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1 Review of the New 2013 ACC/AHA Guidelines on Lipid Management Kathleen Dively NP Associates In Cardiology Clinical Lipid Specialist FNLA.

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Presentation on theme: "1 Review of the New 2013 ACC/AHA Guidelines on Lipid Management Kathleen Dively NP Associates In Cardiology Clinical Lipid Specialist FNLA."— Presentation transcript:

1 1 Review of the New 2013 ACC/AHA Guidelines on Lipid Management Kathleen Dively NP Associates In Cardiology Clinical Lipid Specialist FNLA

2 2 Objectives 1.Discuss and review major changes including the lack of target LDL 2.Discuss the role of niacin and ezetimibe 3.Dicuss the role of biomarker ie ApoB, CIMT 4.Discuss the use of combination therapy 5.Discuss the use of high dose statin therapy 6.Discuss the management of residual risk -

3 3 Previous Guidelines Previous Guidelines –The first priority of treatment is to treat LDL-C to goal (unless TG is >500) Non-HDL-C should be a secondary treatment target, if LDL-C at goal but TG is ≥200 mg/dL Non-HDL-C should be a secondary treatment target, if LDL-C at goal but TG is ≥200 mg/dL Always screen for residual risk, Look at more than the LDL-C Always screen for residual risk, Look at more than the LDL-C

4 4 Treatment Assessment & Goal Establish Goals of Therapy based on risk factors & Lab evaluation Multivariable Risk Assessment High Risk CHD/CHD Risk Equiv. (>20% 10-year risk) Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Low Risk 0-1 Risk Factors (0-10% 10 year risk) LDL-C < 100 LDL Management LDL-C < 130 Treatment Assessment & Goal LDL-C < 160 Treatment Assessment & Goal Lifestyle/statin/other If above goal (LDL-P < 1000)* (LDL-P < 1600)* (LDL-P < 1300)* 1. Contois JH et al. Clin Chem. 2009;55: Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6): *Based on population equivalent cut points

5 Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk The last NCEP-ATPIII report was delivered in 2001 with an update in There has been no concensus reached with ATP IV so the 16 member group reconvened under the auspices of the ACC/AHA and were limited to review only level one research. In response to the 2011 report of the Institute of Medicine on the development of trustworthy clinical guidelines (1), the NHLBI Advisory Council (NHLBAC) recommended that the NHLBI focus specifically on reviewing the highest quality evidence

6 Level I Evidence [ This definition,: Evidence obtained from at least one properly designed randomized controlled trial.‎ and therefore considered ( LIKELY reliable )

7 There is no evidence to support continued use of specific LDL-C and/or non–high- density lipoprotein cholesterol (non–HDL-C) treatment targets Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults

8 Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults The following are no longer considered appropriate strategies: treat to target, lower is best. The new GL recommends: treat to level of ASCVD risk, based upon estimated 10-year or lifetime risk of ASCVD. The guidelines provided no recommendations for initiating or discontinuing statins in NYHA class II-IV ischemic systolic heart failure patients or those on maintenance hemodialysis.

9 Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guidelines for 4 Classes of Statin Eligible Patients Individuals with LDL> 190 mg/dl Age with LDL mg/dl without ASCVD assess 10 year risk, treat if > 7.5% Age with Diabetes and no ASCVD with LDL-C between mg/dl Individuals with clinical ASCVD No recommendations for CHF or hemodialysis patients.

10 Statin Eligible Estimated that 44% of men 22% of women Under the old guidelines about 15% are eligible

11 ► The contribution to risk assessment for a first ASCVD event using ApoB, CKD, albuminuria, or cardiorespiratory fitness is uncertain at present ► CIMT is not recommended for routine measurement in clinical practice for risk assessment for a first ASCVD event Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

12 ► The use of ezetimibe is no longer recommended as a valid treatment for lipid management. ► The use of niacin was not addressed ► The use of fibrates and omega 3s were not addressed ► The use of combination therapy was not addressed due to lack of clinical evidence. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

13 High-intensity statin therapy is defined as a daily dose that lowers LDL-C by ≥50% and moderate- intensity by 30% to <50%. All patients with ASCVD, should receive high-intensity statin therapy; or if not a candidate for high-intensity, should receive moderate-intensity statin therapy. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

14 LDL-C ≥190 mg/dl : Should receive high-intensity or moderate-intensity statin therapy. Statin Intolerant: Other cholesterol-lowering agents can be considered to further lower LDL-C. Diabetics with a 10-year ASCVD ≥7.5%: Should receive high- intensity statins and <7.5% moderate-intensity statin therapy. Persons years with a ≥7.5% 10-year ASCVD risk: should receive moderate- to high-intensity statin therapy. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

15 Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk To the patients not in the 4 statin groups Individuals whose 10-year risk is <7.5% Family history of premature ASCVD, LDL-C >160 mg/dl, HS-crp ≥2 mg/dl, Coronary calcium score ≥300 Agatston units ankle-brachial index <0.9 Elevated lifetime risk of ASCVD may be used to enhance the treatment decision making.

16 Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk Lifestyle modification (i.e., adhering to a heart healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a critical component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies.

17 Basically all targets have been removed Risk stratification remains, but is much more lenient

18 Risk stratification, Statin eligible patients F 10 year risk >7.5% F (was > 20%)

19 Risk Factors, optimal levels F Total Cholesterol 170mg/dl F HDL 50mg/dl F Systolic b/p 110mmhg

20 Desk-top ACC Risk Calculator F 10 year risk ages 40-79yr F Life-time risk ages 20-59yr F Pt age 55, non-smoker, TC 213, HDL50, systolic b/p 120 ( untreated), non-diabetic F White women 2.1% F African American women 3.0% F White man 5.3% F African American Man 6.1%

21 21 Risk Assessment Calculator/No targets of therapy

22 46 year old white male, Family history of HD. TC 164LDL79HDL41 TRI 247FBS 75

23 His 10 year risk with the new calculator was 2%. His 10 year risk with the new calculator was 2%.

24 Asymptomatic, Abnormal stress referred for LHC. 90% proximal LAD 90% proximal LAD Pt was on lipitor and niaspan. Abnormal phytosterol levels. Pt was on lipitor and niaspan. Abnormal phytosterol levels. Changed to crestor. Changed to crestor. LVH by echo. b/p med changed LVH by echo. b/p med changed LDLp 1245 (LDLc 75) LDLp 1245 (LDLc 75)

25 ► Given the strong evidence that statins reduce risk across the range of LDL levels, the best preventive strategy may be to use the patient’s global cardiovascular risk to determine treatment. ► The absolute benefit of statins is greatest for those at higher risk— and those at highest risk would tend to benefit most from higher dose or higher potency statins. ► The benefit diminishes with decreasing risk. A recent analysis of statins for primary prevention showed that a strategy using statins based on patient risk rather than LDL levels can prevent more cardiovascular events while treating fewer people with high dose statins. BMJ 2010;341:

26 Ann Intern Med. 2006;145: “Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe.”

27 Hayward RA et al. Ann Intern Med. 2006;145: Evidenced Based Medicine ► We conclude that there is clear and compelling evidence that most patients at high risk for cardiovascular disease should be taking at least a moderate dose of a statin if tolerated, even if their natural LDL cholesterol level is low ► We could find no published high-quality clinical evidence supporting titration of lipid therapy based on proposed LDL cholesterol targets ► We strongly suggest that those with access to these data conduct further analyses to provide more valid evidence on this important clinical and scientific question

28 ► The trials of cholesterol lowering treatments tested the effect of fixed doses of drugs, not a strategy of progressively intensifying lipid therapy without regard to strategy to reach specific target ranges Save a ton of money – No follow up lab tests! No follow up phone calls! BMJ 2010;341:

29 ► Dosage was adjusted, if necessary, at the 12-week and 6-month visits, on the basis of serum total cholesterol at 6 and 18 weeks. The goal of treatment was to reduce serum total cholesterol to mmol/L ( mg/dL) ► Patients in the simvastatin group whose serum cholesterol was out of range had their dose increased to 40 mg daily, as two 20 mg tablets, or reduced to one 10 mg tablet Pedersen TR. Lancet 1994;344: The first outcome trial ever done using a statin ► 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 212 – 308 mg/dL on a lipid-lowering diet were randomized to double-blind treatment with simvastatin or placebo

30 Evidence-based medicine has enabled payers, purchasers, and governmental authorities to use their financial clout to alter the practice of medicine. Traditionally doctors defined the standard of care. Now, armed with more and better information about medical practices, payers and purchasers can deny payment for medical services that they deem medically unnecessary or ineffective. In so doing, they redefine standards for appropriate medical practice. The Politics of Evidence-Based Medicine By Marc A. Rodwin, Indiana University Journal of Health Politics, Policy and Law, Vol. 26, No. 2, April 2001

31 80% of subjects with cardiac events had lipid levels similar to subjects that were event free 35% of CHD occurs in people with TC<200 Unmet Need: Persistent Incidence of CHD Framingham Heart Study 26 year f/u, Indicates that Measuring Cholesterol Does Not Tell Us Enough 20/10040/10090/100

32 32 Should we consider a failure in detection of risk by “standard methods” an appropriate reason to increase the number of statin eligible patients and forfeit our present guidelines?

33 New ACC/AHA Guidelines Lipids, there is no longer any support for treating to specific targets Obesity, There is no ideal diet for weight loss Risk Assessment, New calculator for 10 year risk assessment ages Ages life-time calculator. (my.americanheart.org/cvriskcalculator) Lifestyle, restriction of fat and sodium

34 34 Treatment Assessment & Goal Steps 2 & 3: Establish Goals of Therapy & Lab evaluation Multivariable Risk Assessment High Risk CHD/CHD Risk Equiv. (>20% 10-year risk) Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Low Risk 0-1 Risk Factors (0-10% 10 year risk) LDL-C < 100 LDL Management LDL-C < 130 Treatment Assessment & Goal LDL-C < 160 Treatment Assessment & Goal Lifestyle/statin/other If above goal (LDL-P < 1000)* (LDL-P < 1600)* (LDL-P < 1300)* 1. Contois JH et al. Clin Chem. 2009;55: Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6): *Based on population equivalent cut points

35 35 Potential problems NO TARGETS OF THERAPY difficult for patient motivation, promotes apathy on the part of the provider NO ROUTINE LABS difficult for motivation, risk HIGH DOSE STATIN side effects HIGH RISK POPULATIONS ischemic CHF, CKD COMBINATION TX excluded WIDE SPREAD USE OF STATINS increased costs ETHNIC SPECIFIC ALGORITHMS not addressed INCREASED PAYOR DENIALS considered guidelines for us (not mandates) but do we really have a choice when payors deny

36 36 Ezetimibe (Zetia) Bowel absorption inhibitor Works at the brush border of the small intestine.

37 37 Cholesterol torsHo DuodenumDuodenum JejunumJejunum IleumIleum CM apoB48 Liver CM Remnant apoB48 VLDL apoB100 EzetimibeX LDL apoB100 ColonColon

38 38 Niacin effectiveness in reducing events. Fats trial ( Familial hypercholesterolemia ) 78 % Hats trial ( HDL atherosclerosis tx ) 61 % AFREGS ( airforce regression ) 53 % Aim High ( no residual risk) 0

39 RESIDUAL RISK IS NOT ADDRESSED

40 40 Evidence of Residual CVD Risk 136,905 hospitalizations for (non-CHF) CAD and lipids w/in 24 hrs of admit (at 541 hospitals) Over 50% of patients with LDL-C <100 mg/dL and 17.6% with LDL-C <70 mg/dL For patients without h/o CAD, 72.1% with LDL-C <130 mg/dL and 41.5% with LDL-C <100 mg/dL Sachdeva A, et al. Am Heart J 2009; 157:111-7.e2. From AHA’s Get with The Guidelines (GWTG) CAD Program and database;

41 Residual Cardiovascular Risk in Major Statin Trials 41 Adapted from Libby PJ, et al. J Am Coll Cardiol, 2005:46:  LDL N %-28%-29%-26%-25% SecondaryHigh RiskPrimary Patients Experiencing Major Coronary Events, %

42 42 Should we consider a failure in detection of risk by “standard methods” an appropriate reason to increase the number of statin eligible patients and forfeit our present guidelines?

43 43 NO!

44 44 Groups that have come out with position statements in support of lipoprotein testing American Diabetes Association / American College of Cardiology Foundation Consensus Statement [3] American Association for Clinical Chemistry Lipoproteins & Vascular Diseases Working Group Recommendations [1] American Association of Clinical Endocrinologists Guidelines for Management of Dyslipidemia [4] National Lipid Association Expert Recommendations [5] Canadian Cardiovascular Society Guidelines [6] ESC/EAS Guidelines for the Management of Dyslipidemia [7] 1] Contois JH Clin Chem 2009;55: ] Otvos et al. J Clin Lipidol 2011;5: ] Brunzell JD et al. j Am Coll Cardiol 2008;51: ] Jellinger PS et al. Endocr Pract 2012;18(suppl 1), 1-78 European Society of Cardiology and European Athrosclerosis society

45 What’s the difference between Lipoproteins and Cholesterol ?

46 = Lipoprotein = Cholesterol

47 Question #1: What causes traffic jams to occur on a highway ? = Number of cars not the number of passengers

48 48 LDL-Cholesterol = the weight of the constituent cholesterol within the particle “LDL” should not imply LDL-Cholesterol The LDL Particle NONPOLAR LIPID CORE Cholesterol Ester Triglyceride POLAR SURFACE COAT Phospholipid Free cholesterol Apo B

49 49 Cholesterol Molecules Apoprotein B-100 Triglyceride Molecules LDL A ParticleLDL B Particle Apoprotein B-100 Triglyceride Molecules Cholesterol Molecules

50 50 At the same LDL cholesterol, more small LDL vs. large LDL particles present Up to 70% More Particles Small LDL Large LDL Cholesterol Balance 100 mg/dL Otvos JD et al. Am J Cardiol 2002;90(suppl):22i-29i LDL-C can vary with particle size Cromwell WC et al. J Clin Lipidology. 2007;1(6):

51 51 A gradient driven process, LDL particles invade the arterial wall and set in motion the cascade of events that leads to atherosclerosis 1,2 After adjustment for LDL-P concentration, particle subclass and size do not impact outcomes 3 1. Fredrickson et al. NEJM 1967; 276: Brunzell, et al. Diabetes Care. 2008;4: Ip et al. Ann Intern Med. 2009;150: LDL particle number (LDL-P), as opposed to size, is a key driver of atherogenic plaque formation Endothelial Cell Arterial Wall Endothelial Gap LDL Particle

52 52 Lipoprotein Particles Chylomicron Remnants VLDL HDL Diameter (nm) Density (g/ml) LDL IDL HDL Cholesterol LDL Cholesterol Triglycerides (mainly) Chylo- microns

53 53 Why Alternate Measures of LDL Quantity are Not Equivalent Concordance: LDL-C and LDL-P “agree” (i.e., are equally high or low) Either LDL measure is an equally good guide to LDL treatment decision-making. Discordance: LDL-C and LDL-P “disagree” (i.e., the values differ, either in their relationship to the normal range or to each other) Which LDL measure should guide clinical decision-making?

54 54 CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study Cromwell WC et al. J Clin Lipidology 2007;1(6):

55 Friedwald Equation (is used to calculate the bad cholesterol, LDL) LDL Cholesterol=Total chol-(HDL)-(TG/5) It assumes all the TG is carried on VLDL And the TG/CHOL ratio of VLDL is constant at 5:1 NOT TRUE when TG>200, DM or metabolic syndrome exist with ^ Chilomycrons, get falsely low HDL and LDL. 55

56 56 Metabolic Syndrome Triglycerides > 150mg/dl FBG > 100 ( or DM) Waist circumference > 35 inches in a women or 40 inches in a man HTN (>130/85 mmHg) or taking B/p medication HDL-C <40mg/dl males or <50mg/dl females NCEP Definition of Metabolic Syndrome 2001 Guidelines 56

57 57 How NMR Lipoprotein Analysis works

58 58 Lipoprotein subclasses of different size broadcast lipid NMR signals that are naturally distinguishable. The measured amplitudes of these signals provide subclass quantification. Jeyarajah EJ et al. Clin Lab Med 2006;26:47-70 NMR Lipoprotein Analysis

59 59 NMR Measures LDL Particle Number, Not LDL Cholesterol Measured LDL-C 90 mg/dL Measured LDL-C 90 mg/dL LDL NMR Signals LDL particles 900 nmol/L LDL particles 1600 nmol/L

60 60 Principles for determining appropriate LDL testing guided by landmark publication Value of the new reference test is best examined in cases of disagreement (discordance) between the new and standard tests. Clinical consequences of disagreements between new and standard test requires a fair “umpire” test. Fair umpire tests include clinical events or disease progression. Glasziou P et al. Ann Intern Med 2008;149:

61 61 Multiple Outcome Studies Demonstrate Difference Between LDL-P and LDL-C

62 62 Relationship of LDL Particle Number with CHD Outcomes

63 63 Framingham Offspring Study Long-running NIH/NHLBI observational study of residents of Framingham, MA to determine risk factors for future cardiovascular disease (CVD) Blood samples obtained in (exam 4) – Lipids measured by traditional chemical methods – Lipoprotein particles measured by NMR spectroscopy Correlated with CVD occurrence during a 15-year follow up – 3,066 subjects – 431 CVD events (MI, stroke, CHD death, angina, congestive heart failure) Discordance defined as either above or below the median for LDL-C and LDL-P Cromwell WC et al. J Clin Lipidology 2007;1(6):

64 64 CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study Cromwell WC et al. J Clin Lipidology 2007;1(6):

65 65 Large NHLBI observational study of the pathogenesis and progression of subclinical atherosclerosis. N= 6,814 asymptomatic men and women free of cardiovascular disease at entry 38% White 28% African-American 22% Hispanic 12% Asian 319 CVD events (MI, CHD death, angina, stroke, stroke death, or other atherosclerotic or CVD death) occurred during 5.5-yr follow-up (n=5598). Multi-Ethnic Study of Atherosclerosis (MESA) Otvos et al. J Clin Lipidol 2011;5:105-13

66 66 MESA: Study Design Baseline assessments: LDL particle number (LDL-P) measured by NMR spectroscopy Calculated LDL cholesterol (LDL-C) Carotid intima-media thickness (IMT) Associations of LDL-C and LDL-P with CVD events (prospective) and carotid IMT (cross-sectional) were determined Overall population Concordant subgroup Discordant subgroup Discordance defined as LDL-C and LDL-P levels differing by  12 percentile units, to give equal-sized concordant and discordant subgroups. Otvos et al. J Clin Lipidol 2011;5:105-13

67 67 MESA: Conclusions The cholesterol content of LDL particles varies greatly, causing LDL-C in many individuals to over-represent or under-represent LDL particle concentrations. LDL-C and LDL-P were both significantly associated with incident CVD overall. For individuals with concordant levels of LDL-C andLDL-P, both measures of LDL quantity were (as expected) equally predictive of risk. For individuals with discordant levels, only LDL-P was significantly associated with incident CVD. Carotid IMT also tracked with LDL-P rather than LDL-C when these measures were discordant. Otvos et al. J Clin Lipidol 2011;5:105-13

68 68 Purpose: Randomized, double-blind trial to determine if increasing low HDL-C will decrease CHD events Subjects: 2531 men with CHD, low HDL-C (31.5 mg/dL), and low LDL-C (111 mg/dL) Therapy: Gemfibrozil (1.2 g/d) vs. placebo Otvos, et al. Circulation 2006;113: VA-HIT Background

69 69 Gemfibrozil treatment resulted in a 22% decrease in nonfatal MI + CHD death 31% decrease in stroke No increase in adverse events VA-HIT: Principal Results Otvos, et al. Circulation 2006;113:

70 70 VA Hit Trial Demonstrated that gemfibrozil reduced 5-yr rate of new CHD events. No effect on LDL-C, HDL-C only raised 6%, tri lowered 31% Increased LDL size and decreased LDL particles number (LDL-P) The decrease in particle number was predictive for CHD future events.

71 71 Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes VA-HIT: Alternative Measures of LDL and HDL As Predictors of CHD Events HDL-CApoA-1HDL-P* Odds Ratio per 1-SD Decrement Odds Ratio per 1-SD Increment LDL-CNon-HDL-CApoBLDL-P* *p<0.001 LDL HDL Otvos, et al. Circulation 2006;113:

72 72 Consensus and Recommendations

73 73 Brunzell et al. Diabetes Care (4): “… the cholesterol content of LDL particles varies from person to person and is influenced by metabolic abnormalities such as insulin resistance and hyperglycemia.” 2.“Hence, measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with the typical lipoprotein abnormalities of cardio-metabolic risk.” 3.“Measurements of apoB or LDL particle number by NMR may more closely quantitative the atherogenic lipoprotein load. Some studies suggest that both are better indices of CVD risk than LDL cholesterol or non-HDL cholesterol …” 2008 ADA/ACC Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk

74 New Guidelines for Lipid Targets in patients with type II Diabetes ApoB <80mg/dl LDL-p <1000nm/l »American Association of clinical endocrinology comprehensive diabetes management 2013 consensus statement

75 75 Recommendations for Using LDL Particle Number Measures as Targets of Therapy Garber AJ, et al. Endocr Pract 2013;19(Suppl 2):1-48.

76 76 Groups that have come out with position statements in support of lipoprotein testing American Diabetes Association / American College of Cardiology Foundation Consensus Statement [3] American Association for Clinical Chemistry Lipoproteins & Vascular Diseases Working Group Recommendations [1] American Association of Clinical Endocrinologists Guidelines for Management of Dyslipidemia [4] National Lipid Association Expert Recommendations [5] Canadian Cardiovascular Society Guidelines [6] ESC/EAS Guidelines for the Management of Dyslipidemia [7] 1] Contois JH Clin Chem 2009;55: ] Otvos et al. J Clin Lipidol 2011;5: ] Brunzell JD et al. j Am Coll Cardiol 2008;51: ] Jellinger PS et al. Endocr Pract 2012;18(suppl 1), 1-78 European Society of Cardiology and European Athrosclerosis society

77 77 NLA Expert Panel Recommendations

78 78 Recommendations from the NLA Expert Panel on Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing Measurement for On-Treatment Management Decisions Davidson, et al. J Clin Lipidol 2011;5:

79 79 1.Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. 2.When LDL-C and LDL-P levels are discordant (esp. diabetes, metabolic syndrome), risk tracks with LDL-P, not LDL-C. 3.LDL-P values should be used to indicate a patient has achieved adequate LDL reduction, because LDL-P is a significant independent predictor of CHD end points. Recommendations from the NLA Expert Panel Davidson, et al. J Clin Lipidol 2011;5:

80 80 Approach to Utilization of Lipids and LDL Particle Number in Clinical Practice

81 81 Clinical Cut-points for LDL nmol/L Percent of Subjects mg/dL Percent of Subjects LDL Cholesterol LDL Particle Number Framingham Offspring 1 MESA 2 Percentile: 20 th 50 th 80 th OptimalHigh 1 Otvos JD, Jayarajah E, Cromwell, WC. Amer J Cardiol 2002;90(8A):22i-29i. 2 Otvos JD et al. J Clin Lipidol 2011;5:

82 82 Step 1: Assess clinical CHD risk Step 2: Establish goals of therapy appropriate for degree of clinical risk present (Lipids and LDL Particle Number) Step 3: Laboratory evaluation Step 4: Consider therapeutic lifestyle changes and medications as indicated to achieve targets: Primary target: LDL Secondary targets: non-HDL and TG Step 5:Assess response to therapy and modify intervention as indicated to achieve LDL-P target Approach to Utilization of Lipids and LDL Particle Number in Clinical Practice Cromwell WC et al. Lipid and Lipoprotein Disorders: Current Clinical Solutions Baltimore: International Guidelines Center; 2009.

83 83 Risk Factors : CV disease Smoking Obesity Sedentary lifestyle HTN Hyperlipidemia Family History of premature heart disease Age, men > 45yrs or women > 55yrs

84 84 *Risk factors are age (>45M;>55W), smoking, hypertension, low HDL-C, family history **10-year risk given by age, gender, TC, HDL-C, SBP/hypertension, and smoking Step 1: Assess Clinical Risk (using NCEP ATP-III Guidelines) Multivariable Risk Assessment High Risk CHD/CHD Risk Equiv. (>20% 10-year risk)** Intermediate Risk 2+ Risk Factors* (10-20% 10-year risk)** Low Risk 0-1 Risk Factor* (0-10% 10 year risk)** Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

85 85 Treatment Assessment & Goal Steps 2 & 3: Establish Goals of Therapy & Lab evaluation Multivariable Risk Assessment High Risk CHD/CHD Risk Equiv. (>20% 10-year risk) Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Low Risk 0-1 Risk Factors (0-10% 10 year risk) LDL-C < 100 LDL Management LDL-C < 130 Treatment Assessment & Goal LDL-C < 160 Treatment Assessment & Goal Lifestyle/statin/other If above goal (LDL-P < 1000)* (LDL-P < 1600)* (LDL-P < 1300)* 1. Contois JH et al. Clin Chem. 2009;55: Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6): *Based on population equivalent cut points

86 86 Pharmacologic Options for Reaching LDL Particle Number Goals Step 4 Adapted from Rosenson et al. Atherosclerosis. 2010; 213:1-7.

87 87 Step 5: Assess Response to Therapy 1.If not at Lipid and LDL Particle Number goal – modify therapy and repeat laboratory tests in 3 months 2.Following therapeutic changes, repeat laboratory testing every 3 months until goal values for lipid and LDL Particle Number are achieved 3.Once at goal – continue therapy and repeat laboratory tests in 1 year Cromwell WC, Barringer TA. Curr Cardiol Reports 2009;11(6):

88 88 1.Unrecognized (and under-treated) LDL particle elevations are common and a significant contributor to the residual risk of many patients with “acceptable” levels of LDL-C. 2.When LDL-C and LDL-P levels are discordant, risk tracks with LDL-P, not LDL-C, especially in higher risk patients with diabetes and metabolic syndrome. 3.LDL-P measurement with findings of discordance between LDL- P and LDL-C yield actionable data for medical decision-making regarding treatment, e.g., statin increase or decrease, combination therapy, etc. Contributors to residual risk

89 89

90 The primary objective of this study was To evaluate treatment patterns between patients monitored with LDL-c alone and patients monitored with LDL-c and LDL-p results. To evaluate treatment patterns between patients monitored with LDL-c alone and patients monitored with LDL-c and LDL-p results. The secondary objectives of this study were: The secondary objectives of this study were: To determine the number and type of cardiovascular events and procedures To determine the number and type of cardiovascular events and procedures To determine the percentage of patients with LDL control according to NCEP Adult Treatment Panel III Guidelines To determine the percentage of patients with LDL control according to NCEP Adult Treatment Panel III Guidelines To determine the percentage of patients with diabetes with A1C control according to ADA To determine the percentage of patients with diabetes with A1C control according to ADA

91 Inclusion Criteria Diabetes or metabolic syndrome Diabetes or metabolic syndrome At least 4 lipid profiles in the 4 years follow-up At least 4 lipid profiles in the 4 years follow-up

92 Gender Distribution

93 Age Distribution

94 Most Prevalent Comorbid Conditions

95 Average LDLc in the Previous 3 Years

96 Conclusions Trending towards decreased CVD events in the group using LDLp to guide therapy. Lower dose statin and more combination tx noted in the group where LDLp guided treatment.

97 % of patients  > LDL-C (mg/dL) on-treatment n = 4,888 L-TAP: Majority of Patients With CHD Do Not Reach NCEP LDL-C Targets Pearson TA et al. Arch Intern Med. 2000;160: Other L-TAP data courtesy of TA Pearson.

98 LIPID CLINIC YEARLY DATA BASE RETROPECTIVE ANALYSIS

99 99 Lipid Clinic LDL-C Goal Attainment July March November August May October Goal Met LDL Goal < % (2/3)92.3% (12/13)84.6% (22/26)92.3% (24/26)89.4 % (59/66)86.1% (130/151) LDL Goal < % (10/17) 65.8% (25/38)75.3% (55/73)69.6% (55/79)66.7% (66/99)71.7% (104/145) LDL Goal < % (12/29) 47.1% (40/85)55.7% (102/183)51.6% (116/225)48.5% (159/328)54.8% (249/454) OVERALL49% (24/49)56.6% (77/136)63.5% (179/282) 59.1% (195/330) 57.6% (284/493) 64.4% (483/750)

100 Overall Office LDL Goal Attainment

101 101 Patient Case Study

102 102 Ms R is a pleasant 55 yr old white female with a history of CAD, hypertension, & hyperlipidemia. She had an MI and stent placement on 2 occasions prior to seeing me. She has been followed at by my Lipid Clinic since October She has maintained a 10 lb. Weight loss and a low risk NMR profile with diet, exercise and medication. She has had no recurrent events.

103 103 What is Mrs R’s goal of therapy? High risk < 70 LDL -C <700 LDL-P

104 104 10/25/20002/14/2005Goal T Chol Triglyceride30553 LDL -C10493 LDL-Particle LDL-P size < 700 HDL-C6792 Blood Sugar14080

105 11/14/2013 Robert Superko ► Trials have not been designed to address such a strict interpretation but reasonable conclusions, regarding benefit of lipoprotein manipulation, can be made from an abundance of heterogeneous clinical trials ► A weakness of this strict constructionist approach is that it ignores the very large number of individuals treated with a statin who continue to have a cardiovascular event ► The new guidelines ignore individuals who continue to have a CHD event despite statin treatment. ► This is the new guidelines greatest failure in my opinion as such an approach creates the danger of ignoring the traditional pathophysiologic/clinical trial approach to understanding disease and treatments that are in the best interest of the individual patient, and worships at the altar of Randomized Clinical Trial strict interpretation

106 Clin. Cardiol. 35, 5, 259–260 (2012) ► Although we are enamored of the notion that we live in the world of truth in evidence- based medicine, the real truth is that we know very little. ► Instead, we understand a great many things with a great deal of probability. For us to practice better medicine and perform superior research, we must all accept this fact. ► There is no end to science; it is an evolutionary discipline. The best we can do at any moment is be familiar with the totality of the literature and practice medicine based upon its trends as well as our knowledge of human physiology and hard-won clinical experience. ► In this process, let us be forever vigilant not to slay the intuitive provider.

107 Gordon C S Smith, Jill P Pell BMJ 2003;327:1459–61 We think that everyone might benefit if the most radical protagonists of evidence based medicine organized and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute randomized Parachutes reduce the risk of injury after gravitational challenge, but their effectiveness has not been proved with randomized controlled trials In fact our search strategy did not find any randomised controlled trials of the parachute

108 Future updates needed 1. Treatment of high triglycerides. 1. Treatment of high triglycerides. 2. Whether on-treatment markers such as apoB, Lp(a), LDL-particles are useful in guiding decisions. 2. Whether on-treatment markers such as apoB, Lp(a), LDL-particles are useful in guiding decisions. 3. Optimal age for starting treatment for reducing lifetime risk of ASCVD. 3. Optimal age for starting treatment for reducing lifetime risk of ASCVD. 4. Tx options for pts with HF, hemodialysis. 5. Long term effects of statin associated new onset diabetes in our patients 4. Tx options for pts with HF, hemodialysis. 5. Long term effects of statin associated new onset diabetes in our patients

109 109 Questions? Dr Thomas Dayspring


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