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Lipids and Primary Prevention: When and How Should We Treat

Peter H. Jones, MD, FACP

Associate Professor

Methodist DeBakey Heart and Vascular Center

Baylor College of Medicine

Houston, Texas

Disclosures

• Advisory board: Merck, Atherotech

• Consultant: Abbvie

So, What’s New in Lipids since the ATP III Update in 2004?

• AHA endorsed LDL-C < 70 mg/dL as a reasonable target in

secondary prevention

• Defining level for HDL-C as a risk is based on gender (< 40

men, < 50 women)

• Primary prevention with statin (JUPITER) is beneficial,

especially in women and age > 70

• More data about CVD risk of MeS

• No benefit from statins in ESRD (dialysis), class 3/4 HF,

dementia and aortic stenosis; some benefit in CKD

(SHARP)

• Incremental benefit of fibrates combined with statin in high

TG/low HDL subgroup (ACCORD Lipid) but no incremental

benefit with niacin + statin (AIM HIGH, HPS 2 THRIVE)

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What should the NCEP ATP IV look like in 2013?

More emphasis on the identification of primary CVD prevention patients for treatment? How to do this –biomarkers? Subclinical atherosclerosis?

• Should apo B, nonHDL-C and/or particle number become targets along with LDL-C?

• Incremental benefit with optimal statin treatment (to LDL-C goal):

Niacin (No)Fenofibrate (low HDL/high TG subgroup)Omega 3?

• What is the driver of incremental benefit?↑ HDL-C↓ Apo B or LDL-PBoth?

• Peri-procedural statins? Emphasis on Stage 3 and 4 CKD for risk reduction with statins?

The Reality of ATP IV:No expert opinionEvidence-based data only

• Determine risk level:Highest (CHD, PAD, Stroke)High risk primary prevention

• Highest risk: Post ACS AT 80 mg (PROVE IT)

Stable CHD - SM 40 (HPS)PRA 40 (LIPID, CARE)AT 80 (TNT, IDEAL, SPARCL)

The Reality of ATP IV:No expert opinionEvidence-based data only

• High risk primary prevention:

PRA 40 (WOSCOPS)

SM 40 (HPS)

RSV 20 (JUPITER)

LOV 20-40 (AFCAPS/TexCAPS)

AT 10 (ASCOT LLA, CARDS)

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CTTC Group Meta-analysis of 170,000 Subjects: Event Reduction per 40 mg/dL LDL-C Decrease

Lancet 2010:

376:1670

Meta-analysis of Statin Effects in Women

JACC 2012;59:572

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CTTC Group Meta-analysis of 27 Trials: Benefit of statins in low risk people

Lancet 2012; online 5/16

Primary Prevention with Statins: Meta-analyses

• Arch Intern Med 2006;166:2307

N = 42,800, f/u 4.3 yr

29% lower MACE, 23% lower CHD death,

and 34% lower cerebrovascular events

• JACC 2008;52:1769

N = 64,000

11% lower CV death, 15% lower MACE,

23% lower MI and 7% lower all-cause death

• QJM 2013;106:299

20% lower cerebrovascular events

Tools for Primary Risk Stratification

NCEP ATP III guidelines

• Classifies individuals into low,

intermediate, high risk

• Uses Framingham Risk Score (FRS)

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Problems With FRS

• 75% of the individuals are low to

intermediate in risk

• 60% of the cardiac events occur in these

risk groups

Berry JD, et al. Circulation. 2009;119(3):382-389.

AK1

http://www.reynoldsriskscore.org

Reynolds Risk Score

Note: add Hb A1C when diabetic

4%• all the above were optimal

The Reynolds Risk Score

Calculating Heart and

Stroke

Risk for Women

www.ReynoldsRiskScore.

org

Ridker PM, et al. JAMA. 2007;297(6):611-619.

Copyright © 2007 American Medical Association.

Slide 13

AK1 Faculty: Reference added. Please confirm. Amanda Kershaw, 2/18/2011

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Additional Markers for Risk Stratification

• Biomarkers

• Imaging

• Genetics

Greenland P, et al. J Am Coll Cardiol. 2010;56(25):e50-103.

JUPITERPrimary Trial EndpointPrimary Trial EndpointPrimary Trial EndpointPrimary Trial Endpoint:::: MI, Stroke, UA/Revascularization, CV DeathMI, Stroke, UA/Revascularization, CV DeathMI, Stroke, UA/Revascularization, CV DeathMI, Stroke, UA/Revascularization, CV Death

Placebo Placebo Placebo Placebo 251 / 8901251 / 8901251 / 8901251 / 8901

Rosuvastatin 20 mg Rosuvastatin 20 mg Rosuvastatin 20 mg Rosuvastatin 20 mg 142 / 8901142 / 8901142 / 8901142 / 8901

HR 0.56 P < 0.00001HR 0.56 P < 0.00001HR 0.56 P < 0.00001HR 0.56 P < 0.00001

Number Needed to Treat (NNT5) = 25

---- 44 %44 %44 %44 %

0 1 2 3 4

0.0

00.0

20.0

40.0

60.0

8

Cu

mu

lati

ve I

ncid

en

ce

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

18

Rosuvastatin Superior

Rosuvastatin Inferior

HR (95% CI)

JUPITER: Primary End Point in Prespecified Subgroups

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Primary and other composite end points as exploratory analysis of

5695 subjects > 70 yr in JUPITER

Ann Intern Med 2010;152:488-496

Time to Occurrence of MACE in JUPITER According to Achieved LDL-C

JACC 2011;57:1666

ASCOT LLA incidence of all-cause mortality and

non-cardiovascular mortality over 11 year

follow up

Eur Heart J 2011; online Aug 28

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Chronic Kidney Disease (CKD)

• Defined as an estimated GFR (determined by

MDRD or CKD-Epi equation) <60 ml/min/1.73 m²

• Stage 3 CKD is GFR 30-59 ml/min

• Stage 4 CKD is GFR 15-29 ml/min

• Renal failure (Stage 5) is GFR < 15 ml/min

• National Kidney Foundation/Kidney Disease

Outcomes Quality Initiative (K/DOQI) considers

Stage 3-5 as CHD equivalent risk

Arch Intern Med 2007;167:1122; Arch Intern Med 2007;167:1386Am J transplant 2004;(Suppl 7):13–53

Framingham Heart Study: CKD as Predictor of CVD Death

3a CKD: GFR 45-59 women, 51-64 men3b CKD: GFR 30-44 women, 30-50 men

Am J Cardiol 2008;102;47

0.3

0.2

0.1

0

0 2 4 6 8 10

Pro

bab

ilit

y o

f C

VD

death

Time (years)

No CKD/+CVD

No CKD/No CVD

CKD3a/No CVD

CKD3b/No CVD

eGFR and Albuminuriaas Predictors of CVD Events in T2DM:FIELD Trial

A: eGFR at baseline and yr 2

B. Albuminuria (↑ACR) at baseline

and yr 2

Diabetologia 2010;54:32-43

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Model Overall Men Women

NRI

(%)

Clinical

NRI

(%)

NRI

(%)

Clinical

NRI

(%)

NRI

(%)

Clinical

NRI (%)

TRF vs. TRF+CIMT 7.4 16.1 8.9 15.7 6.1 15.9

TRF vs. TRF + plaque 11.7 23.4 4.2 10.5 10.2 25.5

TRF vs. TRF+CIMT+

plaque

13.6 27 8.9 16.3 9.7 25.4

TRF +CIMT vs TRF

+CIMT+ plaque

6.3 14.3 0.02 5 3.6 12.7

TRF + plaque vs TRF

+CIMT+ plaque

1.9 7.0 4.7 10.6 -0.3 2.4

Net Reclassification Index in ARIC with CIMT

Nambi V, et al. J Am Coll Cardiol. 2010;55(15):1600-1607.

Copyright © 2010 American College of Cardiology Foundation Published by Elsevier Inc.

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Associations betweenCRP, CACS andCVD events: JUPITERpopulation in MESA

Lancet 2011;378: 684

Median F/U 5.8 yr

N = 950

ESC/EAS Guidelines for Managing Dyslipidemia

• Risk based approach (risk factors and SCORE)A. Very high risk:

Documented CVD (invasive and noninvasive) –MI, stroke, CABG, ACS, PAD, carotid plaque (US)Type 2 DM (CHD, CKD)Type 1 DM with microalbumin, end organ damageCKDSCORE ≥ 10% 10 yr risk for fatal CVD (3 X higher for fatal

and nonfatal events)

B. High risk:A. markedly elevated single RF (severe HTN, HeFH)B. Type DM at any ageC. SCORE ≥ 5 and < 10%

C. Moderate risk:SCORE 1 to < 5%; risk can be modified by FHx, HDL-C, Lp(a), apo B and MeS

Atherosclerosis 2011: 217: S1-S44

Eur Heart J 2011: 32:1769-1818

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AK2 Faculty: Caption added to bottom. Please confirm. Amanda Kershaw, 2/18/2011

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ESC/EAS Guidelines for Managing Dyslipidemias

• Tests not recommended for routine use:Lipoprotein particle sizeLp(a), except in premature CHD or FHxGenotypinghs-CRP as a target of treatment

• Special populations:

1. Autoimmune chronic inflammatory conditions (RA, SLE, psoriaisis) are at high risk

2. Genetic dyslipidemias:FCHL (1:100) : apo B > 120 mg/dL + TG > 135

mg/dL HeFH (1:500)

3. PCI: load with high dose statin before procedure4. Elderly (> 70 yr): consider for primary prevention

Canadian Cardiovascular Society Guidelines 2012

• High risk (not necessarily > 20%)

Type 1 or 2 DM in age > 40 yr

Type 1 or 2 DM more than 15 yr duration in age >

30 yr

CKD – eGFR < 45 ml/min or ACR > 30 mg/mmol

HTN + 3 RF (LVH, male, age > 55, FHx premature CHD,

smoking, ACR > 30)

Single severe RF: familial HC, severe HTN

Surrogate measures:

CACS > 100

CIMT with plaque or > 75th percentile for age

(CACS better than CIMT)

Can J Cardiol 2013;29:151

Most Important Issue for Primary Prevention with Statins?

Adherence to therapy

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Statin Continuation and Primary Prevention of CVD

• Retrospective evaluation of 171,000 subjects

without CVD in Israel started on statin between

1998 and 2009.

• Statin persistence associated with a significantly

lower incidence of cardiac events

• The most persistent users (> 80%) had 42% fewer

events than the least (< 20%)

Am J Cardiol 2012;110:1779

Statin Discontinuations in Routine Care Settings

• Practices with MGH and Brigham and Women’s

Hospital between 2000 and 2008

• Subjects mean age 61, 20% with CHD, 26% with

T2DM. Most frequently used statins – AT and SM

• Muscle symptoms were responsible for nearly

half of statin-related discontinuations. Memory

issues were < 1%

• More than 90% of those rechallenged with a

statin could tolerate one for more than 12

months.

Ann Intern Med 2013;158:526

Lifestyle Changes Important in CHD Risk

• Lancet 2013;381: 394

10,043 veterans followed for 10 yr, avg age 59

Fitness levels were compared on all-cause mortality

Most fit, regardless of statin use, had 60-70% lower

mortality

Most fit who were not on statins had lower mortality

than the least fit on statins

• Circulation 2012;126:2705

13,546 pt in TRANSCEND and ONTARGET trials

(telmasartan)

F/U 4.5 yr, diet score determined

Healthiest quintile of diet score had 22% lower CHD

events, 35% lower CVD death and 19% lower

stroke than lowest quintile, regardless of

study randomization

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Do Statins Increase the Risk of Diabetes?

• JUPITER showed a significant increase in physician-

diagnosed diabetes

• WOSCOPS showed a significant decrease in the

incidence of new diabetes

• Meta-analysis (Diabetes Care 2009;32:1924) of HPS,

LIPID, ASCOT-LLA, JUPITER and CORONA (n=57,593)

showed a significant 13% increase risk of diabetes.

• Meta-analysis (Lancet 2010;375:735) of 13 statin trials

(n=91,140) showed a significant 9% increase risk of

diabetes.

• Meta-analysis of intensive statin vs moderate dose

statins (JAMA 2011;305;2556) in 5 trials (n=32,752)

showed a 12% increased risk for new-onset diabetes.

How to Treat Primary Prevention Patients

• Statins are first-line choice

Use an evidence-based dose

• Monotherapy choice in statin-intolerant patient

Bile acid sequestrant (CPPT)

Fibrate (Helsinki Heart Study)

• Combination therapy to target LDL-C (or

nonHDL-C, apo B, LDL-P)

Statin + BAS

Statin + ezetimibe

Summary

• CTTC meta-analysis confirms an approx 20% reduction in MACE and 10% reduction in total mortality for a 1 mmol/L ↓ in LDL-C. This occurs regardless of baseline LDL, gender or baseline CHD risk.

• Absolute benefit of lipid therapy in primary prevention depends on risk status; the higher the risk, the greater the benefit-to-harm ratio.

• Patient education essential about the benefit of statin therapy as a lifetime commitment