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NCEP ATP IV GuidelineS: 2013 Update

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Presentation on theme: "NCEP ATP IV GuidelineS: 2013 Update"— Presentation transcript:

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

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