Risk factors in heart disease Optimizing patient care

Risk factors in heart diseaseOptimizing patient care

William Cromwell, MD, FAHA, FNLA

Chief Medical Officer – LipoScience, Inc.Chief – Lipoprotein and Metabolic Disorders InstituteAdjunct Associate Professor – Wake Forest University School of Medicine

DisclosuresWilliam Cromwell, MD, FAHA, FNLA

1. Stone NJ, et al. Circulation 2014;129:S1-S45.2. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.3. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.4. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.

5. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.6. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.7. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798.8. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.

1. The causal link between high levels of low-density lipoprotein (LDL) and the development of CVD is well established 1

Increased numbers of circulating LDL particles accelerates development of atherosclerotic cardiovascular disease

The longer the exposure to high LDL, the greater the risk of CVD events

2. Lowering LDL is a central tenet of clinical practice

2013 ACC/AHA guidelines recommend a two step approach to managing LDL-related CVD risk 1

- Use moderate or high dose statin therapy in selected populations;

- Monitor LDL levels on therapy and use clinical judgment in determining next steps in patient management.

Current Perspectives on LDL Management

Two Ways To Measure LDL Quantity

LDL cholesterol (LDL-C) is the traditional measure of LDL, chosen for historical, not analytic or clinical reasons.

Alternatively, LDL can be measured by particle number (LDL-P), or estimated by apolipoprotein B.

Due to differences in the amount of cholesterol contained in LDL, alternate LDL measures (LDL-C vs. LDL-P) frequently disagree (discordance).1-7

1. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.2. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.3. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.

4. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.5. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.6. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798.7. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.

LDL Particle

Triglycerides

Cholesterol

LDL-P LDL-CLDL Particle

Triglycerides

Cholesterol

LDL-P LDL-C

Alternate LDL Measures (LDL-C versus LDL-P)Multi Ethnic Study of Atherosclerosis [MESA] (n=6,697)

Otvos et al. J Clin Lipidol 2011;5:105-13

LDL-C percentile

LD

L-P

perc

entil

e

10 20 30 40 50 60 70 80 90

LD

L-P

(nm

ol/L

)

LDL-C (mg/dL)

10

20

30

40

50

60

70

80

90

10

20

30

40

50

60

70

80

90 1750

1580

1460

1360

1270

1190

1100

1000

880

1750

1580

1460

1360

1270

1190

1100

1000

880

79 90 100 108 116 123 131 141 157

Discordant Measures

LDL-C and LDL-P Different

(50% Subjects)

Concordant Measures

LDL-C and LDL-PSimilar

(50% Subjects)

LDL-P > LDL-C

Less Cholesterol per Particle

LDL-P < LDL-C

More Cholesterol per Particle

Alternate LDL Measures (LDL-C versus LDL-P)Multi Ethnic Study of Atherosclerosis [MESA] (n=6,697)


Alternate LDL Measures (LDL-C versus LDL-P)Type II Diabetes Mellitus Subjects (n=2,355)

LDL-C70-99 mg/dL

(5th – 20th Percentile)

(n=1,484)

LDL-C

< 70 mg/dL(< 5th Percentile)

(n=871)Se-ries

1

0

5

10

15

20

700 1000 1300 1600 (nmol/L)

43%(n=377)

30%(n=260)

9%(n=76)

2%(n=15)

Percentof

Subjects

16%(n=147)

40%

Se-ries

1

0

5

10

15

2024%

(n=364)

Percentof

Subjects

1%(n=19)

5th 20th 50th 80th percentile

700 1000 1300 1600 (nmol/L)

43%(n=631)

21%(n=307)

11%(n=163)

Cromwell WC, Otvos JD. AJC 2006;98:1599-1602

1. Cardiovascular risk tracks with LDL particle number

– When alternate LDL measures (LDL-C vs LDL particle number) agree (concordance) each measure is equally associated with CVD risk.

– When alternate measures are discordant (e.g., diabetes, metabolic syndrome, statin therapy), risk tracks with LDL-P, not LDL-C.1-5

Alternate LDL Measures and Cardiovascular Disease

1. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.2. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.3. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.4. Sniderman AD, et al. Circ Cardio quality and outcomes. 2011;4(3):337-345.5. Sniderman AD, et al. Atherosclerosis. Dec 2012;225(2):444-449.

Better survivalLower risk

Worse survivalHigher risk

Associations of Alternate LDL Measures with CHD Framingham Offspring Study (n=3,066)

Years of Follow-up

Eve

nt-

Fre

e S

urv

iva

l

Concordant

Discordant

Better SurvivalLower Risk

Worse SurvivalHigher Risk

1.00

0.98

0.96

0.94

0.92

0.90

0.88

0.86

0.84

0.82

0.80

0.78

0.76

0.740 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Low LDL-CLow LDL-P

(n=1,249)

High LDL-CHigh LDL-P

(n=1,251)

Low LDL-CHigh LDL-P

(n=282)

High LDL-CLow LDL-P

(n=284)

Cromwell WC et al. J Clin Lipidol 2007;1(6):583-592.

LDL-P and LDL-C Discordance in MESARelations with Incident CVD Events

Follow-up (years)0 1 2 3 4 5

Cum

ulat

ive

Per

cent

In

cide

nce

2

4

6LDL-P < LDL-C

Concordant

LDL-P > LDL-C

0

0.02

0.04

0.06

0.08

0 1 2 3 4 5 6

0 1 2 3 4 5

0.02

Follow-up (years)

Cu

mu

lativ

e In

cid

ence

0.04

0.06

LDL-P > LDL-C

LDL-P < LDL-C

Concordant

LDL-P > LDL-C

LDL-P < LDL-C

Concordant

16%

33%

54%

MetSyn

LDL-C underestimates LDL-attributable risk

LDL-C overestimates LDL-attributable risk

LDL-C

104

117

130

mg/dL

LDL-P

1372

1249

1117

nmol/L

High LDL Despite

Low LDL-C

Low LDL Despite

High LDL-C


LDL-P and LDL-C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-C

0

0.02

0.04

0.06

0.08

0 1 2 3 4 5 6

0 1 2 3 4 5

0.02

Follow-up (years)

Cu

mu

lativ

e In

cid

enc

e

0

0.04

0.06(516)

(1115)

LDL-P LDL-C (n)

Not Low Low

Low Low

Low: < 30th percentile

LDL-C < 100 mg/dLLDL-P < 1060 nmol/L

Concordant

2

4

6

Cum

ulat

ive

Per

cent

In

cide

nce

DiscordantHigh LDL-P


LDL-P and LDL-C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-P 1

0

0.02

0.04

0.06

0.08

0 1 2 3 4 5 6

0 1 2 3 4 5

0.02

Follow-up (years)

Cu

mu

lativ

e In

cid

enc

e

0

0.04

0.06(516)

(1115)

(553)

LDL-P LDL-C (n)

Not Low Low

Low Low

Low Not Low

Low: < 30th percentile

LDL-C < 100 mg/dLLDL-P < 1060 nmol/L Discordant

High LDL-P

Concordant

ACC/AHA Threshold forConsidering Statin Therapy(7.5% risk over 10 years) 2

2

4

6

Cum

ulat

ive

Per

cent

In

cide

nce

1. Otvos et al. J Clin Lipidol 2011;5:105-132. Adapted from Stone et al. Circulation. 2013

A Meta-Analysis of Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, and Apolipoprotein B as Markers of Cardiovascular Risk

Allan D. Sniderman, MD; Ken Williams, MSc; John H. Contois, PhD; Howard M. Monroe, PhD; Matthew J. McQueen, MBChB, PhD; Jacqueline de Graaf, MD, PhD; Curt D. Furberg, MD, PhD

Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.

Study Design:Meta-analysis of all published epidemiologic studies with estimates of

relative risks of fatal or nonfatal ischemic cardiovascular events and measures of non-HDL-C and apoB.

12 independent reports, including 233,455 subjects and 22,950 events, were analyzed.

Major Findings:Whether analyzed individually or in head-to-head comparisons, apoB

was the most potent marker of cardiovascular risk.

Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.

Meta-Analysis of LDL-C, Non-HDL-C, and ApoB as Markers of Cardiovascular Risk

Conclusions:

“The present analysis indicates that non-HDL-C is superior to LDL-C as a marker of cardiovascular risk.”

“The conventional explanation would be that the gain in predictive power is due to the cholesterol in VLDL.”

“The superiority of non-HDL-C over LDL-C is due to the fact that non-HDL-C is a better marker of LDL-P than LDL-C.”

“When apoB and non-HDL-C are concordant, they will predict risk equally, whereas when they are discordant, apoB will be superior.”

Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.

Meta-Analysis of LDL-C, Non-HDL-C, and ApoB as Markers of Cardiovascular Risk

Adapted from Davidson, et al. J Clin Lipidol 2011;5:338-367.

“Many studies document links between small dense LDL particles and

atherosclerotic CVD.”

“However, these statistical associationsbetween small, dense LDL and CV outcomes are either significantly attenuated or abolished when the

analyses are adjusted for the overall number of circulating LDL particles

(LDL-P) either by adjustment for Apo B levels or by adjustment for nuclear

magnetic resonance-derived LDL-P.”

LDL Subclasses: 2011 National Lipid Association Recommendations

“To date, there is no evidence that the shift in LDL subfractions directly translates into change in disease

progression or improved outcome.”

“The NLA Biomarkers Expert Panel was unable to identify any patient subgroups

in which LDL subfractionation is recommended.”

LDL Subclasses: 2011 National Lipid Association Recommendations

Adapted from Davidson, et al. J Clin Lipidol 2011;5:338-367.

Intended Application Type of Biomarker Clinical Use

Impact on Clinical Decision

MakingEvidence Needed to Support Use

Risk Assessment

Novel Biomarker

(lipoprotein particle size / subclasses,

Inflammatory measures)

Biomarker is used to

enhance risk assessment

Allocate patient to different risk

category

Significant improvement in risk stratification with the addition of new

biomarker (net reclassification) 1

Risk Management

Novel Biomarker

(LDL particle size, Inflammatory measures)

Biomarker serves as a

treatment goal

Modify therapy (different agents,

dosage, or combinations) as

indicated to achieve new

therapeutic goal

Outcome improvement established independent of other risk factors

Newer Measure of an Established

Target

(e.g., LDL particle number)

1. Newer measure consistently outperforms the old measure in the setting of discordance.2

2. Improved outcomes are noted when subjects are treated to equivalent levels of the new versus old measure.

1, Ge Y, Wang TJ. J Intern Med. 2012;272(5):430-439.

2. Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822

Expectations for Novel Risk Tests versus An Alternate Measure of an Established Target

Recommendations for Using LDL Particle Number Measures as Targets of Therapy


Step 1: Stratify ASCVD risk and initiate therapy (Statin therapy if triglyceride levels < 500 mg/dL)

Step 2: Assess adequacy (laboratory testing) and tolerance of therapy

Step 3: If not at desired level intensify therapeutic lifestyle, consider additional therapy Intensify statin therapy; Consider combination statin &/or ezetimibe &/or colesevelam &/or niacin

Step 4: Assess adequacy / tolerance of therapy with and consider additional therapeutic adjustment.

Risk Level Moderate Risk High Risk

DM but no other major risk and/or age < 40

DM + major CVD risk(s) (HTN, Family History, Low HDL-C,

smoking) or CVD

Desirable Level

LDL-P (nmol/L) < 1200 < 1000

apoB (mg/dL) < 90 < 80

Adapted from Garber AJ, et al. Endocr Pract 2013;19 (Suppl 2):1-48.


• “These data indicate that both Apo B and LDL-P were generally in agreement in their association with diverse clinical outcomes (58.8%), but with a substantial amount of discordance (21.2%) in which one biomarker was statistically significant whereas the other was not.”

• “In these cases, LDL-P showed a significant association with a clinical outcome more often than apo B alone, and the level of statistical significance, as indicated by the P value, and the strength of association, as indicated by the OR, RR, and HR, was more often higher for LDL-P than it was for apo B.”

Cole TG, et al. Clinical Chemistry February 2013;59(5):752-770

2013 ACC / AHA Cholesterol Guidelines

2013 ACC / AHA Cholesterol GuidelinesOverview

1. Objective:

Produce treatment recommendations, based on randomized controlled trial (RCT) data, to reduce atherosclerotic cardiovascular disease (ASCVD) risk.

2. Based on RCT data significant emphasis was placed on identifying populations most likely to benefit from statin therapy.

“Because the overwhelming body of evidence came from statin RCTs, the Expert Panel appropriately focused on these statin RCTs to develop evidence-based guidelines for the reduction of ASCVD risk.” 1

1. Stone et al. Circulation. 2013

ASCVD Statin Benefit Groups

Stone et al. Circulation. 2013

No

2013 ACC / AHA Cholesterol GuidelinesRole of LDL Testing

1. While acknowledging the causal role of LDL in ASCVD, due to exclusive reliance on RCT data no recommendation was made for LDL treatment goals.

“The panel makes no recommendations for or against specific LDL-C or non- HDL-C targets for the primary or secondary prevention of ASCVD.” 1

2. Although no goal is endorsed, LDL testing is advocated to aid clinical management

– ATP III Recommendation: LDL testing was used to achieve risk-based LDL goal

– 2013 ACC/AHA Recommendation: LDL testing is used to monitor therapeutic response and adherence

3. Modifying individual treatment requires clinical judgment.

“The ultimate decision about care of a particular patient must be made by the healthcare provider and patient in light of the circumstances presented by that patient.” 1

1. Stone et al. Circulation. 2013

Statin Therapy: Monitoring Therapeutic Response and Adherence

Stone et al. Circulation. 2013

1. The 2013 ACC/AHA Guideline is a starting point for population management, but is not an end point for individual care.

This highlights two different opportunities to improve patient care:

- Population strategy (A) – treat population with generalized therapy to achieve relative risk reduction among the group

- Individual optimization strategy (B) – monitor individual response with a reliable LDL measure and adjust care as indicated.

2013 Guidelines advise clinicians to integrate these options:

- Use of A and B (start with population care, followed by individual optimization based on clinical judgment) is recommended;

- Use of A only (population strategy, “Fire and Forget”) is not advised.

2. Exclusive use of a population strategy is incapable of judging individual response to statin therapy or optimizing individual management.

Integrating Population Based and Individual Optimization Strategies in Practice

00

1 2

2

3 4

4

5

6

8

10

12

14

16

18

# MetSyn Components

Pat

ien

ts w

ith

ma

jor

CV

D e

ven

ts (

%) Atorva 10 mg

Atorva 80 mg

Heterogeneous Response to High Intensity Statin Therapy

(LDL-C on-trial 77 mg/dL)

(LDL-C on-trial 101 mg/dL)

Atorvastatin 10 mg

Atorvastatin 80 mg

No BenefitFrom AggressiveTreatment (44 %)

Cardiovascular Events In Treat to New Target “TNT”

Deedwania P, et al. The Lancet. 2006;368:919-928

22% Reduction in Major cardiovascular events

(p=0.0002)

56% Benefited From High Intensity Statin

Therapy

WHY?

Potential Answer to TNT is Supplied by Framingham

Kathiresan S, et al. Circulation 2006;113:20-27

With Higher LDL-P, Greater Benefit Is Expected FromMore Intensive LDL-PLowering.

180

170

160

150

140

130

120

110

MetSyn (-) MetSyn (+)2.3x risk

LD

L-C

(m

g/d

L)

LD

L-P

(n

mo

l/L)

1100

1200

1300

1400

1500

1600

1700

1800

0 1 2 3 4 5

N=30N=113N=233N=355N=407N=286

LDL-C

LDL-P

Relations of Change in Plasma Levels of LDL-C, Non-HDL-C and apoB With Risk Reduction From Statin Therapy: A Meta-Analysis of Randomized Trials

George Thanassoulis, Ken Williams, Keying Ye, Robert Brook, Patrick Couture, Patrick R. Lawler, Jecqueline de Graaf, Curt D. Furgerg and Allan Sniderman

Journal of American Heart Association 2014;3

Objective:

• To evaluate the relationship between the reduction in alternate LDL measures (LDL-C, non-HDL-C, apoB) and observed cardiovascular benefit produced by statin therapy in randomized, placebo controlled trials.

– “The marker whose reduction relates most directly to benefit should also be the marker that is best to identify those whose outcome might be improved by further lipid lowering.”

• Meta-analysis was performed using both frequentist and Bayesian methods.

Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759

Meta-Analysis of LDL Measures and Risk Reduction from Statin Therapy

Studies Selected:

Analyzed all published, placebo-controlled studies, which have reported baseline and on-treatment levels of LDL- C, non-HDL-C, and apoB.



Findings:

Relative risk reduction from statin therapy in the 7 major placebo-controlled statin trials demonstrated:

– Risk reduction was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C.

– Changes in non-HDL-C and LDL-C appeared to be statistically indistinguishable with respect to risk reduction of statin therapy.

Within trial “head-to-head” comparisons of cardiovascular risk relationship with individual LDL markers :

– LDL-C was 2.4% (- 3.6%, 8.4%) > non-HDL-C (P=0.445)– apoB was 21.6% (12.0%, 31.2%) > LDL-C (P<0.001) – apoB was 24.3% (22.4%, 26.2%) > non-HDL-C (P<0.001).



Cardiovascular Risk in Patients Achieving Low-Density Lipoprotein Cholesterol and Particle Targets

Peter P. Toth , MD, PhD Michael Grabner , PhD Rajeshwari S. Punekar , PhD Ralph A. Quimbo , MA Mark J. Cziraky , PharmD Terry A. Jacobson , MD

Atherosclerosis 2014;235(2):585-591

Study Design

• Claims data between 2006 and 2012 were used to identify eligible patients achieving LDL-P <1000 nmol/L (LDL-P cohort) and patients achieving LDL-C<100 mg/dL (LDL-C cohort) without LDL-P measurements.

• Demographic and comorbidity differences between the two cohorts were balanced using propensity score matching however, treatment patterns were left intact.

Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

Baseline Characteristics for Patients with ≥ 12 Months of Follow-Up


Baseline Characteristics for Patients with ≥ 12 Months of Follow-Up



At every follow-up interval the LDL-P cohort demonstrated:

Significant risk reduction (Hazard Ratio):

24% at 12 months

22% at 24 months

25% at 36 months

Significant event reduction (Number of patients with CHD/stroke events)

1.8% (8.12% - 6.26%) at 12 months

2.9% (13.9% - 11.0%) at 24 months

4.4% (19.0% - 14.6%) at 36 months

Study Results

Another metric of event reduction is the “Number Needed to Treat” (NNT).

NNT = 1 / Event Reduction

Represents the number of subjects needed to treat to prevent 1 event. (i.e., number of subjects needed to attain LDL-P <1000 vs LDL-C <100 to prevent 1 CHD/stroke event).


2.9

Study Results

Number Needed to Treat

2014;235(2):585-591.

Step 1: Stratify ASCVD risk (does not require LDL-P)

Step 2: Institute appropriate course of treatment.

Step 3: Use a reliable, FDA cleared, outcome proven LDL measure to monitor adherence and response among those treated.

Step 4: Use clinical judgment in considering the need to modify individual therapy.

Step 5: After modifying therapy, use a reliable, FDA cleared, outcome proven LDL measure to assess patient response.

Use clinical judgment to consider modifications of treatment as indicated to optimize care.

Approach to the Use of LDL in Clinical Practice

Reduce LDL Particle Production(make less)

Improve LDL Particle Clearance

(remove more)

· Diet· Exercise· Weight Loss· Glycemic Control· Co-Morbidity

Management (up to 30-50% 6 LDL-P)

· Marine Omega-3o DHA + EPA

(no 6 LDL-P)o EPA Only

(4-15 % 6 LDL-P)

· Statins (35-55% 6 LDL-P)· Gut agentso Ezetimibe

(15-30% 6 LDL-P)o Resins / Bile Acid

Sequestrates (15-30% 6 LDL-P)

· Statin + Gut (50-70% 6 LDL-P)

· Statin + Gut + Niacin (> 60% 6 LDL-P)

LDL-P Target

Selected Strategies to Reduce Particle Number

Adapted from Cromwell W, Dayspring T. Lipid and lipoprotein disorders: Current clinical solutions. Baltimore: International Guideline Center; 2012.

Conclusions

1. Guidelines recommend a two step approach to managing LDL-related CVD risk: 1

Use moderate or high dose statin therapy in selected populations; Monitor LDL levels on therapy and use clinical judgment in determining

next steps in patient management.

2. Because CVD risk tracks with apoB and NMR LDL-P 2-6, and because frequent discordance exists between LDL-C and measures of LDL-P 2-4,7-10, many expert panels advocate use of LDL particle number to adjudicate response and optimize individual therapy.11-13

3. Clinical utilization data confirms a significant reduction of CVD risk and events among high risk patients attaining low NMR LDL-P (mean 860 nmol/L) versus statin treated subjects with low LDL-C (mean 79 mg/dL).14

1. Stone NJ, et al. Circulation 2014;129:S1-S45.2. Cromwell WC, et al.. J Clin Lipidol. 2007;1(6):583-592.3. Otvos JD, et al. J Clin Lipidol. 2011;5(2):105-113.4. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177.5. Sniderman AD, et al. Circ Cardio quality and outcomes. 2011;4(3):337-345.6. Sniderman AD, et al. Atherosclerosis. Dec 2012;225(2):444-449.7. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i.

8. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798. 9. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602.10. Sniderman AD. J Clin Lipidol. 2008;2(1):36-42.11. Contois JH et al. Clin Chem. 2009;55:407-419.12. Davidson MH et al. J Clin Lipidol. 2011;5:338-367.13. Garber AJ, et al. Endocr Pract 2013;19(Suppl 2):1-48.14. Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

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Risk factors in heart disease Optimizing patient care

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