4Treatment Categories, LDL-C Goals and Cut-points: ATP-III Risk CategoryLDL-C GoalConsider Drug TherapyCHD or CHD risk equivalent<100 mg/dL130 mg/dL*2 Risk Factors10-yr risk 10–20%10-yr risk <10%<130 mg/dL130 mg/dL160 mg/dL<2 Risk Factors<160 mg/dL190 mg/dLTreatment categories, LDL-C goals and cutpointsThe primary goal of clinical lipid management is reduction of low-density lipoprotein cholesterol (LDL-C) to lower coronary heart disease (CHD) risk. Individuals who do not or cannot achieve this goal with therapeutic lifestyle change (TLC) alone are candidates for drug therapy.TLC is an important component of any lipid-lowering program. It can obviate the need for drug therapy, augment the LDL-C lowering achieved with drug therapy, and provide benefits beyond LDL-C lowering which contribute substantially to CHD risk reduction. As with all considerations in the Adult Treatment Panel III (ATP III) recommendations, the decision to initiate drug therapy should be consistent with the patient’s CHD risk. Those with the highest risk should be offered the most aggressive treatment to reduce the risk optimally. Conversely, in patients with the lowest risk, drug therapy may not be cost-effective.Patients with CHD or a CHD risk equivalent have the highest risk, exceeding 20% in 10 years, and are candidates for lipid-modifying drug therapy. Those with levels above 130 mg/dL can be given drugs simultaneously with TLC as lifestyle change alone is unlikely to achieve the treatment goal. Those with levels between 100 and 129 mg/dL should first be treated with TLC, and after an appropriate trial (e.g., 3 months), lipid-lowering drug therapy (for example, a statin or fibrate) may be initiated. Some clinicians prefer to initiate drug therapy simultaneously with TLC in patients being discharged from the hospital following a CHD event or with a CHD risk equivalent. In this case, the therapy can be adjusted on a subsequent visit if the treatment goal is not achieved or if it is exceeded. For CHD or CHD risk equivalent patients who were given LDL-C–lowering drug therapy and have an on-treatment LDL-C of 100–129 mg/dL, clinical judgment should be applied to choose from a number of options. The majority of participants in the statin endpoint trials had on-treatment LDL-C values in this range. Choices include intensifying TLC, adjusting the dose of the LDL-C–lowering drug, initiating nondrug treatment of the metabolic syndrome if it is present, or intensifying treatment of nonlipid risk factors.Patients with 2 or more major risk factors and a 10-year risk between 10 and 20% have an LDL-C goal of <130 mg/dL and should be given TLC; if it is unlikely that this alone will achieve the treatment goal, drug therapy may be initiated simultaneously. In most cases, TLC is tried for about 3 months before making decisions to advance to drug therapy. After adequate LDL-C reduction has been achieved, other risk factors, including obesity and sedentary lifestyle, should be addressed.Patients with 2 or more risk factors and a 10-year risk of <10% as well as patients with <2 risk factors (who mostly have a 10-year risk of <10%) should be treated with TLC unless LDL-C levels are very high, because drug therapy in these patients is the least cost-effective. If treatment goal cannot be achieved with TLC alone, consideration can be given to using lipid-lowering drug therapy.Reference:Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapyExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:
5Major ATP III Risk Factors AgeMale ≥ 45 yearsFemale ≥ 55 yearsFamily HistoryMale first degree relative < 55 yearsFemale first degree relative < 65 yearsHDL-C < 40 mg/dLHypertensionCurrent Smoking
8Goals for Therapy: 2004 Addendum NCEP ATP III guidelines for LDL TherapyLDL-C <160 for 1 or less risk factorsLDL-C <130 for 2+ risk factors< 100 is a therapeutic optionLDL-C <100 for CAD and CAD equivalents<70 is option for very high risk patientsCAD + multiple risk factors, especially diabetesCAD + severe or poorly controlled risk factor(s)CAD + metabolic syndromeAcute coronary syndromeCAD event despite baseline LDL-C < 100
10Residual Risk: Non-HDL-C ATP III: Non-HDL-C is a secondary target of drug therapy when TG ≥ 200mg/dLRepresents all the triglyceride-rich lipoproteins – considered atherogenicNon-HDL-C = Total Cholesterol – HDL-CValid even if patient is non-fastingCost-Effective
11Targets for Therapy after LDL-C Goal in Patients with TG 200 mg/dL Patient CategoryLDL-C target (mg/dL)Non-HDL-C target (mg/dL)CHD or CHD risk equivalent<100<130No CHD, 2+ RF<160No CHD, <2 RF<190Targets for therapy after LDL-C goal in patients with TG 200 mg/dLEpidemiologic and clinical studies have demonstrated that high blood triglyceride level is an independent risk factor for CHD and that CHD risk is amplified in patients who have elevations in both LDL-C and triglyceride levels. An elevated triglyceride level probably does not contribute to atherogenesis per se but most likely signals the presence of a constellation of lipid abnormalities that increase atherogenic risk, including increased levels of cholesterol-carrying remnant particles, low HDL-C levels, increased numbers of particles, and increased levels of small dense LDL. Patients with these abnormalities often have multiple other CHD risk factors, including central obesity, impaired glucose tolerance, and hypertension.To address these issues and to enhance the potential for CHD risk reduction, ATP III recommends that secondary treatment targets, defined by non-HDL-C (total cholesterol – HDL-C), be established for those who have a triglyceride level 200 mg/dL, after the LDL-C goal has been achieved. Non-HDL-C goals may be achieved by intensifying lifestyle modification, accentuating LDL-C–lowering therapy, or adding a triglyceride-lowering drug to the LDL-C–lowering regimen. Time and additional clinical trials will establish the utility of these various approaches.Reference:Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:
13Definition of the Metabolic Syndrome Defined by presence of >3 risk factorsRisk FactorDefining LevelWaist circumference (abdominal obesity)>40 in (>102 cm) in men>35 in (>88 cm) in womenTriglyceride level>150 mg/dlHDL-C level<40 mg/dl in men<50 mg/dl in womenBlood pressure>130/>85 mmHgFasting glucose>100 mg/dlIGrundy, et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI Scientific Statement. Circulation 2005;112:
14Dr. Allison Attempts to Call Forth the Contents of ATP-IV
15Will ATP-IV Signal a New Wave of Lipid Management?
17Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel IV)Expert Panel MembershipCo-ChairsAlice H. Lichtenstein, D.Sc. Tufts University Boston, Massachusetts Neil Stone, M.D. Northwestern University School of Medicine Chicago, Illinois
18Daniel Rader, M. D. University of Pennsylvania Jennifer Robinson, M Daniel Rader, M.D. University of Pennsylvania Jennifer Robinson, M.D, M.P.H. University of IowaFrank M. Sacks, M.D. Harvard UniversitySchool of Public HealthJ. Sanford Schwartz, M.D. University of Pennsylvania Sidney C. Smith, Jr. M.D. University of North Carolina Karol Watson, M.D., Ph.D. University of California at Los Angeles Peter W. F. Wilson, M.D. Emory University School of MedicineC. Noel Bairey Merz, M.D. University of California, Los Angeles Conrad Blum, M.D. Columbia University Robert H. Eckel, M.D. University of Colorado, Denver Anne Carol Goldberg, M.D., FACP, FAHA Washington University Ronald M. Krauss, M.D. Children's Hospital OaklandResearch Institute Donald M. Lloyd-Jones, M.D., Sc.M. Northwestern University Patrick McBride, M.D., M.P.H. University of Wisconsin
19Status Expected Availability for Public Review and Comment: Spring 2011Expected Release Date: Fall 2011
20Issues for ATP-IVShould 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?
21Jupiter TrialTo 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 AddendumRidker PM et al. NEJM 2008;359:
22Jupiter Methods 17,802 subjects (38% women) Men ≥ 50 years; women ≥ 60 yearsTriglycerides < 500 mg/dLRandomized to Rosuvastatin 20 mg/day or placeboPlanned 60 month follow-upPrimary outcome was major CV eventIncluding elective revascularization
23Jupiter ResultsStudy terminated early on with median follow-up of 1.9 yearsCompliance at study termination was 75%44% reduction in primary endpoint0.77% versus 1.36% per year20% reduction in total mortality1.00% versus 1.25% per year
27JUPITER QuestionsWould a lower-cost, generic statin show similar benefit?Is measurement of hsCRP necessary for risk stratification in primary preventionRidker conflict of interest issuesWas the benefit due to LDL-C lowering or hsCRP lowering?
28Risk Factors in Jupiter Subjects Average age = 66 yearsCurrent smokers = 16%Metabolic syndrome = 41%Family history of premature CAD = 11%25% had fasting glucose > 102 mg/dL25% had systolic BP > 145 mmHg
29PROVE IT - TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome < 10 daysASA + Standard Medical TherapyDouble-blind“Standard Therapy”Pravastatin 40 mg“Intensive Therapy”Atorvastatin 80 mgPROVE IT is a double-blind, randomized trial that has enrolled 4,160 patients, at approximately 400 sites in the US, Europe, Canada, and Australia, who have experienced an acute coronary syndrome (Q wave and non-Q-wave MI or unstable angina) within the previous 10 days. Patients received either 40 mg of pravastatin or 80 mg of atorvastatin within 10 days of their event and were followed for a mean follow-up period of 2 years.To study the role of infection in ACS, one half of the patients in the trial also received gatifloxacin 400 mg in addition to either pravastatin or atorvastatin. Gatifloxacin was started on day 15 after the initial episode of ACS for a treatment period of 14 days. Gatifloxacin was subsequently given as a pulsed dose of 400mg per day for 10 days each month for a mean of 2 years. The other half of the patient population received an antibiotic placebo.2x2 Factorial: Gatifloxacin vs. placeboDuration: Mean 2 year follow-up (>925 events)Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
30Changes from (Post-ACS) Baseline in Median LDL-C (mg/dL)Median LDL-C (Q1, Q3)95 (79, 113)62 (50, 79)120100Pravastatin 40mg21%8060Atorvastatin 80mg49% 40P<0.00120<24hRand.30 Days4 Mos.8 Mos.16 Mos.FinalNote: Changes in LDL-C may differ from prior trials:25% of patients on statins prior to ACS eventACS response lowers LDL-C from true baseline
32All-Cause Death or Major CV Events in All Randomized Subjects 30Pravastatin 40mg(26.3%)2520% with EventAtorvastatin 80mg(22.4%)1516% relative risk reduction(p = 0.005)105But absolute residual risk is 22%31821242730691215Months of Follow-up
33Sources 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-HDLHDL or apo A-1Apo BLDL particle numberLDL particle size
34Secondary Lipid Target In ATP-III, non-HDL-C was identified as the secondary lipid targetSum of cholesterol in all atherogenic lipoproteinsLDL-C, Lp(a)-C, VLDL-C, IDL-CNo major trial since publication of ATP-III in 2001 that specifically treated non-HDL-C
35Lowering non-HDL-C Increase the statin dose Add fibrate Add niacin High dose fish oilExercise, CHO restriction, weight loss
36FIELD Study Fenofibrate to Prevent Cardiovascular Events in Diabetics FIELD Study Investigators Lancet 2005; 366:
37FIELD Mortality No significant benefit shown in ACCORD-Lipids for fenofibrate added to Simvastatin 40 mg/day.NEJM 2010, March 14.
38LDL Particles Cause Atherosclerosis Low Density Lipoproteinparticles (LDL) are the causalagents in atherosclerosis.1The 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.Atherosclerosis comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It involves deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances in the inner lining of an artery. This buildup is called plaque.The hard truth about cholesterol is, unless there is a lipoprotein particle carrying cholesterol – it can’t make it through the space to cause atherosclerosis. The cholesterol in the green oval will get metabolized by the liver. The cholesterol in the red ovals can kill you. The higher the number of particles, the more cholesterol will be transported through the endothelial gap.1 Fredrickson et al. NEJM 1967; 276: 148
40LDL-C is not LDL This is LDL This is LDL Cholesterol POLAR Apo B SURFACE COATPhospholipidFree cholesterolThis is LDLNONPOLARLIPID CORECholesterol EsterTriglycerideThis is LDLCholesterolJames Otvos 2007
43LDL Particle Number Distribution in MESA LDL-C <100 mg/dL (n=1,425)5th th th th percentile10%(n=141)42%(n=603)36%(n=509)10%(n=150)2%(n=22)PercentofSubjectsWhat I’m showing you here from MESA is the distribution of LDL particle number among those with low LDL cholesterol (1st quartile; <100 mg/dL). All of these people have low LDL-C and a good number of them in green have correspondingly low numbers of LDL particles, so they are the concordant individuals (ie., no discrepancy between LDL-C and LDL-P). But a lot of individuals (about half) have greater numbers of LDL particles, and some of these have very high numbers of LDL particles.And guess what – the people in the group with the greatest disconnect between LDL cholesterol and the number of LDL particles (in red), have the smallest LDL size. And they have the lowest HDL-C. And they have the highest triglycerides. So yes – people with greater numbers of LDL particles have small LDL particle size, lower HDL-C and higher TG. But it’s the LDL particle number that may be most relevant to the atherosclerotic risk of these individuals.(nmol/L)LDL Size (nm) (0.7) (0.6) (0.5)HDL-C (mg/dL) (18) (15) (11)Triglycerides (mg/dL) (60) (71) (75)AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006
44LDL Particle Number Distribution in MESA LDL-C = mg/dL5th th th th percentile1%(n=10)24%(n=215)54%(n=484)19%(n=168)3%(n=26)MetSyn (-)(n=903)PercentofSubjects63%22%(nmol/L)The reason this is important, particularly for people at this meeting, is that there is a greater prevalence of a discrepancy between LDL particle number and LDL cholesterol among those with metabolic syndrome and diabetes.Here’s more data from MESA, this time looking at LDL-P distributions in those with (bottom) and without (top) the metabolic syndrome. The subjects shown here are those with LDL-C in the second quartile ( mg/dL). For individuals with the metabolic syndrome, the LDL-P distribution is clearly shifted to the right. 63% of people with LDL-C in this range (25th -50th percentile) have LDL particle number greater than the 50th percentile, as compared to only 22% of people without metabolic syndrome.So metabolic syndrome is a condition highly enriched in people who have discrepant LDL particle number compared to LDL cholesterol.0%(n=0)4%(n=20)33%(n=153)46%(n=210)17%(n=76)MetSyn (+)(n=459)PercentofSubjects(nmol/L)AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006
45CHD Event Associations of NMR LDL Particle Number (LDL-P) versus LDL Cholesterol (LDL-C) Cromwell WC et al: J Clinical Lipidology 2007;1:
46Brief Comments 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 syndromeNon-HDL costs nothing extra to measureApo B measurement does not require unique, expensive technology
47Apo B gives equal weight to each particle: LDL, Lp(a), VLDL, IDL Not equal atherogenicityTreatment strategies different for each particleNon-HDL similarly lumps particle types togetherExample 1TC=200, HDL=50, TG=200, non-HDL=150Example 2TC=170, HDL=20, TG=500, non-HDL=150Is risk equivalent for these 2 patients?
48Prediction of Lifetime Risk for Cardiovascular Disease by Risk Factor Burden at 50 Years of Age Donald M. Lloyd-Jones et alCirculation 2006;113:
51Generic Prevention Drugs Drug Monthly CostStatin $4.00Beta blocker $4.00Metformin $4.00ACE-inhibitor ± HCTZ $4.00Amlodipine $4.00All national discount pharmacy chainsLower price ($10) for 3 months supplyCan potentially reduce cost further with a pill cutter
52Living Under the Umbrella of Good Cardiovascular Health LDL-C<100FBG<100SBP<120Living Under the Umbrella of Good Cardiovascular Health
53Predictions for ATP-IV 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.