1 / 54

Lipid Management Standard and Advanced Preview of ATP-IV - PowerPoint PPT Presentation

  • Uploaded on

Lipid Management Standard and Advanced Preview of ATP-IV. Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN USA. DISCLOSURE. Relevant Financial Relationship(s) None Off Label Usage None. Treatment Categories, LDL-C Goals and Cut-points: ATP-III.

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about 'Lipid Management Standard and Advanced Preview of ATP-IV' - melantha

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Lipid management standard and advanced preview of atp iv

Lipid ManagementStandard and Advanced Preview of ATP-IV

Thomas G. Allison, PhD, MPH

Mayo Clinic

Rochester, MN



Relevant Financial Relationship(s)


Off Label Usage


Treatment categories ldl c goals and cut points atp iii
Treatment Categories, LDL-C Goals and Cut-points: ATP-III

* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Major atp iii risk factors
Major ATP III Risk Factors

  • Age

    Male ≥ 45 years

    Female ≥ 55 years

  • Family History

    Male first degree relative < 55 years

    Female first degree relative < 65 years

  • HDL-C < 40 mg/dL

  • Hypertension

  • Current Smoking

Cad equivalents
CAD Equivalents

  • Coronary Artery Disease (CAD)

  • Diabetes Mellitus

  • Abdominal Aortic Aneurysm

  • Carotid Artery Disease (>50% stenosis)

  • Prior CVA or TIA

  • Peripheral Arterial Disease

  • Framingham Score >20% 10 yr Risk

Cad risk equivalents
CAD Risk Equivalents?

  • Chronic Renal Insufficiency

  • Abnormal Coronary Calcium Scores

    • Agatston score > 400

Goals for therapy 2004 addendum
Goals for Therapy: 2004 Addendum

  • NCEP ATP III guidelines for LDL Therapy

    LDL-C <160 for 1 or less risk factors

    LDL-C <130 for 2+ risk factors

    < 100 is a therapeutic option

    LDL-C <100 for CAD and CAD equivalents

    <70 is option for very high risk patients

    • CAD + multiple risk factors, especially diabetes

    • CAD + severe or poorly controlled risk factor(s)

    • CAD + metabolic syndrome

    • Acute coronary syndrome

    • CAD event despite baseline LDL-C < 100

Ldl c therapy
LDL-C Therapy

  • Lifestyle Change

  • Statins

  • Bile Acid Sequestrants

  • Ezetimibe

  • Niacin

  • Plant Stanols, Sterols, Phytosterols

Residual risk non hdl c
Residual Risk: Non-HDL-C

  • ATP III: Non-HDL-C is a secondary target of drug therapy when TG ≥ 200mg/dL

  • Represents all the triglyceride-rich lipoproteins – considered atherogenic

  • Non-HDL-C = Total Cholesterol – HDL-C

  • Valid even if patient is non-fasting

  • Cost-Effective

Targets for therapy after ldl c goal in patients with tg 200 mg dl
Targets for Therapy after LDL-C Goal in Patients with TG 200 mg/dL

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Potential goal modifying factors
Potential Goal Modifying Factors

  • Lp(a)

  • High sensitivity CRP

  • Metabolic Syndrome

Definition of the Metabolic Syndrome

Defined by presence of >3 risk factors

Grundy, et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI Scientific Statement. Circulation 2005;112:2735-2752.

Detection, Evaluation, and Treatment

of High Blood Cholesterol in Adults

(Adult Treatment Panel IV)

Expert Panel Membership


Alice H. Lichtenstein, D.Sc.Tufts UniversityBoston, MassachusettsNeil Stone, M.D.Northwestern University School of MedicineChicago, Illinois

Daniel Rader, M.D.University of Pennsylvania Jennifer Robinson, M.D, M.P.H.University of Iowa

Frank M. Sacks, M.D.Harvard University

School of Public Health

J. Sanford Schwartz, M.D.University of Pennsylvania Sidney C. Smith, Jr.   M.D. University of North CarolinaKarol Watson, M.D., Ph.D.University of California at Los AngelesPeter W. F. Wilson, M.D.Emory University School of Medicine

C. Noel Bairey Merz, M.D.University of California, Los AngelesConrad Blum, M.D.Columbia UniversityRobert H. Eckel, M.D.University of Colorado, DenverAnne Carol Goldberg, M.D., FACP, FAHAWashington UniversityRonald M. Krauss, M.D.Children's Hospital Oakland

Research InstituteDonald M. Lloyd-Jones, M.D., Sc.M.Northwestern University Patrick McBride, M.D., M.P.H.University of Wisconsin


Expected Availability for Public Review

and Comment:  Spring 2011

Expected Release Date:  Fall 2011

Issues for atp iv
Issues for ATP-IV

  • Should the goals for LDL-C in primary prevention be lowered?

  • What to do with CRP – routine use in risk stratification, secondary target?

  • What about secondary target?

    • Non-HDL-C, HDL-C, apo B, LDL Particle concentration?

  • Move from 10-year to lifetime risk?

Jupiter trial
Jupiter Trial

  • To test the hypothesis that statin treatment will reduce CV events in patients without baseline CVD with “normal” LDL-C (< 130 mg/dL) and elevated hsCRP (≥ 2.0 mg/L)

  • The most innovative and potentially important lipid-lowering trial since the 2004 ATP-II Addendum

Ridker PM et al. NEJM 2008;359:2195-2207

Jupiter methods
Jupiter Methods

  • 17,802 subjects (38% women)

    • Men ≥ 50 years; women ≥ 60 years

    • Triglycerides < 500 mg/dL

  • Randomized to Rosuvastatin 20 mg/day or placebo

  • Planned 60 month follow-up

  • Primary outcome was major CV event

    • Including elective revascularization

Jupiter results
Jupiter Results

  • Study terminated early on 3-30-08 with median follow-up of 1.9 years

  • Compliance at study termination was 75%

  • 44% reduction in primary endpoint

    • 0.77% versus 1.36% per year

  • 20% reduction in total mortality

    • 1.00% versus 1.25% per year

Jupiter questions
JUPITER Questions

  • Would a lower-cost, generic statin show similar benefit?

  • Is measurement of hsCRP necessary for risk stratification in primary prevention

    • Ridker conflict of interest issues

  • Was the benefit due to LDL-C lowering or hsCRP lowering?

Risk factors in jupiter subjects
Risk Factors in Jupiter Subjects

  • Average age = 66 years

  • Current smokers = 16%

  • Metabolic syndrome = 41%

  • Family history of premature CAD = 11%

  • 25% had fasting glucose > 102 mg/dL

  • 25% had systolic BP > 145 mmHg

Prove it timi 22 study design
PROVE IT - TIMI 22: Study Design

4,162 patients with an Acute Coronary Syndrome < 10 days

ASA + Standard Medical Therapy


“Standard Therapy”

Pravastatin 40 mg

“Intensive Therapy”

Atorvastatin 80 mg

2x2 Factorial: Gatifloxacin vs. placebo

Duration: Mean 2 year follow-up (>925 events)

Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke

Changes from (Post-ACS) Baseline in Median LDL-C



Median LDL-C (Q1, Q3)

95 (79, 113)

62 (50, 79)



Pravastatin 40mg




Atorvastatin 80mg

49% 






30 Days

4 Mos.


8 Mos.

16 Mos.

  • Note: Changes in LDL-C may differ from prior trials:

    • 25% of patients on statins prior to ACS event

    • ACS response lowers LDL-C from true baseline

PROVE IT:Concomitant Therapies

PCI for initial ACS pre-random. 69%

Aspirin 93%

Warfarin 8%

Clopidogrel (initial) 72% (at F/U) 20%

B-blockers 85%

ACE 69%

ARB 14%












All-Cause Death or Major CV Events in All Randomized Subjects


Pravastatin 40mg




% with Event

Atorvastatin 80mg



16% relative risk reduction

(p = 0.005)



But absolute residual risk is 22%


Months of Follow-up

Sources of residual risk
Sources of Residual Risk

  • Not providing appropriate medical therapy?

  • Inadequate control of non-lipid risk factors?

  • Not addressing emerging risk factors?

    • CRP, Lp(a)

  • Inadequate control of lipids using LDL target only?

    • Non-HDL

    • HDL or apo A-1

    • Apo B

    • LDL particle number

    • LDL particle size

Secondary lipid target
Secondary Lipid Target

  • In ATP-III, non-HDL-C was identified as the secondary lipid target

    • Sum of cholesterol in all atherogenic lipoproteins

      • LDL-C, Lp(a)-C, VLDL-C, IDL-C

  • No major trial since publication of ATP-III in 2001 that specifically treated non-HDL-C

Lowering non hdl c
Lowering non-HDL-C

  • Increase the statin dose

  • Add fibrate

  • Add niacin

  • High dose fish oil

  • Exercise, CHO restriction, weight loss

Field study fenofibrate to prevent cardiovascular events in diabetics
FIELD StudyFenofibrate to Prevent Cardiovascular Events in Diabetics

FIELD Study Investigators Lancet 2005; 366:1849-1861

Field mortality
FIELD Mortality

No significant benefit shown in ACCORD-Lipids

for fenofibrate added to Simvastatin 40 mg/day.

NEJM 2010, March 14.

Ldl particles cause atherosclerosis
LDL Particles Cause Atherosclerosis

Low Density Lipoprotein

particles (LDL) are the causal

agents in atherosclerosis.1

The more LDL particles a person has, the higher the risk for plaque buildup that causes heart attacks, regardless of how much cholesterol those particles carry.

1 Fredrickson et al. NEJM 1967; 276: 148

This is LDL


LDL-C is not LDL




Free cholesterol

Apo B

This is LDL



Cholesterol Ester


James Otvos 2007




LDL Particle Number Distribution in MESA

LDL-C <100 mg/dL (n=1,425)

5th 20th 50th 80th percentile














700 1000 1300 1600 (nmol/L)

LDL Size (nm) 21.3 (0.7) 20.5 (0.6) 20.1 (0.5)

HDL-C (mg/dL) 58 (18) 47 (15) 41 (11)

Triglycerides (mg/dL) 98 (60) 136 (71) 199 (75)

AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006



LDL Particle Number Distribution in MESA

LDL-C = 100-118 mg/dL

5th 20th 50th 80th percentile











MetSyn (-)





700 1000 1300 1600 (nmol/L)











MetSyn (+)





700 1000 1300 1600 (nmol/L)

AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006

Chd event associations of nmr ldl particle number ldl p versus ldl cholesterol ldl c
CHD Event Associations of NMR LDL Particle Number (LDL-P) versus LDL Cholesterol (LDL-C)

Cromwell WC et al: J Clinical Lipidology 2007;1:583-592

Brief comments apo b or non hdl versus ldl p
Brief Comments versus LDL Cholesterol (LDL-C)Apo B or Non-HDL versus LDL-P

  • Apo B and non-HDL are likely better predictors of risk than LDL-C in patients with cardiometabolic syndrome

  • Non-HDL costs nothing extra to measure

  • Apo B measurement does not require unique, expensive technology

  • Apo B gives equal weight to each particle: LDL, Lp(a), VLDL, IDL

    • Not equal atherogenicity

    • Treatment strategies different for each particle

  • Non-HDL similarly lumps particle types together

    Example 1

    • TC=200, HDL=50, TG=200, non-HDL=150

      Example 2

    • TC=170, HDL=20, TG=500, non-HDL=150

  • Is risk equivalent for these 2 patients?

Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age
Prediction of Lifetime Risk for Cardiovascular Disease by Risk Factor Burden at 50 Years of Age

Donald M. Lloyd-Jones et al

Circulation 2006;113:791-798

Generic prevention drugs
Generic Prevention Drugs Risk Factor Burden at 50 Years of Age

Drug Monthly Cost

Statin $4.00

Beta blocker $4.00

Metformin $4.00

ACE-inhibitor ± HCTZ $4.00

Amlodipine $4.00

All national discount pharmacy chains

  • Lower price ($10) for 3 months supply

    Can potentially reduce cost further with a pill cutter

Living under the umbrella of good cardiovascular health
Living Under the Umbrella of Good Cardiovascular Health Risk Factor Burden at 50 Years of Age







Predictions for atp iv
Predictions for ATP-IV Risk Factor Burden at 50 Years of Age

  • The goals for LDL-C in primary prevention will be lowered.

  • There will be a stronger statement on hsCRP, but routine use in risk stratification or use as secondary target will not be specifically endorsed.

  • Non-HDL-C will remain the secondary lipid target, but optional use of apo B or LDL-P will be endorsed.

  • A new risk calculator providing lifetime risk estimates will be provided.

  • Comments? Risk Factor Burden at 50 Years of Age

  • Questions?