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Risk factors in heart disease Optimizing patient care

Risk factors in heart disease Optimizing patient care. William Cromwell, MD, FAHA, FNLA Chief Medical Officer – LipoScience, Inc. Chief – Lipoprotein and Metabolic Disorders Institute Adjunct Associate Professor – Wake Forest University School of Medicine.

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Risk factors in heart disease Optimizing patient care

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  1. Risk factors in heart disease Optimizing patient care William Cromwell, MD, FAHA, FNLA Chief Medical Officer – LipoScience, Inc. Chief – Lipoprotein and Metabolic Disorders Institute Adjunct Associate Professor – Wake Forest University School of Medicine

  2. DisclosuresWilliam Cromwell, MD, FAHA, FNLA

  3. Current Perspectives on LDL Management • The causal link between high levels of low-density lipoprotein (LDL) and the development of CVD is well established 1 • Increased numbers of circulating LDL particles accelerates development of atherosclerotic cardiovascular disease • The longer the exposure to high LDL, the greater the risk of CVD events • Lowering LDL is a central tenet of clinical practice • 2013 ACC/AHA guidelines recommend a two step approach to managing LDL-related CVD risk 1 - Use moderate or high dose statin therapy in selected populations; - Monitor LDL levels on therapy and use clinical judgment in determining next steps in patient management. 1. Stone NJ, et al. Circulation 2014;129:S1-S45. • 2. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i. 3. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602. • 4. Cromwell WC, et al.. J ClinLipidol. 2007;1(6):583-592. • 5. Otvos JD, et al. J ClinLipidol. 2011;5(2):105-113. • 6. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177. • 7. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798. • 8. Sniderman AD. J ClinLipidol. 2008;2(1):36-42.

  4. Two Ways To Measure LDL Quantity • LDL cholesterol (LDL-C) is the traditional measure of LDL, chosen for historical, not analytic or clinical reasons. • Alternatively, LDL can be measured by particle number (LDL-P), or estimated by apolipoprotein B. • Due to differences in the amount of cholesterol contained in LDL, alternate LDL measures (LDL-C vs. LDL-P) frequently disagree (discordance).1-7 Triglycerides LDL Particle Cholesterol Triglycerides LDL-C LDL-P LDL Particle LDL-P LDL-C Cholesterol 4. Otvos JD, et al. J ClinLipidol. 2011;5(2):105-113. 5. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177. 6. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798. 7. Sniderman AD. J ClinLipidol. 2008;2(1):36-42. 1. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i. 2. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602. 3. Cromwell WC, et al.. J ClinLipidol. 2007;1(6):583-592.

  5. Alternate LDL Measures (LDL-C versus LDL-P) Multi Ethnic Study of Atherosclerosis [MESA] (n=6,697) Otvos et al. J ClinLipidol2011;5:105-13

  6. Alternate LDL Measures (LDL-C versus LDL-P) Multi Ethnic Study of Atherosclerosis [MESA] (n=6,697) LDL-P > LDL-C Less Cholesterol per Particle Discordant Measures LDL-C and LDL-P Different (50% Subjects) LDL-P < LDL-C More Cholesterol per Particle Concordant Measures LDL-C and LDL-P Similar (50% Subjects) Otvos et al. J ClinLipidol2011;5:105-13

  7. 5th 20th 50th 80th percentile 1% (n=19) 24% (n=364) 43% (n=631) 21% (n=307) 11% (n=163) Percent of Subjects 7001000 1300 1600 (nmol/L) 16% (n=147) 43% (n=377) 30% (n=260) 9% (n=76) 2% (n=15) 40% Percent of Subjects 700 1000 1300 1600 (nmol/L) Alternate LDL Measures (LDL-C versus LDL-P) Type II Diabetes Mellitus Subjects (n=2,355) LDL-C 70-99 mg/dL (5th – 20th Percentile) (n=1,484) LDL-C < 70 mg/dL(< 5th Percentile) (n=871) Cromwell WC, Otvos JD. AJC 2006;98:1599-1602

  8. Cardiovascular risk tracks with LDL particle number When alternate LDL measures (LDL-C vs LDL particle number) agree (concordance) each measure is equally associated with CVD risk. When alternate measures are discordant (e.g., diabetes, metabolic syndrome, statin therapy), risk tracks with LDL-P, not LDL-C.1-5 Alternate LDL Measures and Cardiovascular Disease 1. Cromwell WC, et al.. J ClinLipidol. 2007;1(6):583-592. 2. Otvos JD, et al. J ClinLipidol. 2011;5(2):105-113. 3. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177. 4. Sniderman AD, et al. Circ Cardio quality and outcomes. 2011;4(3):337-345. 5. Sniderman AD, et al. Atherosclerosis. Dec 2012;225(2):444-449.

  9. Associations of Alternate LDL Measures with CHD Framingham Offspring Study (n=3,066) 1.00 Better survival Lower risk Low LDL-C Low LDL-P (n=1,249) 0.98 0.96 0.94 0.92 Better Survival Lower Risk Worse survival Higher risk 0.90 High LDL-C Low LDL-P (n=284) 0.88 High LDL-C High LDL-P (n=1,251) Event-Free Survival 0.86 0.84 Worse Survival Higher Risk 0.82 Low LDL-C High LDL-P (n=282) 0.80 Concordant Discordant 0.78 0.76 0.74 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Years of Follow-up Cromwell WC et al. J ClinLipidol 2007;1(6):583-592.

  10. LDL-P and LDL-C Discordance in MESA Relations with Incident CVD Events LDL-P LDL-C MetSyn High LDL Despite Low LDL-C 54% LDL-P > LDL-C 1372 104 33% Concordant 6 16% LDL-P < LDL-C LDL-C underestimates LDL-attributable risk 117 1249 4 Cumulative Percent Incidence Low LDL Despite High LDL-C 1117 130 2 mg/dL nmol/L LDL-C overestimates LDL-attributable risk 0 1 2 3 4 5 Follow-up (years) Otvos et al. J ClinLipidol2011;5:105-13

  11. LDL-P and LDL-C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-C Discordant High LDL-P 6 4 Cumulative Percent Incidence Concordant 2 Otvos et al. J ClinLipidol2011;5:105-13

  12. LDL-P and LDL-C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-P 1 6 Discordant High LDL-P 4 ACC/AHA Threshold for Considering Statin Therapy (7.5% risk over 10 years) 2 Cumulative Percent Incidence Concordant 2 1. Otvos et al. J ClinLipidol 2011;5:105-13 2. Adapted from Stone et al. Circulation. 2013

  13. A Meta-Analysis of Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, and Apolipoprotein B as Markers of Cardiovascular Risk Allan D. Sniderman, MD; Ken Williams, MSc; John H. Contois, PhD; Howard M. Monroe, PhD; Matthew J. McQueen, MBChB, PhD; Jacqueline de Graaf, MD, PhD; Curt D. Furberg, MD, PhD Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.

  14. Study Design: Meta-analysis of all published epidemiologic studies with estimates of relative risks of fatal or nonfatal ischemic cardiovascular events and measures of non-HDL-C and apoB. 12 independent reports, including 233,455 subjects and 22,950 events, were analyzed. Major Findings: Whether analyzed individually or in head-to-head comparisons, apoB was the most potent marker of cardiovascular risk. Meta-Analysis of LDL-C, Non-HDL-C, and ApoB as Markers of Cardiovascular Risk Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.

  15. Conclusions: “The present analysis indicates that non-HDL-C is superior to LDL-C as a marker of cardiovascular risk.” “The conventional explanation would be that the gain in predictive power is due to the cholesterol in VLDL.” “The superiority of non-HDL-C over LDL-C is due to the fact that non-HDL-C is a better marker of LDL-P than LDL-C.” “When apoB and non-HDL-C are concordant, they will predict risk equally, whereas when they are discordant, apoB will be superior.” Meta-Analysis of LDL-C, Non-HDL-C, and ApoB as Markers of Cardiovascular Risk Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.

  16. LDL Subclasses: 2011 National Lipid Association Recommendations “Many studies document links between small dense LDL particles and atherosclerotic CVD.” “However, these statistical associations between small, dense LDL and CV outcomes are either significantly attenuated or abolished when the analyses are adjusted for the overall number of circulating LDL particles (LDL-P) either by adjustment for Apo B levels or by adjustment for nuclear magnetic resonance-derived LDL-P.” Adapted from Davidson, et al. J Clin Lipidol 2011;5:338-367.

  17. LDL Subclasses: 2011 National Lipid Association Recommendations “To date, there is no evidence that the shift in LDL subfractions directly translates into change in disease progression or improved outcome.” “The NLA Biomarkers Expert Panel was unable to identify any patient subgroups in which LDL subfractionation is recommended.” Adapted from Davidson, et al. J Clin Lipidol 2011;5:338-367.

  18. Expectations for Novel Risk Tests versus An Alternate Measure of an Established Target 1, Ge Y, Wang TJ. J Intern Med. 2012;272(5):430-439. 2. Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822

  19. Recommendations for Using LDL Particle Number Measures as Targets of Therapy

  20. Recommendations for Using LDL Particle Number Measures as Targets of Therapy Step 1: Stratify ASCVD risk and initiate therapy (Statin therapy if triglyceride levels < 500 mg/dL) Step 2: Assess adequacy (laboratory testing) and tolerance of therapy Step 3: If not at desired level intensify therapeutic lifestyle, consider additional therapy • Intensify statin therapy; • Consider combination statin &/or ezetimibe &/or colesevelam &/or niacin Step 4: Assess adequacy / tolerance of therapy with and consider additional therapeutic adjustment. Adapted from Garber AJ, et al. EndocrPract2013;19 (Suppl 2):1-48.

  21. Recommendations for Using LDL Particle Number Measures as Targets of Therapy

  22. “These data indicate that both Apo B and LDL-P were generally in agreement in their association with diverse clinical outcomes (58.8%), but with a substantial amount of discordance (21.2%) in which one biomarker was statistically significant whereas the other was not.” “In these cases, LDL-P showed a significant association with a clinical outcome more often than apo B alone, and the level of statistical significance, as indicated by the P value, and the strength of association, as indicated by the OR, RR, and HR, was more often higher for LDL-P than it was for apo B.” Cole TG, et al. Clinical Chemistry February 2013;59(5):752-770

  23. 2013 ACC / AHA Cholesterol Guidelines

  24. 2013 ACC / AHA Cholesterol GuidelinesOverview • Objective: Produce treatment recommendations, based on randomized controlled trial (RCT) data, to reduce atherosclerotic cardiovascular disease (ASCVD) risk. • Based on RCT data significant emphasis was placed on identifying populations most likely to benefit from statin therapy. “Because the overwhelming body of evidence came from statin RCTs, the Expert Panel appropriately focused on these statin RCTs to develop evidence-based guidelines for the reduction of ASCVD risk.” 1 1. Stone et al. Circulation. 2013

  25. ASCVD Statin Benefit Groups No Stone et al. Circulation. 2013

  26. 2013 ACC / AHA Cholesterol GuidelinesRole of LDL Testing • While acknowledging the causal role of LDL in ASCVD, due to exclusive reliance on RCT data no recommendation was made for LDL treatment goals. “The panel makes no recommendations for or against specific LDL-C or non- HDL-C targets for the primary or secondary prevention of ASCVD.” 1 • Although no goal is endorsed, LDL testing is advocated to aid clinical management • ATP III Recommendation: LDL testing was used to achieve risk-based LDL goal • 2013 ACC/AHA Recommendation: LDL testing is used to monitor therapeutic response and adherence • Modifying individual treatment requires clinical judgment. “The ultimate decision about care of a particular patient must be made by the healthcare provider and patient in light of the circumstances presented by that patient.” 1 1. Stone et al. Circulation. 2013

  27. Statin Therapy: Monitoring Therapeutic Response and Adherence Stone et al. Circulation. 2013

  28. The 2013 ACC/AHA Guideline is a starting point for population management, but is not an end point for individual care. This highlights two different opportunities to improve patient care: - Population strategy (A) – treat population with generalized therapy to achieve relative risk reduction among the group - Individual optimization strategy (B) – monitor individual response with a reliable LDL measure and adjust care as indicated. 2013 Guidelines advise clinicians to integrate these options: - Use of A and B (start with population care, followed by individual optimization based on clinical judgment) is recommended; - Use of A only(population strategy, “Fire and Forget”) is not advised. Exclusive use of a population strategy is incapable of judging individual response to statin therapy or optimizing individual management. Integrating Population Based and Individual Optimization Strategies in Practice

  29. Heterogeneous Response to High Intensity Statin Therapy Cardiovascular Events In Treat to New Target “TNT” 18 Atorva 10 mg Atorvastatin 10 mg 16 (LDL-C on-trial 101 mg/dL) Atorva 80 mg 14 Atorvastatin 80 mg 12 (LDL-C on-trial 77 mg/dL) No Benefit From Aggressive Treatment (44 %) 10 22% Reduction in Major cardiovascular events (p=0.0002) Patients with major CVD events (%) 8 6 56% Benefited From High Intensity Statin Therapy WHY? 4 2 0 0 1 2 3 4 5 # MetSyn Components Deedwania P, et al. The Lancet. 2006;368:919-928

  30. Potential Answer to TNT is Supplied by Framingham N=286 N=407 N=355 N=233 N=113 N=30 180 1800 LDL-C 170 1700 LDL-P 160 1600 With Higher LDL-P, Greater Benefit Is Expected From More Intensive LDL-P Lowering. 150 1500 LDL-C (mg/dL) LDL-P (nmol/L) 140 1400 130 1300 120 1200 1100 110 0 1 2 3 4 5 MetSyn (-) MetSyn (+)2.3x risk Kathiresan S, et al. Circulation 2006;113:20-27

  31. Relations of Change in Plasma Levels of LDL-C, Non-HDL-C and apoB With Risk Reduction From Statin Therapy: A Meta-Analysis of Randomized Trials George Thanassoulis, Ken Williams, Keying Ye, Robert Brook, Patrick Couture, Patrick R. Lawler, Jecqueline de Graaf, Curt D. Furgerg and Allan Sniderman Journal of American Heart Association 2014;3

  32. Objective: To evaluate the relationship between the reduction in alternate LDL measures (LDL-C, non-HDL-C, apoB) and observed cardiovascular benefit produced by statin therapy in randomized, placebo controlled trials. “The marker whose reduction relates most directly to benefit should also be the marker that is best to identify those whose outcome might be improved by further lipid lowering.” Meta-analysis was performed using both frequentist and Bayesian methods. Meta-Analysis of LDL Measures and Risk Reduction from Statin Therapy Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759

  33. Studies Selected: Analyzed all published, placebo-controlled studies, which have reported baseline and on-treatment levels of LDL- C, non-HDL-C, and apoB. Meta-Analysis of LDL Measures and Risk Reduction from Statin Therapy Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759

  34. Findings: Relative risk reduction from statin therapy in the 7 major placebo-controlled statin trials demonstrated: Risk reduction was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C. Changes in non-HDL-C and LDL-C appeared to be statistically indistinguishable with respect to risk reduction of statin therapy. Within trial “head-to-head” comparisons of cardiovascular risk relationship with individual LDL markers : LDL-C was 2.4% (- 3.6%, 8.4%) > non-HDL-C (P=0.445) apoB was 21.6% (12.0%, 31.2%) > LDL-C (P<0.001) apoB was 24.3% (22.4%, 26.2%) > non-HDL-C (P<0.001). Meta-Analysis of LDL Measures and Risk Reduction from Statin Therapy Thanassoulis G, et al. J Am Heart Assoc. 2014;3:e000759

  35. Cardiovascular Risk in Patients Achieving Low-Density Lipoprotein Cholesterol and Particle Targets Peter P. Toth , MD, PhD Michael Grabner , PhD Rajeshwari S. Punekar , PhD Ralph A. Quimbo , MA Mark J. Cziraky , PharmD Terry A. Jacobson , MD Atherosclerosis 2014;235(2):585-591

  36. Study Design • Claims data between 2006 and 2012 were used to identify eligible patients achieving LDL-P <1000 nmol/L (LDL-P cohort) and patients achieving LDL-C<100 mg/dL (LDL-C cohort) without LDL-P measurements. • Demographic and comorbidity differences between the two cohorts were balanced using propensity score matching however, treatment patterns were left intact. Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

  37. Baseline Characteristics for Patients with ≥ 12 Months of Follow-Up Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

  38. Baseline Characteristics for Patients with ≥ 12 Months of Follow-Up Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

  39. Study Results At every follow-up interval the LDL-P cohort demonstrated: Significant risk reduction (Hazard Ratio): • 24% at 12 months • 22% at 24 months • 25% at 36 months Significant event reduction (Number of patients with CHD/stroke events) • 1.8% (8.12% - 6.26%) at 12 months • 2.9% (13.9% - 11.0%) at 24 months • 4.4% (19.0% - 14.6%) at 36 months Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

  40. Study Results Another metric of event reduction is the “Number Needed to Treat” (NNT). • NNT = 1 / Event Reduction • Represents the number of subjects needed to treat to prevent 1 event. (i.e., number of subjects needed to attain LDL-P <1000 vs LDL-C <100 to prevent 1 CHD/stroke event). 2.9 Adapted from Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

  41. Number Needed to Treat 2014;235(2):585-591.

  42. Approach to the Use of LDL in Clinical Practice Step 1: Stratify ASCVD risk (does not require LDL-P) Step 2: Institute appropriate course of treatment. Step 3: Use a reliable, FDA cleared, outcome proven LDL measure to monitor adherence and response among those treated. Step 4: Use clinical judgment in considering the need to modify individual therapy. Step 5: After modifying therapy, use a reliable, FDA cleared, outcome proven LDL measure to assess patient response. Use clinical judgment to consider modifications of treatment as indicated to optimize care.

  43. Selected Strategies to Reduce Particle Number Improve LDL Particle Clearance (remove more) Reduce LDL Particle Production (make less) • Statins • (35-55% 6 LDL-P) • Gut agents • Ezetimibe • (15-30% 6 LDL-P) • Resins / Bile Acid Sequestrates • (15-30% 6 LDL-P) • Statin + Gut (50-70% 6 LDL-P) • Statin + Gut + Niacin (> 60% 6 LDL-P) • Diet • Exercise • Weight Loss • Glycemic Control • Co-Morbidity Management • (up to 30-50% 6 LDL-P) • Marine Omega-3 • DHA + EPA • (no 6 LDL-P) • EPA Only • (4-15 % 6LDL-P) LDL-P Target Adapted from Cromwell W, Dayspring T. Lipid and lipoprotein disorders: Current clinical solutions. Baltimore: International Guideline Center; 2012.

  44. Conclusions • Guidelines recommend a two step approach to managing LDL-related CVD risk: 1 • Use moderate or high dose statin therapy in selected populations; • Monitor LDL levels on therapy and use clinical judgment in determining next steps in patient management. • Because CVD risk tracks with apoB and NMR LDL-P 2-6, and because frequent discordance exists between LDL-C and measures of LDL-P 2-4,7-10, many expert panels advocate use of LDL particle number to adjudicate response and optimize individual therapy.11-13 • Clinical utilization data confirms a significant reduction of CVD risk and events among high risk patients attaining low NMR LDL-P (mean 860 nmol/L) versus statin treated subjects with low LDL-C (mean 79 mg/dL).14 1. Stone NJ, et al. Circulation 2014;129:S1-S45. 2. Cromwell WC, et al.. J ClinLipidol. 2007;1(6):583-592. 3. Otvos JD, et al. J ClinLipidol. 2011;5(2):105-113. 4. Sniderman AD, et al. Am J Cardiol. 2003;91(10):1173-1177. 5. Sniderman AD, et al. Circ Cardio quality and outcomes. 2011;4(3):337-345. 6. Sniderman AD, et al. Atherosclerosis. Dec 2012;225(2):444-449. 7. Otvos JD, et al. Am J Cardiol. 2002;90(8A):22i-29i. 8. Sniderman AD, et al. Am J Cardiol. 2001;87(6):792-793, A798. 9. Cromwell WC, Otvos JD. Am J Cardiol. 2006;98(12):1599-1602. 10. Sniderman AD. J ClinLipidol. 2008;2(1):36-42. 11. Contois JH et al. Clin Chem. 2009;55:407-419. 12. Davidson MH et al. J Clin Lipidol. 2011;5:338-367. 13. Garber AJ, et al. Endocr Pract 2013;19(Suppl 2):1-48. 14. Toth PP, et al. Atherosclerosis 2014;235(2):585-591.

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