Review of the New 2013 ACC/AHA Guidelines on Lipid Management K athleen Dively NP Associates In Cardiology Clinical Lipi

1. Review of the New 2013 ACC/AHA Guidelines on Lipid ManagementKathleen Dively NPAssociates In CardiologyClinical Lipid SpecialistFNLA

2. Objectives • Discuss and review major changes including the lack of target LDL • Discuss the role of niacin and ezetimibe • Dicuss the role of biomarker ieApoB, CIMT • Discuss the use of combination therapy • Discuss the use of high dose statin therapy • Discuss the management of residual risk

3. 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 • Always screen for residual risk , Look at more than the LDL-C

4. Establish Goals of Therapy based on risk factors & Lab evaluation Multivariable Risk Assessment LDL Management High Risk Lifestyle/statin/other If above goal CHD/CHD Risk Equiv. (>20% 10-year risk) Treatment Assessment & Goal LDL-C < 100 (LDL-P < 1000)* Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Treatment Assessment & Goal (LDL-P < 1300)* LDL-C < 130 Low Risk Treatment Assessment & Goal (LDL-P < 1600)* LDL-C < 160 0-1 Risk Factors (0-10% 10 year risk) *Based on population equivalent cut points 1. Contois JH et al. Clin Chem. 2009;55:407-419 2. Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p. 249-59. 3. Cromwell WC, Barringer TA. CurrCardiol Reports 2009;11(6):468-475

5. ACC/AHA Guideline on the Assessment of Cardiovascular Risk The last NCEP-ATPIII report was delivered in 2001 with an update in 2004. 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 Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

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

7. ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults 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

8. 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. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

9. ACC/AHA Guidelines for 4 Classes of Statin Eligible Patients Individuals with LDL> 190 mg/dl Age 40-75 with LDL 70-189mg/dl without ASCVD assess 10 year risk, treat if > 7.5% Age 40-75 with Diabetes and no ASCVD with LDL-C between 70-189mg/dl Individuals with clinical ASCVD No recommendations for CHF or hemodialysis patients. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

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

11. ACC/AHA Guideline on the Assessment of Cardiovascular Risk • 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

12. ACC/AHA Guideline on the Assessment of Cardiovascular Risk • 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

13. ACC/AHA Guideline on the Assessment of Cardiovascular Risk • 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

14. ACC/AHA Guideline on the Assessment of Cardiovascular Risk • 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 40-75 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

15. 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 Agatstonunits ankle-brachial index <0.9 Elevated lifetime risk of ASCVD may be used to enhance the treatment decision making. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

16. 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. Stone NJ et al. Task Force on Practice Guidelines. Circulation or JACC: on line 2013

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

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

19. Risk Factors, optimal levels • Total Cholesterol 170mg/dl • HDL 50mg/dl • Systolic b/p110mmhg

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

21. Risk Assessment Calculator/No targets of therapy

22. 46 year old white male , Family history of HD .

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

24. Asymptomatic, Abnormal stress referred for LHC. • 90% proximal LAD • Pt was on lipitor and niaspan. Abnormal phytosterol levels. • Changed to crestor. • LVH by echo. b/p med changed • 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;341:332-333

26. “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.” Ann Intern Med. 2006;145:520-530

27. 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 Hayward RA et al. Ann Intern Med. 2006;145:520-530

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;341:332-333

29. 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 • 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 3.0-5.2 mmol/L (115-200 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;344:1383-1389

30. The Politics of Evidence-Based Medicine 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. By Marc A. Rodwin, Indiana University Journal of Health Politics, Policy and Law, Vol. 26, No. 2, April 2001 http://www.ahrq.gov/clinic/jhppl/rodwin.htm

31. Unmet Need: Persistent Incidence of CHD Framingham Heart Study 26 year f/u, Indicates that Measuring Cholesterol Does Not Tell Us Enough • 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 20/100 40/100 90/100

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 40-75. Ages 20-59 life-time calculator. (my.americanheart.org/cvriskcalculator) • Lifestyle, restriction of fat and sodium

34. Steps 2 & 3: Establish Goals of Therapy & Lab evaluation Multivariable Risk Assessment LDL Management High Risk Lifestyle/statin/other If above goal CHD/CHD Risk Equiv. (>20% 10-year risk) Treatment Assessment & Goal LDL-C < 100 (LDL-P < 1000)* Intermediate Risk 2+ Risk Factors (10-20% 10-year risk) Treatment Assessment & Goal (LDL-P < 1300)* LDL-C < 130 Low Risk Treatment Assessment & Goal (LDL-P < 1600)* LDL-C < 160 0-1 Risk Factors (0-10% 10 year risk) *Based on population equivalent cut points 1. Contois JH et al. Clin Chem. 2009;55:407-419 2. Cromwell WC. In: Clinical Challenges in Lipid Disorders.Toth PP, Sica DA, editors. Oxford: Clinical Publishing; 2008.p. 249-59. 3. Cromwell WC, Barringer TA. CurrCardiol Reports 2009;11(6):468-475

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 ALGORITHMSnot addressed INCREASED PAYOR DENIALS considered guidelines for us (not mandates) but do we really have a choice when payors deny

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

37. X Ezetimibe Cholesterol torsHo LDLapoB100 Liver Duodenum VLDLapoB100 Jejunum Ileum CM RemnantapoB48 CM apoB48 Colon

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 RESIDUAL RISK IS NOT ADDRESSED

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; 2000-2006.

41. Residual Cardiovascular Risk in Major Statin Trials Patients Experiencing Major Coronary Events, % N 4444 9014 4159 20 536 6595 6605 LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary Adapted from Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.

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. NO!

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 ClinChem 2009;55:407-419 2] Otvos et al. J ClinLipidol 2011;5:105-113 3] Brunzell JD et al. j Am CollCardiol 2008;51:1512-1524 4] Jellinger PS et al. EndocrPract 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 carsnotthe number of passengers =

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

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

50. Up to 70% More Particles Cholesterol Balance LDL-C can vary with particle size At the same LDL cholesterol, more small LDL vs. large LDL particles present 100 mg/dL 100 mg/dL Large LDL Small LDL Otvos JD et al. Am J Cardiol2002;90(suppl):22i-29i Cromwell WC et al. J ClinLipidology. 2007;1(6):583-592.