Presentation on theme: "NCEP ATP IV GuidelineS: 2013 Update"— Presentation transcript:
1NCEP ATP IV GuidelineS: 2013 Update Kerry Haney, PharmD, BCACP, CPPUM Skaggs School of Pharmacy1/12/13The 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.
2Learning ObjectivesList three anticipated changes to the ATP IV guidelinesCompare and contrast two validated risk assessment tools used to stratify risk of developing cardiovascular disease and individualize LDL-c goalsDescribe the primary treatment targets from the ATP III guidelines and potential changes for ATP IVReview ATP III recommendations and compare to potential areas of change.
3National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) Guidelines U.S. guidelines for the detection, evaluation, and treatment of hyperlipidemia in adultsDeveloped 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 guidelinesFirst JNC report published 1976ATP release history:ATP I First released in 1988ATP II 1993ATP III 2001
4For 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 evidenceEliminate 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-ITTo check status: check websiteCholesterol, 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:
5Potential Changes for ATP IV Current guidelinesATP IIIFocus on LDL-cGreatest intensity of treatment for patients at highest riskOther dyslipidemia management guidelinesChanges in LDL-c targets for those at highest riskSome modifications of risk factorsDirection from expert panel for ATP IVCritical questionsScientific evidence from clinical trialsATP 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.
6U.S. Guidelines for Management of Dyslipidemias 2001 NCEP ATP III guidelines2004 NCEP ATP III implications2008 ADA/ACCF Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk2011 AHA/ACC guidelines for secondary preventionAACE Guidelines for the Management of Dyslipidemia and Prevention of Atherosclerosis2013 ADA Standards of Medical Care in DM2001- Updated ATP II1. lowered TG goal < 150 and raised HDL cut points2. DM became a CV risk equivalent3. FRS used further identify those at risk and stratify treatment4. Non-HDL was identified as a secondary target for those with elevated TG >2002004 – 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 10-20ADA/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
7Critical 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
8Before 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)
9Overview of Potential Changes for ATP IV Modification of CVD Risk EstimationAdjustment of major risk factors and CHD risk equivalentsAlternative risk assessment tool to Framingham Risk Score (FRS)Changes in Treatment TargetsChanges in LDL-c goalsMore aggressive treatments in those at elevated risk of CHDChanges in target emphasisRecommended Pharmacologic TreatmentContinued use of statins at optimal dosingHighlight lack of CV outcome evidence for adjunctive therapiesThere are several projections for changes for ATP IV recommendations based on research, other available guidelines and expert opinionAdd-on therapies will further reduce LDL, but generally insignificant reduction in CV events
10Let’s review classification of cholesterol concentrations Let’s review classification of cholesterol concentrations. What does the number mean?
11ATP III Classification of Cholesterol Concentrations LipoproteinConcentration (mg/dL)InterpretationTC< 200≥240DesirableBorderline highHighLDL-c<100≥190OptimalNear/above optimalVery highHDL-c<40≥60LowTG<150≥500NormalNo 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.
12ATP III Treatment Targets Exception: TG lowering is an immediate target if ≥ 500 mg/dLPrimary Target:LDL-cSecondary 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 lipoproteinsSome 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
13NCEP ATP III: Determining LDL-c Goals Presence of ASVD, DMYes No≥2 major CV risk factors*10-year CHD risk: FRSCurrent : how we assign an individual LDL goal based on risk – stratified based on level of riskASVD:CHD: (MI), angina, coronary artery procedures (angioplasty, bypass)CHD risk equivalents:Non-coronary forms of ASVDPeripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), carotid artery disease, renal artery stenosisDiabetes (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/dLMod-high Risk:<130mg/dL, optional <100mg/dLModerate risk<130mg/dLLower risk<160mg/dL
14ATP III 2004 Implications Very high risk definition: Presence of CVD plus:Multiple major risk factors (DM)Severe and poorly controlled risk factors (smoking)Metabolic syndromeACSOptional goal of LDL-c < 70For 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 patientsMet Sx: waist circumference men > 40 in , women > 35 in
15Potential Change for ATP IV CHD Risk Equivalents Chronic kidney disease (CKD)Potentially added as a CHD risk equivalentIncreased risk of CHD and premature CHDEvidence suggests patients with CKD have expected 10-yr risk CHD > 20%GuidelinesNational Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) Group 2003AHA supported recommendation 2003Treating patients with CKD with statin-based therapy results in CV events lowering: SHARPPre-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
16NCEP ATP III: Determining LDL-c Goals Presence of ASVD, DMYes No≥2 major CV risk factors*10-year CHD risk: FRSHigh-Risk:<100mg/dL, optional <70mg/Dl>20%10-20%<10%High-Risk:<100mg/dLMod-high Risk:<130mg/dL, optional <100mg/dLModerate risk<130mg/dLLower risk<160mg/dL
17ATP III Risk Stratification for LDL-c Goal Determine presence of other major risk factorsAgeMen≥45Women ≥55Family history of premature CHDFirst degree relative with heart disease in males before 55 or women before 65Hypertension≥ 140/90 or on antihypertensive medicationsCigarette smokingLow HDL< 40mg/dL* (negative risk factor if HDL > 60)If 2 or more risk points are present, then calculate FRSPoint for each category.This is intermediate category. FRS is used for further risk stratification
18NCEP ATP III: Determining LDL-c Goals Presence of ASVD, DMYes No≥2 major CV risk factors*10-year CHD risk: FRSHigh-Risk:<100mg/dL, optional <70mg/Dl>20%10-20%<10%High-Risk:<100mg/dLMod-high Risk:<130mg/dL, optional <100mg/dLModerate risk<130mg/dLLower risk<160mg/dL
19Framingham Risk Assessment Tool BackgroundDerived from the Framingham Heart StudyValidated 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)ScoreLow <10%, Moderate 10-20%, High >20%LimitationsPredicts risk bestages 30-65Less 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 riskAvailablethey 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 undervaluedThe 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 womenThey 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.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.
20Framingham 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 diseaseAge, TC, smoking status, HDL, SBP
21Alternative Risk Assessment Tools Reynolds Risk Assessment (RRS)Tool has been developed to improve 10-year risk estimationFRS may underestimate risk in the young and in women who are classified as low riskUtilizes 7 risk factors:age, SBP, TC, HDL-c, smokinghs-CRP<1 mg/L low, 1-3 mg/L (intermediate), >3 mg/L (high risk)parental history of premature MIAn optional assessment tool in the Canadian Cardiovascular Society guidelines 2009 and AACE Dyslipidemia GuidelinesRRS differs from FRS by incorporating hs-CRP and parental history of premature MIhs-CRPAcute 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 ratioAHA supports it as a strong independent CV predictor and selective useUse when 2+ RF and FRS 10-20%Intensify treatment if CRP > 1Mass screening not recommended. Not measured in pts with active inflammationJupiter trial – patients with LDL-c < 130 hs-CRP > 2 primary prevention.Decreased by: weight loss, activity, statins, fibrates, Zetia, ASAEven after adjustment for standard CVD RF, inc hs-Crp has a progressive association with inc MI and stroke in men 40-84
22NCEP ATP III: Determining LDL-c Goals Presence of ASVD, DMYes No≥2 major CV risk factors*10-year CHD risk: FRSHigh-Risk:<100mg/dL, optional <70mg/Dl>20%10-20%<10%High-Risk:<100mg/dLMod-high Risk:<130mg/dL, optional <100mg/dLModerate risk<130mg/dLLower risk<160mg/dL
23Anticipated Changes to LDL-c Goals Optional goals will become new treatment goalsLDLc goal < 70 for very high riskHigh risk and moderate risk less clearSeveral 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/dLPROVEIT-TIMI22, A-to-Z, TNT, IDEALOne study has also shown coronary atheroma regression when LDL-c levels are lowered below 80mg/dL (average 60.8mg/dL) with high potency statinsAsteriodTwo studies have shown continuous risk reduction in patients with moderate risk taking statinsASCOT, JUPITEROf 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 JUPITERHigh potency = atorvastatin, rosuvastatinNo 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 factorsCTT and TNTSaseen < 70 will become the goal for patients with CHD (most data behind this)Asteriod rosuvastatin 40mg in pts with CHDASCOT 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)
24ADA/ACCF Consensus Statement Lipoprotein Management in Patients with Cardiometabolic Risk LDLc (mg/dL)Non-HDLc (mg/dL)Apo B (mg/dL)Very High RiskEstablished CVDDM and ≥ 1 major CVD risk factors*<70<100<80High RiskNo 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 CADBrunzell JD, et al. Diabetes Care 2008; 31:
25AACE LDLc Treatment Goals Risk CategoryPatient PopulationLDLc (mg/dL)Very High RiskEstablished or recent hospitalization for coronary, carotid or peripheral vascular diseaseDM with ≥ additional risk factors< 70High Risk≥ 2 major risk factors and FRS > 20%CHD risk equivalent< 100Moderately High Risk≥ 2 major risk factors and FRS 10-20%<130Moderate Risk≥ 2 major risk factors and FRS < 10%< 130Low Risk≤ risk factor< 160CHD risk equivalent = DM, PAD, AAA, CADEndocr Pract ; 18 (Suppl 1)
26Treatment Strategies Statins Recommended first line:Most robust data for efficacy in reducing CHD eventsLDL lowering with statin therapy correlates with 30-35% CVD relative risk reductionLowers LDL 21-63%Pleiotropic effectsImproves endothelial functionInhibits platelet aggregationDecreases LDL oxidationReduces vascular inflammationStabilizes atherosclerotic plaquesCV event reduction has been disappointing when adding on other lipid lowering therapiesEnhance, SEAS – statin plus ezetimibeAIM-HIGH – statin plus niacinACCORD – fenofibrate plus simvastatin (in DM)Statins – RRR in primary and secondary preventionThese 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 agentLess 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.
27QuestionsTechniques to refine risk stratification. Most need further study. Some may receive stronger endorsementEBCTElectron-beam computed tomographyHighly sensitive, non-invasive test used to detect calcium buildup in the coronary arteriesCorrelates with the degree of atherosclerosisCIMTCarotid intima-media thicknessUltrasound of carotid arteries that allows visualization of subclinical atherosclerosis