1. NCEP ATP IV GuidelineS: 2013 Update
Kerry Haney, PharmD, BCACP, CPP
UM Skaggs School of Pharmacy
1/12/13
The National Cholesterol Education Program Adult Treatment Panel guidelines, national guidelines for the management of dyslipidemias in adults.
The last update, ATP III, were released in ATP IV was originally scheduled for release in 2009, but there have been many factors involved with the delays.
This session will focus on the current development process for ATP IV, potential areas of change for those guidelines, and some practice changes that have already been occurring based on research evidence over the past decade.

2. Learning Objectives
List three anticipated changes to the ATP IV guidelines
Compare and contrast two validated risk assessment tools used to stratify risk of developing cardiovascular disease and individualize LDL-c goals
Describe the primary treatment targets from the ATP III guidelines and potential changes for ATP IV
Review ATP III recommendations and compare to potential areas of change.

3. National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) Guidelines
U.S. guidelines for the detection, evaluation, and treatment of hyperlipidemia in adults
Developed by an expert panel for the National Heart, Lung, and Blood Institute (NHLBI)
Division of National Institutes of Health (NIH)
Long history of developing clinical practice guidelines
First JNC report published 1976
ATP release history:
ATP I First released in 1988
ATP II 1993
ATP III 2001

4. For more information or to check status:
This process has been taking a very long time and began in The review process has become much more complicated this time.
Used a new methodology to comprehensively review of the literature and systematically evaluate the evidence
Eliminate forms of bias (expert opinion)
Develop an integrated set of cardiovascular risk reduction guidelines (HTN, Obesity, lifestyle, CV risk assessment)
4. Perhaps some delay to review results of some major trials due to be completed in Studies: HPS2-Thrive : Treatment of HDL to reduce incidence of vascular events simva plus high dose Niacin ER. Results expected in 2013, Dal-outcomes, Reveal, Improve-IT
To check status: check website
Cholesterol, Risk assessment and lifestyle guidelines in draft form, have completed federal and expert review and are currently being reviewed by NHBLI advisory council, who will then review, comment and recommend approval.
Next step is to be released for public comment. Process takes roughly six months and then final guidelines are published.
For more information or to check status:

5. Potential Changes for ATP IV
Current guidelines
ATP III
Focus on LDL-c
Greatest intensity of treatment for patients at highest risk
Other dyslipidemia management guidelines
Changes in LDL-c targets for those at highest risk
Some modifications of risk factors
Direction from expert panel for ATP IV
Critical questions
Scientific evidence from clinical trials
ATP III – LDL will remain a primary target. There is a log-linear relationship between LDL-c levels and relative risk for CHD.
Numerous RCT have demonstrated the reduction of LDL reduces CHD risk in primary and secondary prevention and in angiographic trials.
Growing evidence to show targeting LDLc is not the complete picture.

6. U.S. Guidelines for Management of Dyslipidemias
2001 NCEP ATP III guidelines
2004 NCEP ATP III implications
2008 ADA/ACCF Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk
2011 AHA/ACC guidelines for secondary prevention
AACE Guidelines for the Management of Dyslipidemia and Prevention of Atherosclerosis
2013 ADA Standards of Medical Care in DM
2001- Updated ATP II
1. lowered TG goal < 150 and raised HDL cut points
2. DM became a CV risk equivalent
3. FRS used further identify those at risk and stratify treatment
4. Non-HDL was identified as a secondary target for those with elevated TG >200
2004 – recommendations to modify ATP III goals based on results of several (5) clinical trials with statin therapy. Established optional goals for very high risk individuals or those moderately high risk with FRS 10-20
ADA/ACCF – Lipid goals for patients with cardiometabolic risk (HTN, obesity, IR, abnormal lipid metabolism, family history, inflammation/hypercoagulability) more stringent goals for very high risk LDL< 70, non-HDL < 100 apo B < 80, high risk LDL< 100, apo < 90 (similar to optional goals from 2004 ATP III update.)
AHA/ACC 2nd prevention in those with ASVD. This panel is Planning to review their recommendations when ATP guidelines are released. States that LDL goal < 70 is reasonable for very high risk patients (C)
AACE -
1.Recommends lower LDL goals for very high and high risk patients.
2. Recommend patients with pre-DM have same treatment goals as DM pts.
3. Recommends FRS or RRS.
4. these guidelines support use of apo B or LDL particle number to further assess residual risk in patients with TG > 150 and HDL < 40.
ADA – updated annually. Goals are same as 2004 NCEP update. Recommend expanded statin use in DM with CHD regardless of baseline lipids and for DM > 40 with 1 risk factor.
AACE = American Association of Clinical Endocrinologists, ACC = American College of Cardiology, ACCF = American College of Cardiology Foundation, ADA = American Diabetes Association, AHA= American Heart Association

7. Critical Questions for ATP IV
What evidence supports LDL-c goals for secondary prevention?
What evidence supports LDL-c goals for primary prevention?
What is the impact of the major cholesterol drugs on efficacy/safety in the populations?
AHA Scientific Sessions in Nov 2011, chairs from each expert committee presented prioritized list of critical questions which will be used as the basis for recommendations
#1 Looking at evidence in subpopulations: Women, DM, metabolic syndrome, CKD, smokers, LDLc <100,
Clinical trial have used fixed doses rather than titration to goal, review the evidence needed.
#2 – subpopulations: DM, 10-year risk categories < 5, 5-10, 10-20, > 20, men/women, ethnicity
#3 – efficacy at different LDL, TG, HDL cut points and safety in different populations: transplant, HIV +/- PIs

8. Before we discuss the changes, let’s review the major classes of lipoproteins and role in atherogenesis.
Cholesterol is a relatively water-insoluble molecule, so it is packaged with TG and phospholipids into a carrier protein called a lipoprotein which is water-soluble and allows for transportation of cholesterol in the blood.
Lipoprotein vary in size and density with regard to fat and protein content. The major lipoproteins are listed here based on size.
HDL – “Good cholesterol”. Involved in reverse cholesterol transport -Acquires cholesterol from the body’s tissues and promotes efflux from foam cells from AS lesions and transports it back to the liver. Also has antioxidant and antiinflammatory properties, protects LDL from oxidation- that inhibit atherogenesis. Raising HDL through targeted drug therapy has not proven to show benefit, current evidence does not support practice.
LDL-c is responsible for transporting cholesterol from the liver to cells throughout the body and carries up 60-70% of TC. It is the most atherogenic of the lipoproteins. When levels are in excess, LDL readily enters arterial wall and accumulates leading to atherogenic changes. Different densities. Small, dense LDL is assoc with increased risk of CVD. May migrate into the arterial wall more readily and are more susceptible to oxidation. It is preferred to have an LDL pattern with more large buoyant molecules – ‘light, fluffy’ compared to small and dense. May have ‘normal’ LDL levels, but increased number of small dense LDL particles.
IDL: precursor to LDL, number included in LDL in a cholesterol panel.
Very low density lipoproteins (VLDL) are also TG rich, Are a precursor to LDL. VLDL reminants are atherogenic – another type of ‘bad cholesterol’
Chylomicrons are TG-rich lipoproteins that are formed following consumption of dietary fat. Not normally present in plasma after a 12 hour fast.
Lipoproteins carry different types of surface apolipoproteins which direct the processing and removal of lipoprotein particles. Apolipoprotein B are contained on the surface of lipoproteins that are atherogenic (LDL, VLDL, IDL, Lp (a) and chymlomicrons) while HDL carries - Apolipoprotein A.
If we just look and measure the LDL cholesterol, part of the picture may be missing.
Non-HdL number – TC –HDL = estimates total atherogenic, apo B containing cholesterol (to further reduce risk)

9. Overview of Potential Changes for ATP IV
Modification of CVD Risk Estimation
Adjustment of major risk factors and CHD risk equivalents
Alternative risk assessment tool to Framingham Risk Score (FRS)
Changes in Treatment Targets
Changes in LDL-c goals
More aggressive treatments in those at elevated risk of CHD
Changes in target emphasis
Recommended Pharmacologic Treatment
Continued use of statins at optimal dosing
Highlight lack of CV outcome evidence for adjunctive therapies
There are several projections for changes for ATP IV recommendations based on research, other available guidelines and expert opinion
Add-on therapies will further reduce LDL, but generally insignificant reduction in CV events

10. Let’s review classification of cholesterol concentrations
Let’s review classification of cholesterol concentrations. What does the number mean?

11. ATP III Classification of Cholesterol Concentrations
Lipoprotein
Concentration (mg/dL)
Interpretation TC
< 200
≥240
Desirable
Borderline high
High
LDL-c
<100
≥190
Optimal
Near/above optimal
Very high
HDL-c
<40
≥60
Low TG
<150
≥500
Normal
No anticipated major changes here:
ATP II HDL low was < 35, ATP III < 40, goal was set to be the same for both men and women because of the view that a given level of HDL would impart the same risk for both genders (no sources sited)
These are classification of parameters, not goals. LDL goal and treatment is individualized based on risk.

12. ATP III Treatment Targets
Exception: TG lowering is an immediate target if ≥ 500 mg/dL
Primary Target:
LDL-c
Secondary Target:
Non-HDL-c
(Once LDL goal met and if TG ≥200)
Treatment targets are our primary focus to reduce CV risk and reduce CHD event. Expected to be an area of change..
If fasting TG > 500, then TG are primary target because of the risk of pancreatitis.
In all other patients, LDL-c is primary target for initiating and titrating therapy.
Non-HDL is identified as a secondary target in patients with fasting TG > 200. Many trials have demonstrated non-HDL levels are a better predictor of CVD risk than is LDLc. LDL underestimates the burden of atherogenic, cholesterol-carrying lipoproteins
Some experts are expecting more emphasis on non-HDL as a target in ATP IV. Some have gone as far to say it may become a co-target with LDL-c. It is an easy number available with current testing practices.
A recent meta-analysis published in JAMA March 2012 (8 trials, over 60,000 patients) evaluated the strengths of associations between LDL-c, non-HDL-c and apo B with CV risk in patients receiving statins. Although LDL-c, non-HDL-c and apo B levels were each strongly associated with risk of major CV events, the strength of association of future major CV events was higher for non-HDL-c than with LDL-c and apo B. Non-HDL may be proving to be a better surrogate marker for CHD risk and risk reduction. Guidelines are anticipated to reflect this information.
Based on recent trial data and Canadian and European guidelines: it is anticipated that HDL and TG as treatment targets will be deemphasized. But are indicators of metabolic syndrome/IR and other risk factors to modify.
No specific goal for raising HDL because of lack of evidence for benefit

13. NCEP ATP III: Determining LDL-c Goals
Presence of ASVD, DM
Yes No
≥2 major CV risk factors*
10-year CHD risk: FRS
Current : how we assign an individual LDL goal based on risk – stratified based on level of risk
ASVD:
CHD: (MI), angina, coronary artery procedures (angioplasty, bypass)
CHD risk equivalents:
Non-coronary forms of ASVD
Peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), carotid artery disease, renal artery stenosis
Diabetes (most pts have high risk of CHD events)
Framingham Risk Score > 20%= high risk of CHD event in next 10 year.
High-Risk:
<100mg/dL,
optional <70mg/dL
>20%
10-20%
<10%
High-Risk:
<100mg/dL
Mod-high Risk:
<130mg/dL, optional <100mg/dL
Moderate risk
<130mg/dL
Lower risk
<160mg/dL

14. ATP III 2004 Implications Very high risk definition:
Presence of CVD plus:
Multiple major risk factors (DM)
Severe and poorly controlled risk factors (smoking)
Metabolic syndrome
ACS
Optional goal of LDL-c < 70
For patients already in the high risk category with multiple risk factors they are considered to have elevated risk of CHD.
Heart Protection Study (HPS) and PROVE IT raised the question whether < 100 is sufficient in high risk patients. In both studies, <100 did not appear to be a threshold below which no further benefit was seen.
<100 was considered a minimal goal in high risk patients. At the time of this publication, other trials were underway to review intensive LDL lowering in high risk patients
Met Sx: waist circumference men > 40 in , women > 35 in

15. Potential Change for ATP IV CHD Risk Equivalents
Chronic kidney disease (CKD)
Potentially added as a CHD risk equivalent
Increased risk of CHD and premature CHD
Evidence suggests patients with CKD have expected 10-yr risk CHD > 20%
Guidelines
National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) Group 2003
AHA supported recommendation 2003
Treating patients with CKD with statin-based therapy results in CV events lowering: SHARP
Pre-DM: ACE/AACE (American College of Endocrinology and American Assoc of Clinical Endocrinologists) recommend same goals for BP and lipids for preDM as with DM. It is unclear at which point the risk of CHD increases with hyperglycemia. Data is limited to support this recommendation and long-term studies are needed.
Other group: HIV. Inflammatory condition increases risk of CVD, medications also associated.
Pre-D

16. NCEP ATP III: Determining LDL-c Goals
Presence of ASVD, DM
Yes No
≥2 major CV risk factors*
10-year CHD risk: FRS
High-Risk:
<100mg/dL, optional <70mg/Dl
>20%
10-20%
<10%
High-Risk:
<100mg/dL
Mod-high Risk:
<130mg/dL, optional <100mg/dL
Moderate risk
<130mg/dL
Lower risk
<160mg/dL

17. ATP III Risk Stratification for LDL-c Goal
Determine presence of other major risk factors
Age
Men≥45
Women ≥55
Family history of premature CHD
First degree relative with heart disease in males before 55 or women before 65
Hypertension
≥ 140/90 or on antihypertensive medications
Cigarette smoking
Low HDL
< 40mg/dL* (negative risk factor if HDL > 60)
If 2 or more risk points are present, then calculate FRS
Point for each category.
This is intermediate category. FRS is used for further risk stratification

18. NCEP ATP III: Determining LDL-c Goals
Presence of ASVD, DM
Yes No
≥2 major CV risk factors*
10-year CHD risk: FRS
High-Risk:
<100mg/dL, optional <70mg/Dl
>20%
10-20%
<10%
High-Risk:
<100mg/dL
Mod-high Risk:
<130mg/dL, optional <100mg/dL
Moderate risk
<130mg/dL
Lower risk
<160mg/dL

19. Framingham Risk Assessment Tool
Background
Derived from the Framingham Heart Study
Validated method to predict 10-year risk of ‘hard’ coronary heart disease (nonfatal MI or coronary death)
Used in those without ASVD or risk equivalents (DM)
Score
Low <10%, Moderate 10-20%, High >20%
Limitations
Predicts risk best
ages 30-65
Less precise in those with diabetes, pre-diabetes, severe HTN, LVH, younger men and women, and some racial groups – Japanese-Americans, Hispanic men, and Native American women.
Limited to estimation of 10-year risk
Available
they were developed in a large prospective cohort of U.S. men and women aged 30 to 74 years, have been subsequently validated in multiple diverse populations,
risk associated with diabetes mellitus is undervalued
The equations predict the degree of risk less well in men and women younger than age 30 or over age 65, Japanese-American men, Hispanic men, and Native-American women
They also are less precise in patients with diabetes, severe hypertension, or left ventricular hypertrophy because fewer numbers of participants in the original Framingham cohort had these risk factors.[13]
Algorithm heavily weighted on age.
Based on population data and cost-effectiveness estimates were in an era where statin therapy was more expensive.
Majority of events happen in the intermediate risk pop because that is where the vast majority falls.
Lower thresholds for risk categories may be chosen.

20. Framingham Risk Assessment Tool
This tool is used in patients over 20 years old to estimate a 10-year risk of a hard CHD endpoint., meaning MI or death.
Reviews 5 major risk factors for the development of CV disease
Age, TC, smoking status, HDL, SBP

21. Alternative Risk Assessment Tools
Reynolds Risk Assessment (RRS)
Tool has been developed to improve 10-year risk estimation
FRS may underestimate risk in the young and in women who are classified as low risk
Utilizes 7 risk factors:
age, SBP, TC, HDL-c, smoking
hs-CRP
<1 mg/L low, 1-3 mg/L (intermediate), >3 mg/L (high risk)
parental history of premature MI
An optional assessment tool in the Canadian Cardiovascular Society guidelines 2009 and AACE Dyslipidemia Guidelines
RRS differs from FRS by incorporating hs-CRP and parental history of premature MI
hs-CRP
Acute phase reactant and sensitive marker for systemic inflammation (pts must be clinically stable w/o inflammatory conditions)
Has substantial predictive value regarding risk of future CHD events when used with TC/HDL ratio
AHA supports it as a strong independent CV predictor and selective use
Use when 2+ RF and FRS 10-20%
Intensify treatment if CRP > 1
Mass screening not recommended. Not measured in pts with active inflammation
Jupiter trial – patients with LDL-c < 130 hs-CRP > 2 primary prevention.
Decreased by: weight loss, activity, statins, fibrates, Zetia, ASA
Even after adjustment for standard CVD RF, inc hs-Crp has a progressive association with inc MI and stroke in men 40-84

22. NCEP ATP III: Determining LDL-c Goals
Presence of ASVD, DM
Yes No
≥2 major CV risk factors*
10-year CHD risk: FRS
High-Risk:
<100mg/dL, optional <70mg/Dl
>20%
10-20%
<10%
High-Risk:
<100mg/dL
Mod-high Risk:
<130mg/dL, optional <100mg/dL
Moderate risk
<130mg/dL
Lower risk
<160mg/dL

23. Anticipated Changes to LDL-c Goals
Optional goals will become new treatment goals
LDLc goal < 70 for very high risk
High risk and moderate risk less clear
Several clinical trials have shown consistent reduction in CHD events (patients with CHD or ACS) when achieving LDL-c of 60-80mg/dL compared to LDL-c levels of 100mg/dL
PROVEIT-TIMI22, A-to-Z, TNT, IDEAL
One study has also shown coronary atheroma regression when LDL-c levels are lowered below 80mg/dL (average 60.8mg/dL) with high potency statins
Asteriod
Two studies have shown continuous risk reduction in patients with moderate risk taking statins
ASCOT, JUPITER
Of all potential changes, this is the most likely to occur. Exactly which risk groups will be included in the changes is more of a question mark.
Since the 2004 implications were published, many trials in patients with ACS and trials with CHD show consistent reduction in CHD events when using a high-potency statin and achieving LDL-c of 60-80mg/dL compared to moderate statin therapy achieving LDL-c 100mg/dL.
ProveIT- TIMI22 (ACS)
AtoZ (ACS)
TNT (CHD)
IDEAL (CHD)
Continuous risk reduction is seen in trials in people with intermediate risk as well. ASCOT and JUPITER
High potency = atorvastatin, rosuvastatin
No concerning safety problems have emerged with intensive LDL-c lowering
< 70 appropriate for all patients with coronary heart disease regardless of presence of other risk factors
CTT and TNT
Saseen < 70 will become the goal for patients with CHD (most data behind this)
Asteriod rosuvastatin 40mg in pts with CHD
ASCOT trial showed significant reduction in CV events in mod-high risk pts treated with standard doses of statins. Supporting optional goal of < 100 in these pts. (Change with implications for ATP III) Factors that may influence this decision advancing age, 2 risk factors, severe risk factors (cigarette smoking, strong fam hx of premature ASVD, high TG plus high non-HDL, metabolic syndrome, or presence of emerging risk factors (hsCRP, CAC score)

24. ADA/ACCF Consensus Statement Lipoprotein Management in Patients with Cardiometabolic Risk
LDLc (mg/dL)
Non-HDLc (mg/dL)
Apo B (mg/dL)
Very High Risk
Established CVD
DM and ≥ 1 major CVD risk factors*
<70
<100
<80
High Risk
No CVD and ≥ 2 major CVD risk factors*
DM and no major CVD risk factors*
<130
<90
*Risk factors: dyslipidemia, smoking, HTN, family history of premature CAD
Brunzell JD, et al. Diabetes Care 2008; 31:

25. AACE LDLc Treatment Goals
Risk Category
Patient Population
LDLc (mg/dL)
Very High Risk
Established or recent hospitalization for coronary, carotid or peripheral vascular disease
DM with ≥ additional risk factors
< 70
High Risk
≥ 2 major risk factors and FRS > 20%
CHD risk equivalent
< 100
Moderately High Risk
≥ 2 major risk factors and FRS 10-20%
<130
Moderate Risk
≥ 2 major risk factors and FRS < 10%
< 130
Low Risk
≤ risk factor
< 160
CHD risk equivalent = DM, PAD, AAA, CAD
Endocr Pract ; 18 (Suppl 1)

26. Treatment Strategies Statins
Recommended first line:
Most robust data for efficacy in reducing CHD events
LDL lowering with statin therapy correlates with 30-35% CVD relative risk reduction
Lowers LDL 21-63%
Pleiotropic effects
Improves endothelial function
Inhibits platelet aggregation
Decreases LDL oxidation
Reduces vascular inflammation
Stabilizes atherosclerotic plaques
CV event reduction has been disappointing when adding on other lipid lowering therapies
Enhance, SEAS – statin plus ezetimibe
AIM-HIGH – statin plus niacin
ACCORD – fenofibrate plus simvastatin (in DM)
Statins – RRR in primary and secondary prevention
These trials did not show improvement in CV outcome results compared to placebo arm or statin only arm.
ATP III recommendation was if high TG or low HDL, consideration can be given to combining a fibrate or niacin with an LDL-lowering agent
Less emphasis on adding drugs to reduce TG and/or increase HDL conc.
When maximally tolerated doses of statins fail to significantly lower LDLc (<30% from baseline) there is NO strong evidence that combination therapy should be used to achieve additional LDL lowering.
Niacin, fibrates, ezetimibe, and bile acid sequestrants all offer additional LDL lowering to statins alone, but without evidence that such combination therapy for LDLc provides a significant increment in CVD risk reduction over statin therapy alone.

27. Questions
Techniques to refine risk stratification. Most need further study. Some may receive stronger endorsement
EBCT
Electron-beam computed tomography
Highly sensitive, non-invasive test used to detect calcium buildup in the coronary arteries
Correlates with the degree of atherosclerosis
CIMT
Carotid intima-media thickness
Ultrasound of carotid arteries that allows visualization of subclinical atherosclerosis