1. Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPS Clinical Pharmacy Director & PGY1 Residency Director PHS Claremore Indian Hospital Clinical Assistant Professor, University of Oklahoma College of Pharmacy 1

2. Objectives Identify novel cardiovascular biomarkers that correlate with enhanced cardiovascular risk Review contemporary literature likely to impact future cardiovascular guidelines Analyze new therapeutic approaches aimed at reducing cardiovascular morbidity and mortality 2

3. Overview Lipid/Lipoprotein review Review of NCEP ATP III* guideline targets Current shortfalls in CV risk assessment Recent studies of interest – INTERHEART – Emerging Risk Factors Collaboration – JUPITER Predictions?? 3 *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)

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5. Lipid Component Review Lipid Composition – Cholesterol – Triglycerides (TGY) – Phospholipids Complexed with proteins to form “Lipoproteins” – Oil and water don’t mix! – Transport cholesterol & TGY’s throughout the body – LDL, VLDL, HDL, etc. 5

6. Major Lipoproteins LDL-c HDL-c VLDL-c – (i.e., TGY/5) IDL-c Chylomicrons 6 Adapted from Pharmacotherapy – A Pathophysiological Approach 7 th edition. Dipiro et al. (McGraw – Hill, 2008).

7. Lipoproteins LDL, VLDL, IDL – Transport cholesterol in aqeuous media – All contain an apolipoprotein B subtype (ApoB) – Collectively represent the “atherogenic” components HDL – Promotes reverse cholesterol transport from cells in the vessel wall to the liver for disposal – Contain “atheroprotective” apolipoprotein A1 (ApoA1) 7

8. Lipoproteins in atherosclerosis 8

9. 9 CVD Progression

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11. 11 NCEP ATP III Released: 2001

12. NCEP ATP III Guidelines 12 “LDL is the major atherogenic lipoprotein and has long been identified by NCEP as the primary target of cholesterol-lowering therapy” “This focus on LDL has been strongly validated by recent clinical trials, which show the efficacy of LDL-lowering therapy for reducing risk for CHD”

13. NCEP ATP III Guidelines 13

14. CV biomarker shortfalls “Half of all myocardial infarctions and strokes occur despite apparently healthy men and women with LDL levels below currently recommended thresholds for treatment” 1 “Even with adequate LDL lowering, many patients on statin therapy have significant CVD risk” 2 14 1.Ridker PM, et al. Reduction in C-reactive protein and LDL cholesterol and CV events after initiation of rosuvastatin: a propective study of the JUPITER trial. Lancet. 2009:373: 1175-82. 2.Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811-22.

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16. Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811-22. 16

17. Emerging Risk Factors – ATP III excerpt 17

18. Ideal new biomarker characteristics Can the biomarker be easily, precisely, and cost-effectively measured in a clinical setting? Are there available treatment strategies to positively alter the biomarker? Are the treatment strategies effective in reducing cardiovascular events? 18 Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement for the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31: 811-22.

19. New Cholesterol/CVD Biomarkers? Non-HDL cholesterol Apolipoproteins (Apo) – Apolipoprotein A1 (ApoA1) – Apolipoprotein B (ApoB) – Apolipoprotein B/A1 ratio C-reactive Protein (CRP) LDL particle size Lipoprotein (a) Lipoprotein-Associated Phospholipase A 2 Homocysteine 19

20. Non-HDL Cholesterol 20

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22. Reasons non-HDL may be better than LDL non-HDL includes VLDL/TGY’s in risk equation – both LDL and TGY’s included Hypertriglyceridemia: – ↑ number of LDL particles (more atherogenic) – ↓ LDL size (small dense LDL are more atherogenic) – ↓ number of HDL particles (less anti-atherogenic) – ↓ HDL size (small dense HDL are less anti-atherogenic) 22

23. 23 “In other words, because non-HDL cholesterol incorporates the 2 atherogenic components, it appears overall to be a better predictor of CHD risk than LDL cholesterol alone”

24. Non-HDL trials vs. LDL Other studies demonstrating non-HDL as a better predictor of future CVD events – Cui Y, et al. Arch Intern Med. 2001 – Bittner V, et al. Circulation. 2002 – Von Muellen D, et al. Am J Cardiol. 2003 – Lu W, et al. Diabetes Care. 2003 – Farwell W, et al. Am J Cardiol. 2005 – Ridker P, et al. JAMA. 2005 – Liu J, et al. Diabetes Care. 2005 – Pischon T, et al. Circulation. 2005 – Rallidis L, et al. Atherosclerosis. 2005 – Liu J, et al. Am J Cardiol. 2006 – Everett B, et al. J Am Coll Cardiol. 2006 24

25. Non-HDL cholesterol Advantages – Already available in lipid panel lack of expense – Easy calculation – May not require a fasting state* Emerging Risk Factors & INTERHEART trial – Non-HDL goals are ↑30mg/dL than LDL goal 25

26. Apolipoproteins 26

27. Apolipoprotein B (ApoB) Where’s the evidence? – ApoB is suggested to more accurately represent the total burden of atherogenic particles – LDL-c underestimates CV risk due to small, dense LDL particles 27

28. Apolipoproteins 28 Adapted from Pharmacotherapy – A Pathophysiological Approach 7 th edition. Dipiro et al. (McGraw – Hill, 2008).

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30. ApoB trials vs. LDL Favor ApoB (vs. LDL-c) – Gotto A, et al. Circulation. 2000 – Walldius G, et al. Lancet. 2001 – Shai I, et al. Circulation. 2004 – Ridker P, et al. JAMA. 2005 – Pischon T, et al. Circulation. 2005 – Everett B, et al. J Am Coll Cardiol. 2006 – St. Pierre A, et al. Am J Cardiol. 2006 – Hsia S, et al. Am J Cardiol. 2006 – Ingelsson E, et al. JAMA. 2007 – Benn M, et al. Arterioscler Thromb Vasc Biol. 2007 30

31. ApoB advantages More trials favor CV risk predictability with ApoB than LDL, especially in statin-treated patients ApoB is accurate in a non-fasting state Practical way to estimate ApoB? calculate non-HDL cholesterol 31

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34. LDL, non-HDL, and ApoB vs. CVD Post-hoc analysis of the TNT and IDEAL trials 34 Post-hoc analysis of the TNT and IDEAL trials Kastelein J, et al. Circulation 2008; 117:3002-9.

35. INTERHEART study - July 2008 - 35 McQueen M, et al. Lipids, lipoproteins and apolipoproteins as risk marker s of myocardial infarction in 52 countries (The INTERHEART study). Lancet. 2008; 372:224-33.

36. INTERHEART results 36 McQueen M, et al. Lipids, lipoproteins and apolipoproteins as risk marker s of myocardial infarction in 52 countries (The INTERHEART study). Lancet. 2008; 372:224-33. ApoB Non-HDL HDL ApoA1

37. INTERHEART results 37 Authors interpretation: non-fasting ApoB/ApoA1 was superior to any cholesterol ratio for estimation of risk of acute MI in all ethnic groups, in both sexes, and at all ages, and should be introduced into worldwide clinical practice ApoB/ApoA1 TC/HDL

38. The Emerging Risk Factors Collaboration - November 2009 - 38

39. Emerging Risk Factors Collaboration - results 39 Non-HDL Apo B Apo A1 HDL Danesh J. The Emerging Risk Factor Collaboration. J Am Med Assoc. 2009;302:1993-2000.

40. Emerging Risk Factors Collaboration Authors conclusions – CHD risk assessment: use either lipids or apolipoproteins – Should hinge on practical considerations (cost, availability) – Fasting lipid values (vs. non-fasting) offer little value 40 Hazard Ratio 95% CI LDL1.381.09-1.73 non-HDL1.421.06-1.91 ApoB/ApoA11.491.39-1.60 non-HDL/HDL1.501.38-1.62 Danesh J. The Emerging Risk Factor Collaboration. J Am Med Assoc. 2009;302:1993-2000.

41. C-Reactive Protein (hsCRP) 41

42. High sensitivity CRP Identified as a marker of underlying systemic inflammation Shown to independently predict future vascular events Can be reduced by statin therapy 42

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44. < 1 mg/L 1 to 3 mg/L> 3 mg/L PHS 1997 WHS 2000UK 2000MONICA 2004ARIC 2004 Iceland 2004 NHS 2004 HPFUS 2004EPIC-N 2005Strong 2005Kuopio 2005FHS 2006 CHS 2005 PIMA 2005 Fully Adjusted Relative Risk hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated

45. Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in Ridker PM. Rationale and design of the JUPITER study. Circulation 2003;108:2292-97. No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela

46. JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo (251 / 8901) Rosuvastatin (142 / 8901) HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 - 44 % 01234 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581,353983544157 8,9018,6218,3536,5083,8721,9631,333955534174

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48. We certainly know nothing certain!! – Non-HDL and ApoB > LDL in CV risk prediction – Non-HDL > ApoB (but likely interchangeable) – Ratios appears better than single biomarkers – Non-HDL/HDL = ApoB/ApoA1 ratio > TC/HDL – Consider treating CRP with LDL (or whichever!) 48 Summary

49. LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPS PHS Claremore Indian Hospital Ryan.Schupbach@ihs.gov (918) 342-6455 49