesterol, Cholesterol Therapies, and Cholesterol Guidelinesand Cholesterol Guidelines

Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease

Prevention GuidelinesPrevention Guidelines

Page 5: 4 acc prevention cholesterol

Sources:P. Barter. Role of Lipoproteins in Inflammation presentation, 2001. Available at

http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416. Doi H et al. Circulation 2000;102:670-676

Colome C et al. Atherosclerosis 2000;149:295-302 Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994

HDLLDLChylomicrons,VLDL, and

their catabolic remnants> 30 nm 20–22 nm

Potentially pro-inflammatory

9–15 nm

Potentiallyanti-inflammatory

Lipoprotein ClassesLipoprotein Classes

Page 6: 4 acc prevention cholesterol

HDL

LiverOxidative

modificationof LDL

LDL+

VLDL

Cholesterolexcreted

High plasmaLDL

LDL infiltrationinto intima

+Macrophages

Foam cells

Fatty streak

Advancedfibrocalcific

lesion

Endothelialinjury

Adherenceof platelets

Releaseof PDGFOther

growthfactors

LCATAPO-A1

APO-A1=Apolipoprotein A1, HDL=High density lipoprotein, LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein, PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein

(-)

Role of Lipoproteins in Role of Lipoproteins in AtherogenesisAtherogenesis

Page 7: 4 acc prevention cholesterol

Source: Yusuf S et al. Lancet. 2004;364:937-952

36

127 10

20

33

0

20

40

60

80

100

Smoking Fruits/Veg

Exercise Alcohol Psycho-social

Lipids All 9 risk factors

PA

R (

%)

1418

90

DiabetesAbdominalobesity

Hyper-tension

Lifestyle factors

50

INTERHEART Study

n=15,152 patients and 14,820 controls in 52 countries

MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors)

Attributable Risk FactorsAttributable Risk Factorsfor a First Myocardial Infarctionfor a First Myocardial Infarction

Page 8: 4 acc prevention cholesterol

Change in Total Cholesterol LevelsChange in Total Cholesterol Levelsin the United States Over Timein the United States Over Time

Source: Ford ES et al. Circulation 2009;120:1181-1188

0%

10%

20%

60%

40%

50%

30%

70%

80%

90%

100%

>240 mg/dL (>6.21 mmol/L)

Tota

l C

hole

stero

l m

g/d

l (m

mol/L)

age-a

dju

sted p

erc

enta

ge

National Health and Nutrition Examination Survey (NHANES)

200-240 mg/dL (5.17-6.21 mmol/L)

<200 mg/dL (<5.17 mmol/L)

Page 9: 4 acc prevention cholesterol

3.7

2.9

2.2

1.7

1.3

1.0

40 70 100 130 160 190

Rela

tive R

isk

for

Coro

nary

H

eart

Dis

ease

(Lo

g S

cale

)

LDL-Cholesterol (mg/dL)

Source: Grundy S et al. Circulation 2004;110:227-239

CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol

Coronary Heart Disease Risk Coronary Heart Disease Risk According to LDL-C LevelAccording to LDL-C Level

Page 10: 4 acc prevention cholesterol

Soluble fiberSoy protein

Stanol esters

Dietary Adjuncts

Ezetimibe (Zetia)Cholesterol absorption inhibitor

Cholestyramine (Questran)Colesevelam (Welchol)

Colestipol (Colestid)

Bile acid sequestrants

Atorvastatin (Lipitor)Fluvastatin (Lescol XL)Lovastatin (Mevacor)Pitavastatin (Livalo)

Pravastatin (Pravachol)Rosuvastatin (Crestor)

Simvastatin (Zocor)

3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins]

Drug(s)Class

Nicotinic acid Niacin

Therapies to Lower Levels of LDL-CTherapies to Lower Levels of LDL-C

Page 11: 4 acc prevention cholesterol

AcetylCoA

HMG-CoA

Mevalonate

Farnesylpyrophosphate

Squalene Cholesterol

Squalenesynthase

Dolichol

Farnesyl-transferase

Farnesylated

proteins

E,E,E-Geranylgeranylpyrophosphate

Geranylgeranylated

proteins

Ubiquinones

HMG-CoA Reductase

Inhibition of the cholesterol biosynthetic pathway

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Mechanism of ActionMechanism of Action

Page 12: 4 acc prevention cholesterol

LDL-R–mediated hepatic uptake of LDL and VLDL remnants

Serum VLDL remnants

Serum LDL-C

Cholesterol synthesis

LDL receptor (B–E receptor) synthesis

Intracellular Cholesterol

Apo B

Apo E

Apo B

Systemic CirculationHepatocyte

The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and

increases uptake of non-HDL particles from the systemic circulation

LDLLDL

Serum IDL

VLDLRVLDLR

VLDL

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Mechanism of ActionMechanism of Action

Source: McKenney JM. Selecting Successful Lipid-lowering Treatment presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4.

HDL=High density lipoprotein, LDL=Low density lipoprotein

Page 13: 4 acc prevention cholesterol

The Rule of 6’s

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Dose-Dependent EffectDose-Dependent Effect

37

19

35

27

28

18

12

12

6

12

0 10 20 30 40 50 60

Atorvastatin 10/80*

Fluvastatin 20/80*

Simvastatin 20/80*

Pravastatin 20/40*

Lovastatin 20/80*

46 6

32 11

Rosuvastatin 10/20†

Pitavastatin 1/4‡

Sources: *Illingworth DR. Med Clin North Am 2000;84-23-42

†Crestor Package Insert. http://www1.astrazeneca-us.com/pi/crestor.pdf ‡Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf

Each doubling of the statin dose produces an approximate 6% reduction in the LDL-C level

Page 14: 4 acc prevention cholesterol

Sources: Law MR et al. BMJ 2003;326:1423-1427

Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf

78 (42)69 (37)60 (32)51 (27)Simvastatin

108 (58)99 (53)90 (48)80 (43)Rosuvastatin§

62 (33)53 (29)45 (24)37 (20)Pravastatin

83 (45)68 (37)54 (29)39 (21)Lovastatin‡

61 (33)50 (27)39 (21)29 (15)Fluvastatin

102 (55)91 (49)80 (43)69 (37)Atorvastatin

80 mg/d40 mg/d20 mg/d10 mg/d Statin

#Data presented as absolute reductions in LDL-C* (mg/dL) and percent reductions in LDL-C (in

parentheses)

A meta-analysis of 164 trials*†‡

FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Reduction in LDL-CReduction in LDL-C

*Standardized to LDL-C 186 mg/dL (mean concentration in trials) before Rx.† Independent of pre-Rx LDL-C

‡Maximum dose of 80 mg/day administered as two 40-mg tablets§Not FDA approved at 80 mg/day

‡Although not included in this analysis, pitavastatin would be expected to achieve a 32%, 36%, and 43% mean reduction in

LDL-C levels at the 1 mg, 2 mg, and 4 mg daily doses, respectively

Page 15: 4 acc prevention cholesterol

Study populations:

Primary prevention

Acute coronary syndromes (Secondary prevention)

Chronic coronary heart disease (Secondary prevention)

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Chronological Order of Event Driven Chronological Order of Event Driven TrialsTrials

1994 4S 2002 PROSPER

1995 WOSCOPS 2002 ALLHAT-LLA

1996 CARE 2002 ASCOT-LLA

1998 AFCAPS/TEXCAPS 2004 PROVE- IT

1998 LIPID 2004 A to Z

2001 MIRACL 2005 TNT

2002 HPS 2005 IDEAL 2008 JUPITER

2010 SEARCH

Page 16: 4 acc prevention cholesterol

West of Scotland Coronary Prevention Study (WOSCOPS)

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

Source: Shepherd J et al. NEJM 1995;333:1301-1307

Placebo

7.5

Pravastatin

9

6

3

0

5.3

P<0.001

31% RRRR

ate

of

MI or

CH

D d

eath

(%

)

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years

A statin provides significant benefit in those with average cholesterol levels

Page 17: 4 acc prevention cholesterol

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

Source: Ford I et al. NEJM 2007;357:1477-1486

West of Scotland Coronary Prevention Study (WOSCOPS)

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

RRR=18%, p<0.02

RRR=27%, p<0.001

Long-term follow-up at 5 and 10 years after conclusion of the study

A statin provides long-term benefit in those with average cholesterol levels

Page 18: 4 acc prevention cholesterol

Rate

of

MI, u

nst

able

angin

a, or

SC

D (

%)

Placebo

5.5

Lovastatin

6

4

2

0

3.5

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS)

P<0.001

37% RRR

LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death

Source: Downs JR et al. JAMA 1998;279:1615–1622

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

6,605 patients with average LDL-C levels randomized to lovastatin (20-40 mg) or placebo for 5 years

A statin provides benefit in those with average LDL-C levels

Page 19: 4 acc prevention cholesterol

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Arm (ALLHAT-

LLA)

Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007

CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

RR, 0.99; P=0.88

1 2 3 4 5 6

32% cross-over among patients with CHD

Cum

ulat

ive

rate

%

PravastatinUsual care

0

3

6

9

12

15

18

Years

10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin (40 mg) or usual care for 5 years

The failure to demonstrate benefit with a statin may be the result of a high rate of cross over

Page 20: 4 acc prevention cholesterol

Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA)

Source: Sever PS et al. Lancet. 2003;361:1149-1158

*Post-treatment LDL-C level

CHD=Coronary heart disease, HTN=Hypertension, LDL-C=Low density lipoprotein cholesterol, RRR=Relative risk reduction

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Atorvastatin 90 mg/dl*

Placebo 126 mg/dl*

P=0.0005

Cum

ulat

ive

inci

denc

e of

M

I and

fata

l CH

D (

%)

Follow-up (yr)

36% RRR

10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years

A statin provides significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals

Page 21: 4 acc prevention cholesterol

Source: O’Keefe JH Jr et al. JACC 2004;43:2142-2146

–1

10

0

2

4

6

8

Statin

PlaceboWOSCOPS

AFCAPS

LDL cholesterol (mg/dL)

55 1951751551351159575

CH

D e

vent

rate

(%

)

WOSCOPS

ASCOT

AFCAPS

ASCOT

P=0.0019

Relationship between LDL-C levels and event rates in select primary prevention statin trials

AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, LDL-C=Low density

lipoprotein cholesterol, WOSCOPS= West of Scotland Coronary Prevention Study

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

Page 22: 4 acc prevention cholesterol

Num

ber

of

advers

e

CV

events

* per

10

00

pers

on y

ears

Placebo

5.0

Pravastatin

6

4

2

0

3.3

Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial

P=0.01

33% RRR

Source: Nakamura H et al. Lancet 2006;368:1155-63

*Composite of cardiac and sudden death, myocardial infarction, angina, and cardiac or vascular intervention

7,832 men (age 40-70 years) and postmenopausal women (up to age 70 years) with total cholesterol levels of 220-270 mg/dL

randomized to pravastatin (10-20 mg) or placebo for 5.3 years

A statin provides benefit in those with high cholesterol levels

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

CV=Cardiovascular

Page 23: 4 acc prevention cholesterol

Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)17,802 men (>50 years) and women (>60 years) with LDL-C

<130 mg/dL and hs-CRP >2 mg/L randomized to rosuvastatin (20 mg) or placebo for up to 5 years*

A statin provides benefit in those with elevated hs-CRP levels

0 1 2 3 40.0

00

.04

0.0

8

Follow-up (years)

RosuvastatinPlacebo

44% RRR

P<0.00001, NNT=25

Cum

ula

tive inci

dence

of

CV

death

, M

I, s

troke

, hosp

italiz

ati

on

for

unst

able

angin

a, and

art

eri

al re

vasc

ula

riza

tion

Ridker PM et al. NEJM 2008;359:2195-2207

*The study was stopped prematurely after 1.9 years

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Primary PreventionPrimary Prevention

CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction

Page 24: 4 acc prevention cholesterol

0

5

10

15

Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial

17.4%

14.8%

RR=0.84, P=0.048C

om

bin

ed C

V

event

rate

(%

)*

Weeks

*Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization.

4 8 12 160

Atorvastatin

Source: Schwartz GG et al. JAMA 2001;285:1711-1718

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Placebo15

10

5

0

ACS=Acute coronary syndrome, CV=Caradiovascular

3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks

Acute intensive statin therapy provides significant CV benefit

Page 25: 4 acc prevention cholesterol

Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study

ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction, UA=Unstable angina

Source: Cannon CP et al. NEJM 2004;350:1495-1504

4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months

Acute intensive statin therapy provides significant CV benefit

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Follow-up (months) 3 6 9 12 15 18 21 24 27 30

30

25

20

15

10

5

0P=0.005

Rec

urre

nt M

I, ca

rdia

c de

ath,

U

A, r

evas

cula

rizat

ion,

or

stro

ke

16% RRR

Atorvastatin

Pravastatin

Page 26: 4 acc prevention cholesterol

Aggrastat to Zocor (A to Z) Trial

Source: de Lemos JA et al. JAMA 2004;292:1307-1316

*Includes CV death, MI, readmission for an ACS, and CVA

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Time from randomization (months)

Cum

ulat

ive

even

t ra

te (

%)*

0

5

10

15

20

0 4 8 12 16 20 24

Placebo/Simvastatin 20 mg/day

HR=0.89, P=0.14

Simvastatin 40/80 mg/day

ACS=Acute coronary syndrome, CV=Cardiovascular, CVA=Cerebrovascular accident, MI=Myocardial infarction

4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months

Acute intensive statin therapy does not provide CV benefit

Page 27: 4 acc prevention cholesterol

Scandinavian Simvastatin Survival Study (4S)

Mort

alit

y (

%)

Placebo

11.5

Simvastatin

12

8

4

0

8.2

P<0.001

30% RRR

Source: 4S Group. Lancet 1994;344:1383–1389

LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction

4,444 patients with angina pectoris or previous MI randomized to simvastatin (20-40 mg) or placebo for 5.4 years

A statin provides significant benefit in those with average LDL-C levels

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Page 28: 4 acc prevention cholesterol

Cholesterol and Recurrent Events (CARE) Study

Placebo

13.2

Pravastatin

15

10

5

0

10.2

P=0.003

24% RRRR

ate

of

MI or

CH

D d

eath

(%

)

Srouce: Sacks FM et al. NEJM 1996;335:1001–1009

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

4,159 patients with a history of MI randomized to pravastatin (40 mg) or placebo for 5 years

A statin provides significant benefit in those with average cholesterol levels

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Page 29: 4 acc prevention cholesterol

Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study

CH

D D

eath

(%

)

Placebo

8.3

Pravastatin

9

6

3

0

6.4

P<0.001

24% RRR

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

Source: LIPID Study Group. NEJM 1998;339:1349–1357

9,014 patients with a history of MI or hospitalization for unstable angina randomized to pravastatin (40 mg) or placebo for 6.1 years

A statin provides significant benefit across a broad range of cholesterol levels

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Page 30: 4 acc prevention cholesterol

Baseline LDL-C (mg/dL)

Statin (n = 10,269)

Placebo (n = 10,267)

<100 282 (16.4%) 358 (21.0%)

100–129 668 (18.9%) 871 (24.7%)

130 1083 (21.6%) 1356 (26.9%)

All patients 2033 (19.8%) 2585 (25.2%)

Event Rate Ratio (95% CI)

Statin Better Statin Worse

0.4 0.6 0.8 1.0 1.2 1.4

0.76 (0.72–0.81)P<0.0001

Heart Protection Study (HPS)

CAD=Coronary artery disease, CI=Confidence interval, CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol

Source: HPS Collaborative Group. Lancet 2002;360:7-22

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

A statin provides significant CV benefit regardless of baseline LDL-C level

Page 31: 4 acc prevention cholesterol

Source: Shepherd J et al. Lancet 2002;360:1623-1630

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

0

10

20

0 1 2 3 4

CH

D d

eath

, non

-fat

al

MI,

stro

ke (

%)

Years

Placebo

15% RRR, P=0.014

Pravastatin

5,804 patients aged 70-82 years with a history of, or risk factors for, vascular disease randomized to pravastatin (40 mg) or placebo for

3.2 years

A statin provides CV benefit in older men

Page 32: 4 acc prevention cholesterol

Treating to New Targets (TNT) Trial

CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction

Source: LaRosa JC et al. NEJM 2005;352:1425-35

*Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Years

Maj

or C

V E

vent

* (%

)

0 1 2 3 4 5 6

P<0.001

22% RRRAtorvastatin (10 mg)

0.00

0.05

0.10

0.15

Atorvastatin (80 mg)

10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years

High-dose statin therapy provides benefit in chronic CHD

Page 33: 4 acc prevention cholesterol

Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial

Source: Pedersen TR et al. JAMA 2005;294:2437-2445

CV=Cardiovascular, HR=Hazard ratio, MI=Myocardial infarction

*Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Cum

ulat

ive

Haz

ard

(%)

Years Since Randomization

01 2 3 4 5

4

8

12

HR=0.89, P=0.07

Simvastatin (20 mg)

Atorvastatin (80 mg)

8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years

High-dose statin therapy does not provide CV benefit after a MI

Page 34: 4 acc prevention cholesterol

Source: LaRosa JC et al. NEJM 2005;352:1425-1435

Relationship between LDL-C levels and event rates in secondary prevention statin trials of patients with stable CHD

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

30

25

20

15

10

5

00 70 90 110 130 150 170 190 210

LDL-C (mg/dL)

TNT (atorvastatin 80 mg/d)TNT (atorvastatin 10 mg/d)

HPSCARE

LIPIDLIPIDCARE

HPSEve

nt (

%) 4S

4SStatinPlacebo

CARE=Cholesterol and Recurrent Events Trial, CHD=Coronary heart disease, HPS=Heart Protection Study, LDL-C=Low density lipoprotein

cholesterol, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease, 4S=Simvastatin Survival Study, TNT=Treating to New Targets

Page 35: 4 acc prevention cholesterol

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH)

12,064 patients with a history of MI randomized to simvastatin (80 mg) or simvastatin (20 mg) for a mean of 6.7 years

High-dose statin therapy does not provide CV benefit after a MI

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Secondary PreventionSecondary Prevention

Source: SEARCH Collaborative Group. Lancet 2010;376:1658-1669

CHD=Coronary heart disease, MI=Myocardial infarction

*Includes coronary death, myocardial infarction, stroke, or arterial revascularization

*

Page 36: 4 acc prevention cholesterol

Source: Thavendiranathan P et al. Arch Intern Med 2006;166:2307-2313

Meta-analysis of randomized controlled trials comparing risk reductions between primary and secondary prevention patients

Primary Secondary Primary Secondar

y

Primary Secondar

y

Major CHD events

29.2 20.8 1.66 2.4 60 33

Major CV events 14.4 17.8 0.37 0.8 268 125

Nonfatal MI 31.7 NA 1.65 NA 61 NA

PCI or CABG 33.8 20.3 1.08 2.7 93 37

RelativeRisk Reduction

AbsoluteRisk Reduction

Number NeededTo Treat

CABG=Coronary artery bypass graft surgery, CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction,

PCI=Percutaneous coronary intervention

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Degree of Benefit in Prevention Degree of Benefit in Prevention TypesTypes

Page 37: 4 acc prevention cholesterol

Source: Cannon CP et al. JAMA 2005;294:2492-2494

RR in MI or CHD Death

(%)

RR in Primary End

Point (%)

LDL-C Reduction (mg/dL)

Duration

(years)

PopulationTrial

1111235Stable CAD (N = 8888)

IDEAL

2122245Stable CAD (N =10,001)

TNT

1511142ACS

(N = 4497)A to Z

1616332ACS

(N = 4162)PROVE IT-

TIMI 22

Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259

ACS=Acute coronary syndrome, CAD=Coronary artery disease, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RR=Relative reduction

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Effect of Intensive TherapyEffect of Intensive TherapyMagnitude of event reduction among trials of intensive

statin therapy

Page 38: 4 acc prevention cholesterol

HMG-CoA Reductase Inhibitor HMG-CoA Reductase Inhibitor Evidence:Evidence:Effect of Intensive TherapyEffect of Intensive TherapyCholesterol Treatment Trialists’ (CTT) Collaboration

Meta-analysis of 169,138 patients randomized to at least 2 years of statin therapy

0 1 2 3 4 5

01

01

52

0

LDL cholesterol level (mmol/L)

Fiv

e ye

ar r

isk

of a

maj

orva

scul

ar e

vent

, %

Control

21% relative riskreduction per mmol/LStatin

16% relative riskreduction per 0.5 mmol/LMore statin

There is a proportionate reduction in CV events with greater LDL-cholesterol reduction

Source: Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-1681

CV=Cardiovascular, LDL=Low density lipoprotein

Page 39: 4 acc prevention cholesterol

Source: Kashani A et al. Circulation 2006;114:2788-2797

• 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm)

• Dose-dependent phenomenon that is usually reversible• 15.4% incidence of myalgias* (18.7% incidence in control arm)

• 0.9% incidence of myositis (0.4% incidence in control arm)

• 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm)

74,102 subjects in 35 randomized clinical trials with statins

*The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in

the 80 mg and 10 mg arms, respectively

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Adverse EffectsAdverse Effects

Hepatocyte

Skeletal myocyte

Page 40: 4 acc prevention cholesterol

Concomitant Use of Meds

Fibrate

Nicotinic acid (Rarely)

Cyclosporine

Antifungal azoles**

Macrolide antibiotics†

HIV protease inhibitors

Nefazadone

Verapamil, Amiodarone

Other Conditions

Advanced age (especially >80 years)

Women > Men especially at older age

Small body frame, frailty

Multisystem disease‡

Multiple medications

Perioperative period

Alcohol abuse

Grapefruit juice (>1 quart/day)

Risk factors for the development of myopathy*

Source: Pasternak RC et al. Circulation 2002;106:1024-1028

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Adverse EffectsAdverse Effects

*General term to describe diseases of muscles**Itraconazole, Ketoconazole

†Erythromycin, Clarithromycin‡Chronic renal insufficiency, especially from

diabetes mellitus

Page 41: 4 acc prevention cholesterol

Gall Bladder

LDL Receptors

VLDL and LDL removal

Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion

Liver

BA Excretion

Terminal Ileum

Bile Acid

Enterohepatic

CirculationReabsorption of

bile acids

LDL-C

BA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein

Bile Acid Sequestrant:Bile Acid Sequestrant:Mechanism of ActionMechanism of Action

Page 42: 4 acc prevention cholesterol

Source: Insull W et al. Mayo Clin Proc 2001;76:971-982

*P<0.001 vs placebo†P=0.04 vs placebo

% C

hange f

rom

base

line

at

week

24

TGHDL-CLDL-C

*

Placebo

Colesevelam 3.8 grams/day

Bile Acid Sequestrant Evidence:Bile Acid Sequestrant Evidence:Efficacy at Reducing LDL-CEfficacy at Reducing LDL-C

5

-1

0

10

3

-15

-20

-15

-10

-5

0

5

10

15

HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride

Page 43: 4 acc prevention cholesterol

Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT)

Placebo

8.6

Cholestyramine

9

6

3

0

7.0

P<0.05

19% RRR

Rate

of

MI or

CH

D d

eath

(%

)

Source: The LRC-CPPT Investigators. JAMA 1984;251:351-364

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

3,806 men with primary hypercholesterolemia randomized to cholestyramine (24 grams) or placebo for 7.4 years

A bile acid sequestrant provides benefit in those with high cholesterol levels

Bile Acid Sequestrant Evidence:Bile Acid Sequestrant Evidence:Primary PreventionPrimary Prevention

Page 44: 4 acc prevention cholesterol

Dietary cholesterol

Production in liver Absorption from intestine

Bloodstream

LDL-CVLDL

Cholesterolsynthesis

Biliary cholesterol

Chylomicrons

Fecal sterols and neutral sterols

Ezetimibe:Ezetimibe:Mechanism of ActionMechanism of Action

Page 45: 4 acc prevention cholesterol

LDL-C

Mean %

change f

rom

base

line t

o w

eek

12

–20

–15

–10

–5

0

+5

–16.9*

+0.4

Triglycerides

–5.7

HDL-C

–1.6

+1.3

Placebo

Ezetimibe 10 mg

892 patients with primary hypercholesterolemia randomized to ezetimibe (10 mg) or placebo for 12 weeks

*p<0.01 compared to placebo

Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-1097

Ezetimibe Evidence:Ezetimibe Evidence:Efficacy at Reducing LDL-CEfficacy at Reducing LDL-C

+5.7

HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

Page 46: 4 acc prevention cholesterol

Therapy Dose (g/day) Effect

Dietary soluble fiber 5-10 (psyllium) LDL-C 10-15%

Soy protein 20-30 LDL-C 5-7%

Stanol esters 1.5-2 LDL-C 15-20%

Sources:Kwiterovich Jr PO. Pediatrics 1995;96:1005-1009

Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214Miettinen TA et al. Ann Med 2004;36:126-134

Dietary Adjuncts Evidence:Dietary Adjuncts Evidence:Efficacy at Reducing LDL-CEfficacy at Reducing LDL-C

LDL-C=Low density lipoprotein cholesterol

Page 47: 4 acc prevention cholesterol

4.0

3.0

2.0

1.0

25 45 65

HDL-C (mg/dL)

CH

D r

isk r

ati

o

2.0

1.0

0

4.0

Framingham Study

Source: Kannel WB. Am J Cardiol 1983;52:9B–12B

CHD=Coronary heart disease, HDL-C=High-density lipoprotein cholesterol

CHD Risk According to HDL-C LevelCHD Risk According to HDL-C Level

Page 48: 4 acc prevention cholesterol

Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL cholesterol levels and increased HDL cholesterol

levels

HDL

Serum VLDL results in reduced lipolysis to LDL

Serum LDL

VLDL

VLDL secretion

Apo B

Hepatocyte Systemic Circulation

Mobilization of FFA

TG synthesis

VLDL

LDL

FFA=Free fatty acid, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein

Nicotinic Acid:Nicotinic Acid:Mechanism of ActionMechanism of Action

Source: McKenney JM. Selecting Successful Lipid-lowering Treatments presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14

Apo B

Page 49: 4 acc prevention cholesterol

Mean c

hange f

rom

Base

line

Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105

500

HDL-C

LDL-C

Triglyceride

–9%

–14%

–22% –21%–17%

30%30%26%

22%15%

10%

–28%

–35%

–44%–39%

–11%

–5%

1000 1500 2000 2500Dose (mg) 3000

Nicotinic Acid Evidence:Nicotinic Acid Evidence:Effect on Lipid ParametersEffect on Lipid Parameters

-50

-40

-30

-20

-10

0

10

20

30

HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride

Page 50: 4 acc prevention cholesterol

P=0.0012

1009080706050

40

0 2 4 6 8 10 12 14 16

Years of follow-up

Surv

ival (%

)

Source: Canner PL et al. JACC 1986;8:1245–1255

Nicotinic acid stopped

Coronary Drug Project (CDP)

Nicotinic Acid

MI=Myocardial infarction

Nicotinic Acid Evidence:Nicotinic Acid Evidence:Secondary PreventionSecondary Prevention

Placebo

8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years

Niacin provides long-term benefit following a MI

Page 51: 4 acc prevention cholesterol

Source: Brown BG et al. NEJM 2001;345:1583-1592

HDL-Atherosclerosis Treatment Study (HATS)

*

*Includes cardiovascular death, MI, stroke, or need for coronary revascularization

Nicotinic Acid Evidence:Nicotinic Acid Evidence:Secondary PreventionSecondary Prevention

CAD=Coronary artery disease, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin (10-20 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg bid) + antioxidants, antioxidants, or placebo

for 3 years

A statin plus niacin provides benefit to men with CAD and low HDL-C levels

**p<0.01, but low absolute event rates

****

Placebo (n=34)

Niacin/Simvastatin (n=33)

Placebo + Vitamins (n=39)

Niacin/Simvastatin + Vitamins (n=40)

Page 52: 4 acc prevention cholesterol

Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact of Global

Health Outcomes (AIM-HIGH) Trial

Nicotinic Acid Evidence:Nicotinic Acid Evidence:Secondary PreventionSecondary Prevention

Time (years)

Prim

ary

outc

ome

(%

)**

0

10

20

0

1

2

3

4

MonotherapyCombination Therapy

HR 1.02, p=0.79

16.2%

16.4%

3414 patients with established CV disease randomized to niacin (up to 2000 mg/day) or placebo on a background of statin therapy for a

mean of 3 years*

Niacin provides no benefit to those with CV disease and low HDL-C levels

Source: AIM-HIGH Investigators. NEJM 2011;365:2255-2267

*The study was stopped prematurely

CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol

**Composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary/cerebral revascularization

Page 53: 4 acc prevention cholesterol

Nicotinic Acid Evidence:Nicotinic Acid Evidence:Secondary PreventionSecondary Prevention

Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial

0 1 2 3 4

Years of follow-up

0

10

15

Maj

or v

ascu

lar

eve

nts

(%) 15.0%

14.5%

5

Niacin/LaropiprantPlacebo

HR 0.96, p=0.29

25,673 patients with established CV disease randomized to extended release niacin (up to 2000 mg/day) plus laropiprant (40 mg/day) or

placebo on a background of statin therapy for a median of 3.9 years*

Niacin provides no benefit to those with CV disease and low HDL-C levels

Source: Armitage J et al. Presented at Late Breaking Clinical Trials Session, ACC13, www.thrivestudy.org

*The study was stopped prematurely

CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol

Page 54: 4 acc prevention cholesterol

Inhibition of CETP limits the transfer of cholesterol esters from HDL particles to triglyceride-rich lipoproteins and results in elevated HDL cholesterol levels along with larger and less dense LDL cholesterol

particlesCE=Cholesterol ester, CETP=Cholesterol ester transfer protein, FC=Free

cholesterol HDL=High density lipoprotein, LCAT=Lecithin carnitine acyl transferase, LDL=Low density lipoprotein, VLDL=Very low density lipoprotein

Cholesterol Ester Transfer Protein Cholesterol Ester Transfer Protein Evidence:Evidence:Mechanism of ActionMechanism of Action

LDL/VLDL

Bile

LDL-R

CETPLiver FFCC

SR-B1

CE

Free Cholesterol in Extrahepatic tissues

Vessel Wall

CE

FC

LCAT

HDL

Page 55: 4 acc prevention cholesterol

Cholesterol Ester Transfer Protein Cholesterol Ester Transfer Protein Evidence:Evidence:Secondary PreventionSecondary PreventionInvestigation of Lipid Level Management to

Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial15,067 patients at high CV risk randomized to torcetrapib (60

mg/day) plus atorvastatin versus atorvastation alone for a median of 1.5 years*

The CETP inhibitor, torcetrapib, is associated with increased CV risk

Pri

mary

end poin

t**

(%)

Atorvastatin

5.0

Atorvastatin and

Torcetrapib

9

6

3

0

6.2

P=0.001

All-

cause

mort

alit

y (

%)

Atorvastatin

0.8

Atorvastatin and

Torcetrapib

3

2

1

0

1.2

P=0.006

Source: Barter PJ et al. NEJM 2007;357:2109-2122

CETP=Cholesterol ester transfer protein, CV=Cardiovascular

*The trial was stopped prematurely**Composite of death from coronary heart disease, nonfatal

myocardial infarction, stroke, or hospitalization for unstable angina

Page 56: 4 acc prevention cholesterol

Cholesterol Ester Transfer Protein Cholesterol Ester Transfer Protein Evidence:Evidence:Secondary PreventionSecondary PreventionDal-OUTCOMES Trial

Source: Barter PJ et al. NEJM 2007;357:2109-2122

ACS=Acute coronary syndrome, CETP=Cholesterol ester transfer protein, CV=Cardiovascular

*The trial was stopped prematurely**Composite of death from coronary heart disease, nonfatal myocardial

infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation

15,871 patients with a recent ACS randomized to dalcetrapib (600 mg/day) or placebo for a median of 2.6 years

The CETP inhibitor, dalcetrapib, is associated with no CV benefit

Pri

mary

end poin

t**

(%)

Placebo

8.3

Dalcetrapib

9

6

3

0

8.0

P=0.52

Page 57: 4 acc prevention cholesterol

Source: Sarwar N et al. Circulation 2007;115:450-458

CHD=Coronary heart disease

CHD Risk According to Triglyceride CHD Risk According to Triglyceride LevelsLevelsMeta-analysis of 29 prospective studies evaluating the risk of CHD

relative to triglyceride level (top third vs. bottom third)

An elevated triglyceride level is associated with increased CHD risk

Page 58: 4 acc prevention cholesterol

Liver

TG

IDL

VLDL

LPL

CECE FCFC

MacrophageMature HDL

Nascent HDL

LDL-R

Intestine

CE=Cholesterol ester, FC=Free cholesterol, HDL=High density lipoprotein, IDL=Intermediate density lipoprotein, LDL-R=Low density lipoprotein receptor,

LPL=Lipoprotein lipase, TG=Triglyceride, VLDL=Very low density lipoprotein

Fibrate

+

+

Fibrate:Fibrate:Mechanism of ActionMechanism of Action

Page 59: 4 acc prevention cholesterol

Source: Knopp RH et al. Am J Med 1987;83:50-9

-20*

+11*

-38*

+15*

-45*-50

-40

-30

-20

-10

0

10

20

30

40

50Type IIa hyperlipidemia Type IIb hyperlipidemia

Mean %

change f

rom

base

line

HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride

180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate (100 mg three times daily) or placebo for 24 weeks

LDL TG

HDL

TG

HDL

Fibrate Evidence:Fibrate Evidence:Effect on Lipid ParametersEffect on Lipid Parameters

-6*

LDL

*p<0.01

Page 60: 4 acc prevention cholesterol

Sources: Frick MH et al. NEJM 1987;317:1237-1245

Manninen V et al. Circulation 1992;85:37-45BIP Study Group. Circulation 2000;102:21-27

Rubins HB et al. NEJM 1999;341:410-418

*Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL**Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL

***Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05)

% C

HD

Death

/Non

fata

l M

I

Treatment arm

Placebo

2.7 4.1***

2.7

8

13.615

13

22

17

22***

66%

34%

9%

42% 22%

Secondary PreventionHHS HHS*

Fibrate Evidence:Fibrate Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention

Primary Prevention

HDL-C=High density lipoprotein cholesterol, TG=Triglyceride

Page 61: 4 acc prevention cholesterol

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)

CH

D D

eath

or

Nonfa

tal M

I (%

)

Placebo

5.9

Fenofibrate

9

6

3

0

5.2

P=0.16

11% RRR

9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years

A fibrate does not provide significant additional benefit* in diabetics

Source: Keech A et al. Lancet 2005;366:1849-1861

*Unadjusted for concomitant statin use

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

Fibrate Evidence:Fibrate Evidence:Primary PreventionPrimary Prevention

Page 62: 4 acc prevention cholesterol

Fibrate Evidence:Fibrate Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention

Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial

5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years

On a background of statin therapy, a fibrate does not reduce CV events in diabetics

CV

death

, nonfa

tal st

roke

or

nonfa

tal M

I (%

/year)

Placebo

2.4

Fenofibrate

3

2

1

0

2.2

P=0.32

8% RRR

Source: ACCORD study group. NEJM 2010;362:1563-1574

CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction

Page 63: 4 acc prevention cholesterol

HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglyceride

Good- 9%+ 1%- 18%- 13%Ezetimibe

Good- 14-29%+ 4-12%- 25-50%- 19-37%Statins*

Good- 30%+ 11-13%- 4-21%- 19%Fibrates

Reasonable to Poor

- 30-70%+ 14-35%- 10-20%- 10-20%Nicotinic acid

PoorNeutral or + 3%- 10-18%- 7-10%Bile acid sequestrants

Patient tolerability

TGHDL-CLDL-CTCTherapy

Effect of PharmacotherapyEffect of Pharmacotherapyon Lipid Parameterson Lipid Parameters

*Daily dose of 40mg of each drug, excluding rosuvastatin

Page 64: 4 acc prevention cholesterol

% R

educt

ion

Triglyceride

*P<0.05

-10

-20

-30

-40

-50

0

-46*

-21*

Total Cholesterol

Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731

27 patients with hypertriglyceridemia and low HDL-C treated with omega-3 fatty acid (4 grams/day) for 7 months

Omega-3 Fatty Acids Evidence:Omega-3 Fatty Acids Evidence:Effect on Lipid ParametersEffect on Lipid Parameters

HDL-C=High-density lipoprotein cholesterol

Page 65: 4 acc prevention cholesterol

Source: Yokoyama M et al. Lancet 2007;369:1090-1098

Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)

*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG

Years

Omega-3 Fatty Acids Evidence:Omega-3 Fatty Acids Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention

18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years

Omega-3 fatty acids provide CV benefit, particularly in secondary prevention

CV=Cardiovascular, EPA=Eicosapentaenoic acid

Page 66: 4 acc prevention cholesterol

Omega-3 Fatty Acids Evidence:Omega-3 Fatty Acids Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention

Outcome Reduction with Initial Glargine Intervention (ORIGIN)12,536 patients with IFG, IGT, DM, established CV disease, or CV risk

factors randomized in 2 x 2 trial design to omega 3 fatty acids (at least 900 mg/day), insulin glargine (with a target fasting blood

glucose <95 mg/dL) or placebo for a median of 6.2 years

Low dose omega-3 fatty acids do not provide CV benefit in at risk individuals

CV

death

(%

)

Placebo

9.3

Omega 3 fatty acids

15

10

5

0

9.1

P=0.72

2% RRR

Source: ORIGIN Trial Investigators. NEJM 2012;367:309-318

CV=Cardiovascular, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance

Page 67: 4 acc prevention cholesterol

Omega-3 Fatty Acids Omega-3 Fatty Acids Evidence:Evidence:Secondary PreventionSecondary Prevention

**p<0.05

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

Omega-3 Fatty Acids

Placebo

Source: Burr ML et al. Lancet 1989;2:757-761

Diet and Reinfarction Trial (DART)

All

cause

mort

alit

y

(%)

*Corresponds to 2.5 grams of EPA (PUFA)

EPA=Eicosapentaenoic acid, MI=Myocardial infarction

2,033 men with a history of a MI randomized to a diet of reduced fat with an increased ratio of polyunsaturated to saturated fat,

increased fatty fish intake*, or increased fiber intake for 2 years

Omega-3 fatty acids reduce all cause mortality** in men after a MI

Page 68: 4 acc prevention cholesterol

Source: GISSI Investigators. Lancet 1999;354:447-455

Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI-Prevenzione)

CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids

Perc

ent

of

pati

ents P=0.04

8P=0.053 P=0.023 P=0.00

8

stroke stroke

02468

10121416

Death,NF MI,

NF stroke(2 way)

CVdeath,NF MI,and NF

Death,NF MI,

NF stroke(4 way)

CVdeath,NF MI,and NF

Omega-3 PUFA

Placebo

Omega-3 Fatty Acids Omega-3 Fatty Acids Evidence:Evidence:Secondary PreventionSecondary Prevention

11,324 patients with a history of a MI randomized to omega-3 polyunsaturated fatty acids [PUFA] (1 gram), vitamin E (300 mg),

both or none for 3.5 years

Omega-3 fatty acids provide significant CV benefit after a MI

Page 69: 4 acc prevention cholesterol

3,827 patients 3-14 days following a MI randomized to omega-3 fatty acids (460 mg EPA + 380 mg DHA) or placebo for 1 year

Omega-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies

OMEGA Trial

Source: Rauch B et al. Circulation 2010;122:2152-2159

Placebo

8.8

Fatty acids

12

8

4

0

10.4

P=0.10

Rate

of

rein

farc

tion,

stro

ke, or

death

* (%

)

DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid,

MI=Myocardial infarction

*This is a secondary endpoint

Omega-3 Fatty Acids Omega-3 Fatty Acids Evidence:Evidence:Secondary PreventionSecondary Prevention

Page 70: 4 acc prevention cholesterol

0 10 20

2 RFs

0-1 RFs

CAD or Risk Equivalent**

A risk assessment tool* is needed for individuals with >2 RFs

Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497

CAD=Coronary artery disease, CHD=Coronary heart

disease, DM=Diabetes mellitus, RF=Risk factor

**Includes DM, non-coronary atherosclerotic vascular disease, and >20% 10-year CHD risk by the FRS

*Such as the Framingham Risk Score (FRS)

10-year CHD Risk

Risk Assessment forRisk Assessment forLDL-C LoweringLDL-C Lowering

Page 71: 4 acc prevention cholesterol

Risk Stratification:Risk Stratification:Framingham Risk Score On Line Framingham Risk Score On Line CalculatorCalculator

Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Risk Assessment Tool. http://hp2010.nhlbihin.net/atpiii/calculator.asp

Page 72: 4 acc prevention cholesterol

Years Points

20-34

-9

35-39

-4

40-44

0

45-49

3

50-54

6

55-59

8

60-64

10

65-69

11

70-74

12

75-79

13

Step 1: Age Points

TC (mg/dl)

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

<160 0 0 0 0 0160-199

4 3 2 1 0

200-239

7 5 3 1 0

240-279

9 6 4 2 1

>280 11 8 5 3 1

Step 2: Total Cholesterol Points

HDL-C (mg/dl) Points

>60 -150-59 040-49 1<40 2

Step 3: HDL-C Points

SBP (mm Hg)

If untreate

d

If treated

<120 0 0120-129 0 1130-139 1 2140-159 1 2

>160 2 3

Step 4: SBP Points

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

Nonsmoker

0 0 0 0 0

Smoker 8 5 3 1 1

Step 5: Smoking Status Points

AgeTotal Cholesterol

HDL-CSystolic Blood

Pressure

Smoking Status

Point Total

Step 6: Sum of Points

Point Total

10-year Risk

Point Total

10-year Risk

Point Total

10-year Risk

<0 <1% 6 2% 13 12%0 1% 7 3% 14 16%1 1% 8 4% 15 20%2 1% 9 5% 16 25%3 1% 10 6% >17 >30%4 1% 11 8%

5 2% 12 10%

Step 7: 10-year CHD Risk

Risk Stratification:Risk Stratification:Framingham Risk Score for MenFramingham Risk Score for Men

Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at http://www.framinghamheartstudy.org/risk/hrdcoronary.html.

CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol,

SBP=Systolic blood pressure, TC=Total cholesterol

Page 73: 4 acc prevention cholesterol

Step 1: Age Points

TC (mg/dl)

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

<160 0 0 0 0 0160-199

4 3 2 1 1

200-239

8 6 4 2 1

240-279

11 8 5 3 2

>280 13 10 7 4 2

Step 2: Total Cholesterol Points

HDL-C (mg/dl) Points

>60 -150-59 040-49 1<40 2

Step 3: HDL-C Points

SBP (mmHg)

If untreate

d

If treate

d<120 0 0

120-129 1 3130-139 2 4140-159 3 5

>160 4 6

Step 4: SBP Points

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

Nonsmoker

0 0 0 0 0

Smoker 9 7 4 2 1

Step 5: Smoking Status Points

AgeTotal Cholesterol

HDL-CSystolic Blood

Pressure

Smoking Status

Point Total

Step 6: Sum of Points

Point Total

10-year Risk

Point Total

10-year Risk

Point Total

10-year Risk

<9 <1% 15 3% 22 17%9 1% 16 4% 23 22%

10 1% 17 5% 24 27%11 1% 18 6% >25 >30%12 1% 19 8%

13 2% 20 11%

14 2% 21 14%

Step 7: 10-year CHD Risk

Risk Stratification:Risk Stratification:Framingham Risk Score for WomenFramingham Risk Score for Women

Years Points

20-34

-7

35-39

-3

40-44

0

45-49

3

50-54

6

55-59

8

60-64

10

65-69

12

70-74

14

75-79

16

Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at http://www.framinghamheartstudy.org/risk/hrdcoronary.html.

CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol,

SBP=Systolic blood pressure, TC=Total cholesterol

Page 74: 4 acc prevention cholesterol

Risk Stratification:Risk Stratification:Reynolds Risk Score On Line Reynolds Risk Score On Line CalculatorCalculator

In addition to information collected as part of the Framingham Risk Score, the Reynolds Risk Score includes a hs-CRP level and a family history of premature CV disease in predicting one’s risk

of adverse CV events

Source: Reynolds Risk Score calculator. http://www.reynoldsriskscore.org/default.aspx

Page 75: 4 acc prevention cholesterol

Risk Category LDL-C Goal Initiate TLCConsider

Drug Therapy

High risk: CHD or CHD risk equivalents (10-year risk >20%)

<100 mg/dL (optional

goal: <70)

100 mg/dL

>100 mg/dL (<100 mg/dL: consider

drug options)

Moderately high risk: 2+ risk factors* (10-year risk 10% to 20%)

<130 mg/dL (optional

goal: <100)

130 mg/dL

>130 mg/dL (100-129 mg/dL:

consider drug options)

Moderate risk: 2+ risk factors* (10 year risk <10%)

<130 mg/dL 130 mg/dL

>160 mg/dL

Lower risk: 0-1 risk factor*

<160 mg/dL 160 mg/dL

>190 mg/dL (160-189 mg/dL: LDL-C lowering drug optional)

Source: Grundy S et al. Circulation 2004;110:227-239

ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes

*Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmHg or on antihypertensive medication, HDL-C <40 mg/dl (>60 mg/dl is a negative risk

factor), family history of premature CHD, age >45 years in men or >55 years in women

ATP III LDL-C Goals andATP III LDL-C Goals andCut-points for Drug TherapyCut-points for Drug Therapy

Page 76: 4 acc prevention cholesterol

Level (mg/dl)

Classification

<200 Desirable

200-239 Borderline High

>240 High

Level (mg/dl)

Classification

>40 Minimum goal*

40-50 Desired goal*

>50 High

Level (mg/dl)

Classification

<150 Normal

150-199 Borderline High

200-499 High

>500 Very High

Total Cholesterol HDL-Cholesterol

Triglyceride

Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497

ATP III Classification of Other Lipoprotein ATP III Classification of Other Lipoprotein LevelsLevels

*These goals apply to men. For women, the minimum goal is >50 mg/dL

HDL=High density lipoprotein

Page 77: 4 acc prevention cholesterol

Source: Buse JB et al. Circulation 2007;115:114-126

• In adult patients, lipid levels should be measured at least annually and more often if needed to achieve goals. In adults <40 years of age with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years.

• Lifestyle modification deserves primary emphasis for all individuals. Patients should focus on the reduction of saturated fat and cholesterol intake, weight loss (if indicated), and increases in dietary fiber and physical activity. These lifestyle changes have been shown to improve the lipid profile.

AHA=American Heart Association, CV=Cardiovascular, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

AHA Primary Prevention of CV Disease in AHA Primary Prevention of CV Disease in DMDMCholesterol RecommendationsCholesterol RecommendationsPrimary Prevention

Page 78: 4 acc prevention cholesterol

Source: Buse JB et al. Circulation 2007;115:114-126

• In those >40 years of age without overt CVD, but with >1 major CVD risk factor*, the primary goal is an LDL-C level <100 mg/dL. If LDL-C lowering drugs are used, a reduction of at least 30-40% in LDL-C levels should be obtained. If the baseline LDL-C level is <100 mg/dL, statin therapy should be initiated based on risk factor assessment and clinical judgment.

• In those <40 years of age without overt CVD, but at increased risk of CVD either by clinical judgment or by risk calculator, the LDL-C goal is <100 mg/dL, and LDL-C lowering drugs should be considered if lifestyle changes do not achieve the goal.

*Includes cigarette smoking, hypertension [BP >140/90 mm Hg or use of antihypertensive medication], low HDL-C cholesterol [<40 mg/dL], and family history of premature CHD [CHD in

male first-degree relative <55 years of age; CHD in female first-degree relative <65 years of age].

AHA Primary Prevention of CV Disease in AHA Primary Prevention of CV Disease in DMDMCholesterol Recommendations (Continued)Cholesterol Recommendations (Continued)Primary Prevention

AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDL-C=High

density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

Page 79: 4 acc prevention cholesterol

• The ADA and AHA suggest different approaches to the management of HDL-C and triglyceride-associated CVD risk.

• The AHA suggests that in patients with triglyceride levels of 200-499 mg/dL, a non-HDL-C goal of <130 mg/dL is a secondary target. If triglycerides are >500 mg/dL, therapeutic options include a fibrate or niacin before LDL-C lowering therapy and treatment of LDL-C to goal after triglyceride-lowering therapy. A non HDL-C level <130 mg/dL should be achieved if possible

• The ADA suggests lowering triglycerides to <150 mg/dL and raising HDL-C to <40 mg/dL. In women an HDL-C goal 10 mg/dL higher (>50 mg/dL) should be considered.

ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDL-

C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

AHA and ADA Primary Prevention of CV AHA and ADA Primary Prevention of CV DiseaseDiseasein DM Cholesterol Recommendationsin DM Cholesterol RecommendationsPrimary Prevention

Sources: Buse JB et al. Circulation 2007;115:114-126

American Diabetes Association. Diabetes Care 2010;33:S11-61

Page 80: 4 acc prevention cholesterol

• In most adult patients, a fasting lipid profile should be measured at least annually. In adults with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years.

• Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; increase of omega-3 fatty acids, viscous fiber, and plant stanols/sterols; weight loss (if indicated); and increased physical activity should be recommended to improve the lipid profile in patients with DM.

Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA=American Diabetes Association, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

ADA Cholesterol Recommendations forADA Cholesterol Recommendations forPatients with Diabetes MellitusPatients with Diabetes Mellitus

Primary Prevention

Page 81: 4 acc prevention cholesterol

• Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels for diabetic patients:

o With overt CV disease

o Without CV disease who are over the age of 40 years and have >1 other CV disease risk factors

• For patients at lower risk (without overt CV disease and <40 years of age), statin therapy should be considered in addition to lifestyle therapy if LDL-C remains >100 mg/dL or in those with multiple CV disease risk factors.

Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA=American Diabetes Association, CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol

ADA Cholesterol Recommendations forADA Cholesterol Recommendations forPatients with Diabetes Mellitus (Continued)Patients with Diabetes Mellitus (Continued)

Primary and Secondary Prevention

Page 82: 4 acc prevention cholesterol

• In individuals without overt CV disease, the primary goal is an LDL-C <100 mg/dL (2.6 mmol/L).

• In individuals with overt CV disease, a lower LDL-C goal of <70 mg/dL (1.8 mmol/L), using a high dose of statin is an option.

• If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL-C of approximately 30-40% from baseline is an alternative therapeutic goal.

• Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy.

Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

ADA Cholesterol Recommendations forADA Cholesterol Recommendations forPatients with Diabetes Mellitus (Continued)Patients with Diabetes Mellitus (Continued)

Primary and Secondary Prevention

Page 83: 4 acc prevention cholesterol

• Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy.

• If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CV disease outcomes or safety.

• Statin therapy is contraindicated in pregnancy.

Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol

ADA Cholesterol Recommendations forADA Cholesterol Recommendations forPatients with Diabetes Mellitus (Continued)Patients with Diabetes Mellitus (Continued)

Primary Prevention

Page 84: 4 acc prevention cholesterol

A lipid profile should be established in all patients, and for hospitalized patients, lipid-lowering therapy as recommended below should be initiated before discharge

Lifestyle modifications including daily physical activity and weight management are strongly recommended for all patients

Dietary therapy for all patients should include reduced intake of saturated fats (to <7% of total calories), trans fatty acids (to <1% of total calories), and cholesterol (to <200 mg/d)

Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

I IIa IIb III

Cholesterol ManagementCholesterol ManagementRecommendations (Continued)Recommendations (Continued)

Secondary Prevention

Page 85: 4 acc prevention cholesterol

In addition to therapeutic lifestyle changes, statin therapy should be prescribed in the absence of contraindications or documented adverse effects

An adequate dose of statin should be used that reduces LDL-C to <100 mg/dL AND achieves at least a 30% lowering of LDL-C

Patients who have triglycerides >200 mg/dL should be treated with statins to lower non–HDL-C to <130 mg/dL

Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

Cholesterol ManagementCholesterol ManagementRecommendations (Continued)Recommendations (Continued)

Secondary Prevention

I IIa IIb III

I IIa IIb III

I IIa IIb III

Page 86: 4 acc prevention cholesterol

Patients who have triglycerides >500 mg/dL should be started on fibrate therapy in addition to statin therapy to prevent acute pancreatitis

If treatment with a statin (including trials of higher-dose statins and higher-potency statins) does not achieve the goal selected for a patient, intensification of LDL-C–lowering drug therapy with a bile acid sequestrant or niacin is reasonable

For patients who do not tolerate statins, LDL-C–lowering therapy with bile acid sequestrants and/or niacin is reasonable

Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

Cholesterol ManagementCholesterol ManagementRecommendations (Continued)Recommendations (Continued)

Secondary PreventionI IIa IIb III

I IIa IIb III

I IIa IIb III

Page 87: 4 acc prevention cholesterol

It is reasonable to treat very high-risk* patients with statin therapy to lower LDL-C to <70 mg/dL

In patients who are at very high risk* and who have triglycerides >200 mg/dL, a non–HDL-C goal of <100 mg/dL is reasonable

The use of ezetimibe may be considered for patients who do not tolerate or achieve target LDL-C with statins, bile acid sequestrants, and/or niacin

Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

Cholesterol ManagementCholesterol ManagementRecommendations (Continued)Recommendations (Continued)

Secondary Prevention

I IIa IIb III

*Presence of established CVD plus 1) multiple major risk factors (especially diabetes), 2) severe and poorly controlled

risk factors (especially continued cigarette smoking), 3) multiple risk factors of the metabolic syndrome (especially

high triglycerides >200 mg/dL plus non-HDL-C >130 mg/dL with low HDL-C <40 mg/dL, and 4) patients with an ACS

ACS=Acute coronary syndrome, CVD=Cardiovascular disease, HDL-C=High density lipoprotein cholesterol,

LDL-C=Low density lipoprotein cholesterol

I IIa IIb III

I IIa IIb III

Page 88: 4 acc prevention cholesterol

For patients who continue to have an elevated non-HDL-C while on adequate statin therapy, consider niacin or fibrate therapy

For all patients, it may be reasonable to recommend omega-3 fatty acids from fish or fish oil capsules (1 gram/day) for CV disease risk reduction

Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

Cholesterol ManagementCholesterol ManagementRecommendations (Continued)Recommendations (Continued)

Secondary Prevention

CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol

I IIa IIb III