1 Comprehensive Lipid Management— Beyond LDL-C Lowering.
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Transcript of 1 Comprehensive Lipid Management— Beyond LDL-C Lowering.
1
Comprehensive Lipid Management—Beyond LDL-C Lowering
2
Objectives
Review current treatment guidelines for reducing CVD risks
Describe additional risk factors for CVD beyond LDL-C
Discuss the need to more aggressively target HDL-C and triglyceride levels
CVD=cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol
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Comprehensive Lipid Management—Beyond LDL-C Lowering
Current Treatment Guidelines for Reducing CVD Risks
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European Guidelines for Lipid Management in Asymptomatic Patients
Total risk <5%Provide lifestyle advice to reduce TC <5 mmol/L (190 mg/dL) and LDL-C <3 mmol/L (115 mg/dL)
Follow-up at a minimum of 5-year intervals
Total risk ≥5%Measure fasting TC, HDL-C, and triglycerides
Calculate LDL-C
Patient to follow lifestyle advice for at least 3 months
Repeat measurements
TC <5 mmol/L (190 mg/dL)LDL-C <3 mmol/L (115 mg/dL)Reinforce lifestyle advice with annual follow-up
If total risk remains ≥5%, consider drugs to achieve cholesterol targets:– TC <4.5 mmol/L (175 mg/dL)– LDL-C <2.5 mmol/L (100 mg/dL)
TC ≥5 mmol/L (190 mg/dL)LDL-C ≥3 mmol/L (115 mg/dL)Reinforce lifestyle advice and start drug therapy
Patients with TC ≥5 mmol/L
Markers of increased CV risk• HDL-C <1.0 mmol/L (40 mg/dL) (men) or <1.2 mmol/L (46 mg/dL) (women)• Fasting triglycerides >1.7 mmol/L (150 mg/dL)
TC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CV=cardiovascularwith permission from De Backer G et al. Eur Heart J. 2003;24:1601–1610.
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Joint British Societies’ Guidelines for Lipid Management: TC and LDL-C Goals
Measure random (nonfasting) TC and HDL-C as part of a CVD risk assessment
Total CVD risk 20%Total CVD risk <20% and no cardiovascular
complications and no diabetes
Provide lifestyle advice and follow-up
Repeat cardiovascular risk assessment within 5 years
Measure fasting TC, HDL-C, and triglycerides
Calculate LDL-C
• HDL-C: inversely related to cardiovascular risk but no treatment target specified• Triglycerides: >1.7 mmol/L associated with increased CVD risk
TC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CVD=cardiovascular diseasefrom Joint British Societies. Heart. 2005;91(suppl V):v1–v52. Reproduced/amended with permission from the BMJ Publishing Group.
Provide lifestyle advice
Monitor blood lipids and treat to target:– TC <4 mmol/L – LDL-C <2 mmol/L
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If LDL-C goal achieved,
treat other lipid risk factors
Progression of Drug Therapy in Primary Prevention
Initiation ofLDL-C lowering
drug therapy
If LDL-C goal not achieved,
intensify LDL-C lowering
drug therapy
If LDL-C goal not achieved, intensify drug
therapy or refer to a lipid
specialist
Monitor response and
adherence to therapy
6Weeks
6Weeks
Every4–6
Months
LDL-C Goal Is a Primary Focus in NCEP ATP III Guidelines
LDL-C=low-density lipoprotein cholesterol; NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel III from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.
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Major Updates to NCEP ATP III Guidelines
LDL-C <2.6 mmol/L (<100 mg/dL) for HIGH RISK
LDL-C <1.8 mmol/L (<70 mg/dL) for VERY-HIGH RISK (optional goal)
LDL-C <3.4 mmol/L (<130 mg/dL) for MODERATE RISK
LDL-C <3.4 mmol/L (<130 mg/dL) for MODERATELY HIGH RISK (optional goal)
The intensity of LDL-C lowering drug therapy in high-risk and moderately high-risk patients should be sufficient to achieve at least a 30%–40% reduction in LDL-C
AHA/NHLBI Scientific Statement:
In patients with low HDL-C (<1.03 mmol/L [<40 mg/dL] in men, <1.3 mmol/L [<50 mg/dL] in women) and high triglycerides (≥1.7 mmol/L [≥150 mg/dL])
Add fibrate or nicotinic acid after LDL-C–lowering drug therapy
NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel III; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; AHA=American Heart Association; NHLBI=National Heart, Lung, and Blood Institutefrom Grundy SM et al. Circulation. 2004;110:227–239; Grundy SM et al. Circulation. 2005;112:2735–2752.
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ADA Recommendations for Adults With Diabetes
Parameter Target
Glycemic control
HbA1C <7.0%a
Preprandial capillary plasma glucose 5.0–7.2 mmol/L (90–130 mg/dL)
Peak postprandial capillary plasma glucoseb <10.0 mmol/L (<180 mg/dL)
Blood pressure <130/80 mm Hg
Lipidsc
LDL-C <2.6 mmol/L (<100 mg/dL)
Triglycerides <1.7 mmol/L (<150 mg/dL)
HDL-C >1.0 mmol/L (>40 mg/dL)d
aReferenced to a nondiabetic range of 4.0%–6.0% using a DCCT-based assay; bPostprandial glucose measurements should be made 1–2 hours after the beginning of a meal, generally peak levels in patients with diabetes; cCurrent NCEP ATP III guidelines suggest that in patients with triglycerides ≥2.3 mmol/L (≥200 mg/dL), the “non–HDL-C” (total cholesterol minus HDL-C) be used. The goal is ≤3.4 mmol/L (≤130 mg/dL); dFor women, it has been suggested that the HDL-C goal be increased by 0.26 mmol/L (10 mg/dL)
ADA=American Diabetes Association; HbA1C=glycosylated hemoglobin; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; DCCT=Diabetes Control and Complications Trial; NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel IIICopyright © 2007 American Diabetes Association from Diabetes Care®, Vol. 30, 2007; S4–S41. Reprinted with permission from the American Diabetes Association.
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Guidelines for Management of Low HDL-C/High Triglycerides
European guidelines Emphasis on lifestyle changes
(eg, reduce body weight, increase physical activity)
Drug therapy may be needed for hypertension, dyslipidemia, diabetes
IDF Consensus Reduce triglycerides/increase HDL-C and
reduce LDL-C
Definition of metabolic syndrome is central obesity plus 2 of 4 factors including HDL-C <1.0 mmol/L (<40 mg/dL) (men)/ <1.3 mmol/L (<50 mg/dL) (women), and triglycerides ≥1.7 mmol/L (≥150 mg/dL)
AHA/NHLBI Statement Modify risk factors (eg, obesity, physical
inactivity, atherogenic diet, smoking)
Drug therapy may be needed for elevations in LDL-C, blood pressure, and glucose
Consider adding fibrates or nicotinic acid for low HDL-C/high non–HDL-C after LDL-C–lowering therapy
ADA Standards of Care Raise HDL-C to >1.2 mmol/L (>46 mg/dL)
(men) or >1.3 mmol/L (>50 mg/dL) (women); lower triglycerides to <1.7 mmol/L (<150 mg/dL)
HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; AHA=American Heart Association; NHLBI=National Heart, Lung, and Blood Institute; IDF=International Diabetes Federation; ADA: American Diabetes Associationwith permission from De Backer G et al. Eur Heart J. 2003;24:1601–1610; Grundy SM et al. Circulation. 2005;112:2735–2752; International Diabetes Federation. Available at: www.idf.org/webdata/docs/metac_syndrome_def.pdf; American Diabetes Association. Diabetes Care. 2006;29(suppl 1):S4–S42.
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Summary: European, British, and US Guidelines for Lipid Management
LDL-C remains primary treatment target Goals for patients at high risk
– European: <2.5 mmol/L (<100 mg/dL)
– British: <2.0 mmol/L (<77 mg/dL)
– US: <2.6 mmol/L (<100 mg/dL)<1.8 mmol/L (<70 mg/dL) for very high-risk optional goal
HDL-C not currently a treatment target Low levels considered marker of increased risk
– European: <1.0 mmol/L (40 mg/dL) (men) and <1.2 mmol/L (46 mg/dL) (women)
– British: Not specified
– US: <1.03 mmol/L (40 mg/dL) (men) and <1.3 mmol/L (50 mg/dL) (women)
LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol with permission from De Backer G et al. Eur Heart J. 2003;24:1601–1610; Joint British Societies. Heart. 2005;91(suppl V):v1–v52; Grundy SM et al. Circulation. 2005;112:2735–2752; Grundy SM et al. Circulation. 2004;110:227–239; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.
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Comprehensive Lipid Management—Beyond LDL-C Lowering
Non–LDL-C Risk Factors for CVD
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Nonlipid Risk Factors for CHD
Risk Factor Values Associated With CHD
Age >45 years (male) or >55 years (female)
Family history First-degree relative with premature CHD
Cigarette smoking Current smoker
Hypertension BP >140/90 mmHg or use of antihypertensive
ObesityBMI >25 kg/m2 + waist >102 cm (men) or >88 cm (women)
CHD=coronary heart disease; BP=blood pressure; BMI=body mass indexfrom Mahley RW et al. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division; 2006:933–966.
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HDL-C: Inverse Correlation With CHD Risk
110
3021
0
20
40
60
80
100
120
<0.9 mmol/L 0.9–1.4 mmol/L >1.4 mmol/L
HDL-C
Inc
ide
nc
e,
pe
r 1
00
0
in 6
Ye
ars
Prospective Cardiovascular Münster (PROCAM) Study
186 events, 4407 men aged 40–65 years
HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart diseasefrom Assmann G et al. In: Lipid Metabolism Disorders and Coronary Heart Disease: Primary Prevention, Diagnosis and Therapy Guidelines for General Practice. 2nd ed. Munich: MMV Medizin Verlag; 1993:19–67. Permission pending.
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Low HDL-C Levels Substantially Increase CHD Risk at all LDL-C Levels
1.2
1.9
2.9
0.60.9
1.5
0.30.4 0.7
0.1 0.2 0.3
The independent effect of raising HDL-C and lowering triglycerides on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Systolic blood pressure=135 mmHg
LDL-C
CH
D R
ela
tiv
e R
isk
2.6 mmol/L 4.1 mmol/L
2.2 mmol/L0
0.5
1.0
1.5
2.0
3.0
2.5
1.7 mmol/L
1.2 mmol/L
0.6 mmol/L
5.7 mmol/L
HDL-C
Framingham Heart Study
HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterolReprinted from Am J Cardiol, Vol. 59, Kannel WB, Status of risk factors and their consideration in antihypertensive therapy, 80A–90A, Copyright 1987, with permission from Elsevier.
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Relationship of HDL-C + Triglyceride Profile to CHD Risk
Framingham Study – Subgroup Analysis
0
50
100
150
350
CH
D/1
000/
10 Y
ears
0
50
100
200
Men Women
150
<1.03 1.03–1.27 >1.27 <1.29 1.29–1.53 >1.53
HDL-C, mmol/L HDL-C, mmol/L
Triglycerides<1.02 mmol/L1.02–1.57 mmol/L>1.57 mmol/L
Triglycerides<0.90 mmol/L0.90–1.34 mmol/L>1.34 mmol/L
200
250
300
CH
D/1
000/
10 Y
ears
HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart diseaseReprinted from Am J Cardiol, Vol. 70, Castelli WP, Epidemiology of triglycerides: a view from Framingham, 3H–9H, Copyright 1992, with permission from Elsevier.
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“Lipid Triad” Increases Coronary Risk vs Elevated LDL-C Only
Scandinavian Simvastatin Survival Study (4S) Placebo Arm —Subgroup Analysis
n=284 n=284
20.9
8.5
35.9
12.2
0
5
10
15
20
25
30
35
40
Major Coronary Events Coronary Mortality
Eve
nt
Rat
e, %
n=237 n=237
Elevated LDL-C onlyElevated LDL-C + lowest HDL-C quartile/highest triglyceride quartile (lipid triad)
LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterolfrom Ballantyne CM et al. Circulation. 2001;104:3046–3051.
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Novel Risk Factors That May Also Contribute to Atherosclerosis
In recent years, a number of new risk factors or markers have been proposed as significant predictors of atherosclerosis and its complications Risk factors or markers can be grouped as
– Inflammatory markers
– Hemostasis/thrombosis markers
– Platelet-related markers
– Lipid-related factors
– Other factors
Four emerging risk factors that have been identified are
– CRP
– Lp (a)
– Fibrinogen
– Homocysteine
CRP=C-reactive protein; Lp (a)=lipoprotein (a)from Hackam DG et al. JAMA. 2003;290:932–940.
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LDL-C Particle Size and CVD Risk
Study Result
Stanford Coronary Risk Intervention Project (SCRIP)
Small, dense LDL-C levels at baseline were the best predictor for progression of coronary stenosis
Pravastatin Limitation of Atherosclerosis in the Coronary arteries trial (PLAC-I)
Small LDL-C was associated with a 5-fold greater risk of angiographic progression
Familial Atherosclerosis Treatment Study (FATS)
Increased LDL-C buoyancy with therapy was the most powerful predictor of coronary stenosis regression
Diabetes Atherosclerosis Intervention Study (DAIS)
Increased LDL-C size and decreased apo B–containing lipoproteins with treatment were associated with decreased coronary stenosis progression
LDL-C=low-density lipoprotein cholesterol; CVD=cardiovascular disease; apo B=apolipoprotein Bfrom Morgan JM et al. Prev Cardiol. 2004;7:182–188.
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Comprehensive Lipid Management—Beyond LDL-C Lowering
Moving Toward More Aggressive Management of Atherosclerosis Risk
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Monocyte
Induction of adhesionmolecules and chemotaxis
AdhesionVCAM-1ICAM-1P-selectinE-selectin
MigrationMCP-1CCR-2oxLDL
Oxidation
CytokinesMMPsEndothelin-1
Endothelialcells
Smooth muscle cells
Inti
ma
Internal elastic lamina
Lu
men
CD36SR-A
Differentiation(GM-CSF)
MacrophageFoam cell
T lymphocyte
CD40
IFN-gamma
Multiple Factors Contribute to Atheroma Formation
LDL-C, β-VLDL, Lp (a)
LDL-C=low-density lipoprotein cholesterol; ß-VLDL=beta-very low-density lipoprotein; Lp (a)=lipoprotein (a); VCAM-1=vascular cell adhesion molecule-1; ICAM-1=intercellular adhesion molecule-1; MCP-1=monocyte chemoattractant protein-1; CCR-2=specific receptor present on the surface of monocytes; oxLDL=oxidized low-density lipoprotein; MMP=matrix metalloproteinases; GM-CSF=granulocyte-macrophage colony-stimulating factor; SR-A=macrophage scavenger receptor class Afrom Fan J et al. J Atheroscler Thromb. 2003;10:63–71. Reprinted with permission from Japan Atherosclerosis Society.
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HDL-C=high-density lipoprotein cholesterol; ß-VLDL=beta-very low-density lipoprotein; Lp (a)=lipoprotein (a); VCAM-1=vascular cell adhesion molecule-1; ICAM-1=intercellular adhesion molecule-1; MCP-1=monocyte chemoattractant protein-1; CCR-2=specific receptor present on the surface of monocytes; oxLDL=oxidized low-density lipoprotein; MMP=matrix metalloproteinases; GM-CSF=granulocyte-macrophage colony-stimulating factor; SR-A=macrophage receptor class A; SR-BI=Scavenger receptor class B type IAdapted from Fan J et al. J Atheroscler Thromb. 2003;10:63–71. Reprinted with permission from Japan Atherosclerosis Society; Rader DJ. J Clin Invest. 2006;116:3090–3100.
Antiatherogenic Actions of HDL-C
LDL-C, β-VLDL, Lp (a)
Monocyte
CD36SR-A
Induction of adhesionmolecules and chemotaxis
AdhesionVCAM-1ICAM-1P-selectinE-selectin
MigrationMCP-1CCR-2oxLDL
OxidationDifferentiation
(GM-CSF)
MacrophageFoam cell
CytokinesMMPsEndothelin-1
Endothelial cells
T lymphocyte
Inti
ma
Lu
menHDL-C
inhibits oxidation of LDL-C
Internal elastic lamina
Smooth muscle cells
CD40
IFN-gamma
HDL-C inhibits expression of
endothelial cell adhesion molecules
and MCP-1
HDL-C promotes efflux of cholesterol from foam cells via the ABCA1 pathway,
ABCG1 pathway, and SR-BI receptor
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The HDL-C/Triglyceride Axis: An Important Therapy Target
Epidemiologic and clinical trials have shown that low HDL-C and elevated triglycerides are independent risk factors for CHD
High triglycerides and low HDL-C often occur together, commonly in metabolic syndrome
Elevated triglycerides combined with low HDL-C is often referred to as “atherogenic dyslipidemia” or the “lipid triad”
– It is often associated with smaller, dense LDL-C particles
NCEP ATP III guidelines place more emphasis on lowering LDL-C than on raising HDL-C
HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart disease; NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel III; LDL-C=low-density lipoprotein cholesterolGotto AM. Am Heart J. 2002;144(suppl 6):S33–S42; Szapary PO et al. Am Heart J. 2004;148:211–221.
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Unmet Need: Optimize HDL-C Levels
If CV risk is high, LDL-C management alone may not be sufficient
Low levels of HDL-C are common, undertreated, and recognized as a risk factor for premature CHD
HDL-C is not identified as a treatment target in treatment guidelines, but CV risk increases with
– HDL-C <1.0 to 1.03 mmol/L in men
– HDL-C <1.2 to 1.3 mmol/L in women
Each 0.026 mmol/L increase in HDL-C reduces CHD risk by 2% to 3%
HDL-C=high-density lipoprotein cholesterol; CV=cardiovascular; LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart diseasefrom Bruckert E et al. Curr Med Res Opin. 2005;21:1927–1934; Mahley RW et al. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division; 2006:933–966; De Backer G et al. Eur Heart J. 2003;24:1601–1610; Joint British Societies. Heart. 2005;91:v1–v52; Gordon DJ et al. Circulation. 1989;79:8–15; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497; American Diabetes Association. Diabetes Care. 2006;29(suppl 1);S4–S42.; Grundy SM et al. Circulation. 2005;112:2735–2752.
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Direction for the Future of Lipid Management
Continue emphasis on LDL-C reduction
Recognize that substantial risk of CHD remains for patients on statins alone
Define and treat to optimal HDL-C levels
Explore new treatment options to increase HDL-C and decrease triglycerides with enhanced tolerability
LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; HDL-C=high-density lipoprotein cholesterolfrom Chapman J. Eur Heart J Suppl. 2005;7(suppl F):F56–F62; Cannon CP. JAMA. 2005;294:2492–2494; Gaw A. Cardiovasc Drugs Ther. 2003;17:53–62.
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Direction for the Future of Atherosclerosis Management
Continue to optimize lipoprotein management
Optimize atherosclerosis management with new methods of risk reduction
– Vascular function
– Plaque morphology and composition
– Biomarker identification and treatment
from Chapman J. Eur Heart J Suppl. 2005;7(suppl F):F56–F62; Duffy D et al. Circulation. 2006;113:1140–1150; Chapman MJ. Curr Med Res Opin. 2005;21(suppl 6):S17–S22.
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Summary
Current treatment guidelines for reducing CVD risks focus on LDL-C lowering
Additional risk factors for CVD beyond LDL-C include low HDL-C, high triglycerides, and a variety of inflammatory, thrombosis, and platelet-related markers
The future of CVD risk management includes a more comprehensive strategy that aggressively targets HDL-C and triglyceride levels
CVD=cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol
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Bibliography
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Bibliography (continued)
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Comprehensive Lipid Management—Beyond LDL-C Lowering
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Merck does not recommend the use of any product in any different manner than as described
in the prescribing information.
Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.
2-09 CVT-2007-W-1246225-SS
01-10-CVT-2009-IT-2653-SS Dep.Aifa 12/02/09
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