10/15/2012

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Lessons Learned from Tim Russert: Investigating Residual Risk

Peter H. Jones, MD, FACPAssociate Professor

Methodist DeBakey Heart and Vascular CenterBaylor College of MedicineHouston, Texas

Tim Russert: Residual CV Risk?

• April 2008

– Preclinical CAD at age 58, started on a statin

– LDL-C 67mg/dL, Triglycerides 300mg/dL, HDL 32mg/dL

– Performed well on stress test

• June 2008

– AMI at work, attempts to resuscitate fail

• Too little, too late?

Grady D. A Search for Answers in Russert’s Death. The New York Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.

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, i ll i d 70especially in women and age > 70

• More data about CVD risk of MeS

• No data from statins in ESRD (dialysis), class 3/4 HF, dementia and aortic stenosis; some benefit in CKD

• Incremental benefit of fibrates combined with statin in high TG/low HDL subgroup (ACCORD Lipid) but no incremental benefit with niacin + statin (AIM HIGH)

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What will the NCEP ATP IV look like in 2011?

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

• Do 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 (probably not)Niacin (probably not)Fenofibrate (low HDL/high TG)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:• 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

Patient Populations of Patient Populations of Primary Prevention Statin TrialsPrimary Prevention Statin Trials

CVD=cardiovascular disease; CHD=coronary heart disease; Total‐C=total cholesterol; LDL‐C=low‐density lipoprotein cholesterol; HDL‐C=high‐density lipoprotein cholesterol; hsCRP=high sensitivity C‐reactive protein; RSV=rosuvastatin; PRA=pravastatin; LOV=lovastatin†n=5742

Shepherd J et al. N Engl J Med. 1995;333;1301-1307.Ridker PM et al. N Engl J Med. 2001;344:1959-1965.Ridker PM et al. Am J Cardiol. 2007;100:1659-1664.

9

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

Placebo 251 / 8901HR 0.56 P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %0.06

0.08

Inci

den

ce

Rosuvastatin 20 mg 142 / 8901

0 1 2 3 4

0.00

0.02

0.04

Cu

mu

lati

ve

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

HR (95% CI)

JUPITER: JUPITER: Primary End Point in Primary End Point in Prespecified SubgroupsPrespecified Subgroups

11

Rosuvastatin Superior

Rosuvastatin Inferior

Primary and other composite end points as exploratory analysis of 5695 subjects > 70 yr in JUPITER

Ann Intern Med 2010;152:488-496

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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

Residual Cardiovascular Risk in Placebo-Controlled Statin Trials

19.420

30

40

Exp

erie

nci

ng

H

D E

ven

ts,

%

PlaceboStatin

28.0

15.9

14S Group. Lancet. 1994;344(8934):1383-1389. 2LIPID Study Group. N Engl J Med. 1998;339(19):1349-1357. 3Sacks FM, et al. N Engl J Med. 1996;335(14):1001-1009. 4HPS Collaborative Group. Lancet. 2002;360(9326):7-22. 5Shepherd J, et al. N Engl J Med. 1995;333(20):1301-1307. 6Downs JR, et al. JAMA. 1998;279(20):1615-1622.

12.310.2

8.75.5 6.8

0

10

LDLN 4444 4159 20,536 6595 56059014

-35% -28% -29% -26% -25%-25%

Secondary High Risk Primary

Pat

ien

ts E

Maj

or

CH

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6

13.211.8

7.910.9

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6

26.3

22.4

20

30

40

Standard statin therapyHigh-dose statin therapy

Exp

erie

nci

ng

V

D E

ven

ts,

%

Residual Cardiovascular Disease Risk in Patients With Intensive Statin Therapy

13.710.912.0

8.7

0

10

Pat

ien

ts E

Maj

or

CV

PROVE IT-TIMI 221 IDEAL2 TNT3

N

LDL-C,* mg/dL

1Cannon CP, et al. N Engl J Med. 2004;350(15):1495-1504. 2Pedersen TR, et al. JAMA. 2005;294(19):2437-2445. 3LaRosa JC, et al. N Engl J Med. 2005;352(14):1425-1435.

4162 8888 10,001

95

*Mean or median LDL-C after treatment

62 104 81 101 77

6

8

10

ence

of

Maj

or

ven

ts,

%

Patients With LDL-C ≤70 mg/dL on Statina,b

CVD Events Across On-Treatment HDL-C Quintiles: Treating to New Targets (TNT) Study

0

2

4

6

HDL-C Quintiles,a

mg/dL

5-Y

ear

Inci

de

CV

D E

v

aOn-treatment level (3 months statin therapy); n=2661bMean LDL-C=58 mg/dL; mean TG=126 mg/dL *P=0.03 for differences among quintiles of HDL-C

Barter P, et al. New Engl J Med. 2007;357(13):1301-1310. Copyright © 2007 Massachusetts Medical Society.

Q1<37

Q237 to <42

Q342 to <47

Q5≥55

Q447 to <55

Hazard Ratiovs Q1*

0.85 0.57 0.55 0.61

Primary Endpoint Incidence Rates in JUPITER According to On-Treatment HDL-C and apoA-I Quartiles

2.01.81.61.41.

PlaceboRosuvastatin 20 mg

son-

year

s

A B

Ridker PM, et al. Lancet. 2010;376(9738):333-339. Copyright © 2010 Elsevier Ltd.

1.21.00.80.60.4

0.20

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Inci

denc

e pe

r 10

0 pe

r

Quartile of on-treatment HDL cholesterol Quartile of on-treatment apoA-I

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Associations between HDL-C levels and cardiovascular outcomes: Statin treatment does not alter inverse relationship

Jafri H et al. Ann Intern Med 2010;153:800-808

Black circles indicate patients who are receiving statin interventions, and green circles indicate patients who are receiving a nonstatin control.

CHD Risk Ratio (95% CI)

N=262,525

Triglyceride Level Is Significant CVD Risk Factor: Meta-analysis of 29 Studies

Duration of follow-up≥10 years 5902<10 years 4256

GenderMale 7728

Female 1994

Groups CHD Cases

Adapted from Sarwar N, et al. Circulation. 2007;115(4):450-458.

aIndividuals in top vs bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most)

1.72 (1.56-1.90)

21Decreased Risk Increased Risk

Fasting statusFasting 7484Nonfasting 2674

Adjusted for HDLYes 4469No 5689

Overall CHD Risk Ratioa

What Is Non–HDL-C?

HDL LDL IDL VLDL Chylomicron remnant

CholesterolTriglyceride

All atherogenic lipoproteins

APO A-1 APO B APO B APO B APO B 48

non-HDL

non–HDL-C = Total cholesterol − HDL-C

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Visceraladiposopathy

FFA TG CETPCholesterol

Renal clearanceSmall,

dense HDLTG

HDL

Elevated Triglycerides Are Metabolically Related to Small LDL and HDL Particles

CETP=cholesteryl ester transfer protein; FFA=free fatty acid Adapted from Bays H, et al. Expert Opin Pharmacother. 2003;4(11):1901-1938.

FFA

Fatty liverCholesterol

ester

TG CETP

CETP

ester

Lipases

Lipases

TGSmall, dense LDL

TG

TGLDL

VLDL

• A strong positive and graded association between non–HDL-C and risk for CHD R

isk

The Framingham Study

2

2.5

Non–HDL-C Is Superior to LDL-C in Predicting CHD Risk

occurred within every level of LDL-C

• Non–HDL-C is a stronger predictor of CHD risk than LDL-C

Liu J, et al. Am J Cardiol. 2006;98(10):1363-1368. Copyright © 2006 Elsevier Inc.

LDL-C,mg/dL

Non–HDL-C, mg/dL

Rel

ativ

e C

HD

<130 130-159 ≥160

≥190160-189

<1600

0.5

1

1.5

ApoB

LDL=130 mg/dL

Fewer Particles More Particles

Cholesterol

More ApoB

Elevated Triglycerides Are Associated With Increased Small LDL Particle Number

Cholesterolester

Data from Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.

Correlates with:TC 198 mg/dLLDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dLNon–HDL-C 148 mg/dL

Correlates with:TC 210 mg/dLLDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dLNon–HDL-C 180 mg/dL

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LDL-C, LDL-P and Apoprotein B in Metabolic Syndrome: Framingham Heart Study

Am J Cardiol 2008:102(suppl); 1K-34K

LDL-C70-99 mg/dL

(n=1484)

24%(n=364)

Percentof

Subjects

1%(n=19)

5th 20th 50th 80th percentile

43%(n=631)

21%(n=307)

11%(n=163)

0

5

10

15

20

LDL Particle Number Distribution in T2DM Subjects

LDL-C

<70 mg/dL(n=871)

700 1000 1300 1600 (nmol/L)

43%(n=377)

30%(n=260)

9%(n=76)

2%(n=15)

Percentof

Subjects

16%(n=147)

40%

700 1000 1300 1600 (nmol/L)

Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602. Copyright © 2006 Elsevier Inc.

0

0

5

10

15

20

ADA/ACC 2008 Consensus Statement:Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities

Goals

LDL-C Non-HDL-C ApoB

Highest-risk patient• Known CVD• Diabetes plus ≥1 additional

j CVD i k f t a

<70 mg/dL <100 mg/dL <80 mg/dL

“In individuals on statin therapy who continue to have low HDL-C or elevated non–HDL-C, especially if ApoB levels remain elevated, combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid…”aMajor risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD.Brunzell JD, et al. Diabetes Care. 2008;31(4):811-822. Copyright © 2008 American Diabetes Association.

major CVD risk factora

High-risk patients• No diabetes or known CVD but ≥2 major CVD risk factorsa

• Diabetes but no other major CVD risk factorsa

<100 mg/dL

<130 mg/dL <90 mg/dL

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Effects of Statins on LDL-C and LDL-P

Sniderman. J Clin Lipidol 2008;2:36-42

Treatments that Alter Cholesterol Content of LDL Treatments that Alter Cholesterol Content of LDL Change LDLChange LDL--C and LDLC and LDL--P Differentially P Differentially 11

Cholesterol per particle decreases with:

• Statins

• Statin + Ezetimibe or Bile Acid Sequestrates

• Estrogen Replacement Therapy

Cholesterol per particle increases with:

• Fibrates

• Niacin

• Pioglitazone

• Omega 3 FAs

E iTherapy

• Anti-retrovirals (some)

• Low fat, High carb diet

Therapy LDL-C MoreThan LDL-P

• Exercise

• Mediterranean and low carb diet

Therapy LDL-P MoreThan LDL-C

Little Change in Cholesterol per Particle with:

• Bile Acid Sequestrate or Ezetimibe Monotherapy

Similar Change in LDL-C and LDL-P

Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p. 249-259.

What is the Evidence that adding a drug to statins can provide incremental outcomes benefit?

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Characteristic Mean or % Characteristic Mean or %

Age (yrs) 62 Total Cholesterol (mg/dl) 175

Women % 31 LDL-C (mg/dl) 101

Race / Ethnicity HDL-C (mg/dl) 38

White % 68 Triglyceride (mg/dl)* 162

Black % 15 Blood pressure (mm Hg) 134/74

ACCORD: Baseline Characteristics

p ( g)

Hispanic % 7 Serum creatinine (mg/dl) 0.9

Secondary prevent % 37 Current smoking % 15

DM duration (yrs)* 9 On a statin % 60

A1c (%) * 8.3 On another LLA % 8

BMI (kg/m2) 32 On Insulin % 33

* Median valuesGinsberg, H N, et al. New Engl J Med. Epub ahead of print. March 14, 2010.

ACCORD Outcomes

Ginsberg, H N, et al. New Engl J Med. Epub ahead of print. March 14, 2010.

Subgroup Fenofibrate Placebo Hazard ratio (95% CI)P value for interaction

% of events (no. in group)

Overall 10.5 (2,765) 11.3 (2,753)

LDL cholesterol

0.12

≤ 84 mg/dL

85-111 mg/dL

≥ 112 mg/dL

9.4 (938)

9.9 (934)

12.4 (877)

12.2 (891)

11.2 (922)

10.6 (927)

HDL cholesterol

ACCORD: Primary Outcome By Treatment Group and Baseline Subgroups

0.24

≤ 34 mg/dL

35-40 mg/dL

≥ 41 mg/dL

12.2 (964)

10.1 (860)

9.1 (925)

15.6 (906)

9.5 (866)

9.0 (968)

Triglycerides

0.64

≤ 128 mg/dL

129-203 mg/dL

≥ 204 mg/dL

9.9 (891)

10.5 (924)

11.1 (934)

11.3 (939)

9.9 (913)

12.8 (888)

Triglyceride-HDL cholesterol combination

0.06

TG ≥ 204 mg/dL + HDL-C ≤ 34 mg/dL

All others

12.4 (485)

10.1 (2264)

17.3 (456)

10.1 (2284)

Glycated hemoglobin

0.20

≤ 8.0%

≥ 8.1%

8.7 (1,324)

12.2 (1,435)

10.6 (1,335)

11.9 (1,415)

1 20Adapted from Ginsberg HN, et al. N Engl J Med. 2010;362(17):1563-1574. Copyright © 2010 Massachusetts Medical Society. Fenofibrate better Placebo better

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Atherothrombosis Intervention in Metabolic Syndrome with low HDL/high trigylcerides: Impact on Global Health (AIM HIGH) Results

• 3414 subjects with CVD; age 64; 34% with T2DM and 71% with MeS; 94% had prior statin use

• Randomized to simvastatin to reduce LDL-C < 80 mg/dL, and then to niacin ER 2 gm in 1718 or PBO in 1696in 1696

• Baseline lipids: LDL-C 71TG 161HDL 35nonHDL-C 106apo B 81

AIM HIGH: HDLAIM HIGH: HDL--C at Baseline & FollowC at Baseline & Follow--upup

4545

5050

5555

LL

Combination TherapyCombination Therapy

MonotherapyMonotherapy

* *P < 0.001

*

2525

3030

3535

4040

BaselineBaseline Year 1Year 1 Year 2Year 2 Year 3Year 3

mg

/dL

mg

/dL

AIM HIGH: LDLAIM HIGH: LDL--C at Baseline & FollowC at Baseline & Follow--upup

7070

7575

8080

LL

Combination TherapyCombination Therapy

MonotherapyMonotherapy

5050

5555

6060

6565

BaselineBaseline Year 1Year 1 Year 2Year 2 Year 3Year 3

mg

/dL

mg

/dL

P < 0.001

*

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h P

rim

ary

Ou

tco

me

h P

rim

ary

Ou

tco

me

3030

4040

5050

MonotherapyMonotherapyCombination TherapyCombination Therapy

HR 1.02, 95% CI 0.87, 1,21HR 1.02, 95% CI 0.87, 1,21

AIM HIGH: Primary OutcomeAIM HIGH: Primary Outcome

16 4%

Time (years)Time (years)

Cu

mu

lati

ve %

wit

hC

um

ula

tive

% w

ith

00

1010

2020

00 11 22 33 44

LogLog--rank P value= 0.79rank P value= 0.79

N at riskN at riskMonotherapyMonotherapy

Combination TherapyCombination Therapy

16961696

17181718

15811581

16061606

13811381

13661366

910910

903903

436436

428428

16.2%

16.4%

Trial TherapyEnd Point N Patients Dates

AIM-HIGH1 Simvastatin +

Niacin ER

CVD 3414 2o prevention

HDL and TG

No benefit

Trials with Niacin and Statin Combination

HPS 2-

THRIVE2,3

Simvastatin +

Niacin ER + laropiprant

CVD 25 000 2o prevention

7000 DM

‘07-’12

(5 yr)

1http://www.aimhigh-heart.com2http://www.clinicaltrials.gov.

3http://controlled-trials.com/isrctn/pf/29503772.4Devine PJ, et al. Cardiovasc Drugs Ther. 2007;21:221-225.

So, What did the EAS/ESC do with their guidelines in 2011?

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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-S44Eur Heart J 2011: 32:1769-1818

ESC/EAS Guidelines for Managing Dyslipidemia• Lipid targets:

Primary - LDL-CNonHDL-C and apo B as alternative targets in mixed

dyslipidemia, T2 DM, MeS, CKDNo targets for HDL-C and TGLp(a) in premature CHD or FHx of premature CHD

• Very high risk:LDL C < 70 mg/dL (< 1 8 mmol/L) or ≥ 50% reduction fromLDL-C < 70 mg/dL (< 1.8 mmol/L) or ≥ 50% reduction from

baseline: apo B < 80 mg/dL, nonHDL-C < 100 mg/dL

• High risk:LDL-C < 100 mg/dL (< 2.5 mmol/L), apo B < 100 mg/dL,

nonHDL-C < 130 mg/dL

• Moderate risk:LDL-C < 115 mg/dL (< 3 mmol/L)

Atherosclerosis 2011: 217: S1-S44Eur Heart J 2011: 32:1769-1818

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(RA, SLE, psoriaisis) are at high risk2. 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

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Summary• CTTC meta-analysis confirms an approx 20%

reduction in MACE and 10% reduction in total mortality for 1 mmol/L ↓ in LDL-C, with no lower limit.

• Residual CVD risk remains after treatment with statins (including intensive statin therapy) to reduce LDL-C

• Low HDL-C probably contributes to residual riskLow HDL C probably contributes to residual risk for CVD, even if LDL-C is at goal

• Elevated triglycerides are a marker for increased remnant lipoproteins that can be atherogenic as well as for increased particle numbers, especially in individuals with insulin resistance

• Non–HDL-C captures these remnant particles and is a better predictor of CVD risk than LDL-C, and is equal to apo B

Summary (Continued)

• After LDL-C, guidelines recommend targeting non–HDL-C (possibly Apo B) to optimize risk reduction and suggest niacin, fibrates and/or intestinally-acting drugs (colesevelam ezetimibe) added to statins(colesevelam, ezetimibe) added to statins

• Identification of appropriate primary prevention candidates for statin Rx is important because therapy will benefit women and age > 70