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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
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.
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
Cholesterol, Cholesterol Therapies, Cholesterol, Cholesterol Therapies, and Cholesterol Guidelinesand Cholesterol Guidelines
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
*
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
% 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
• 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
• 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
• 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
• 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
• 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
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
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
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
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
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
Recommended