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CPT 83704 - Coverage Decision

LDL Particle Number as Measured by NMR. CPT 83704 - Coverage Decision. Agenda. Introductions LDL Particle Number and Weight of Evidence Questions Next Steps. Attendees. Dr. James A. Underberg, MS, MD, FACPM, FACP,FNLA NYU Medical School - James.Underberg@nyumc.org

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CPT 83704 - Coverage Decision

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  1. LDL Particle Number as Measured by NMR CPT 83704 - Coverage Decision

  2. Agenda • Introductions • LDL Particle Number and Weight of Evidence • Questions • Next Steps

  3. Attendees • Dr. James A. Underberg, MS, MD, FACPM, FACP,FNLA NYU Medical School - James.Underberg@nyumc.org • Dr. Jim Otvos – Chief Scientific Officer, LipoScience – jotvos@liposcience.com • Jim Fries – Vice President, Scientific Development, LipoScience – jfries@liposcience.com • Steve Adams – Manager, Payer Relations – LipoScience – sadams@liposcience.com

  4. Rationale for Coverage • Aetna covers apoB, which is a marker for LDL-P • Weight of evidence concludes that managing residual risk in the Cardiometabolic patient is best done through LDL-P • NMR as a clinical standard of care for the at risk patient helps Aetna better manage their covered lives • FDA cleared • Specific CPT code (83704) makes it easy to track

  5. “… all abnormalities in plasma lipidconcentrations, or dyslipidemia, can be translated into dyslipoproteinemia.” “… the shift of emphasis to lipoproteins offers distinct advantages in the recognition and management of such disorders.” LDL-C is the focus of clinical attention for historical and analytical reasons Fredrickson et al., NEJM 1967; 276: 148

  6. Explanation of LDL LDL = Low Density Lipoprotein LDL-C = the amount of cholesterol contained in all LDL particles LDL-P = LDL particle concentration

  7. POLAR SURFACE COAT Phospholipid Free cholesterol Apo B This is an LDL Particle NONPOLAR LIPID CORE Cholesterol Ester Triglyceride This is LDL Cholesterol Lipids vs. Lipoproteins A convenient analytic surrogate of LDL since 1972

  8. Up to 70% More Particles 100 mg/dL 100 mg/dL Cholesterol Balance Among Individuals At The Same LDL-C Level, The Number of LDL Particles Varies Large LDL Small LDL

  9. Up to 40% More Particles 100 mg/dL 100 mg/dL Cholesterol Balance Among Individuals At The Same LDL-C Level, The Number of LDL Particles Varies Normal Cholesterol Carried Per Particle Less Cholesterol Carried Per Particle

  10. LDL treatment targets are consensus, population-based (not derived from clinical trials comparing different targets) Percentile: 20th 50th 80th Optimal Low High LDL Cholesterol Percent of Subjects Framingham Offspring 70 100 130 160 190 220 250 mg/dL LDL Particle Number Percent of Subjects MESA 700 1000 1300 1600 1900 2200 2500 nmol/L

  11. LDL Particle Number is Highly Heterogeneous Among Patients with Type 2 Diabetes Mellitus at LDL Cholesterol Target Goal <100 mg/dL W.C. Cromwell and J.D. Otvos Am J Cardiol. 2006;98:1599-1602

  12. LDL Cholesterol and LDL ParticleNumbers in T2DM Patients with LDL-C < 100 mg/dL (n=2,355) 5th 20th 50th 80th percentile 37% (n=870) 63% (n=1485) LDL-C Percent of Subjects 70 100 130 160 (mg/dL) 7% (n=162) 31% (n=741) 38% (n=891) 16% (n=383) 8% (n=178) Percent of Subjects 24% LDL-P 700 1000 1300 1600 (nmol/L) Am J Cardiol. 2006;98:1599-1602

  13. LDL ParticleNumber Distribution in T2DM Subjects 5th 20th 50th 80th percentile 1% (n=19) 24% (n=364) 43% (n=631) 21% (n=307) 11% (n=163) 32% LDL-C 71-99 mg/dL (n=1,484) Percent of Subjects 700 1000 1300 1600 (nmol/L) 16% (n=147) 43% (n=377) 30% (n=260) 9% (n=76) 2% (n=15) 41% LDL-C < 70 mg/dL (n=871) Percent of Subjects 700 1000 1300 1600 (nmol/L) Am J Cardiol. 2006;98:1599-1602

  14. Weight of Evidence

  15. Better survival Lower risk Low LDL-C Low LDL-P (n=1,249) Worse survival Higher risk High LDL-C High LDL-P (n=1,251) CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study (n=3,066) Event-Free Survival Concordant Discordant Years of Follow-up Cromwell WC et al. J Clin Lipidology 2007;1(6):583-592.

  16. Better survival Lower risk Better survival Lower risk Low LDL-C Low LDL-P (n=1,249) High LDL-C Low LDL-P (n=284) Worse survival Higher risk Worse survival Higher risk High LDL-C Low LDL-P (n=284) High LDL-C High LDL-P (n=1,251) Event-Free Survival Low LDL-C High LDL-P (n=282) Low LDL-C High LDL-P (n=282) Years of Follow-up CHD Event Associations of LDL-P versus LDL-C Framingham Offspring Study (n=3,066) Concordant Discordant Cromwell WC et al. J Clin Lipidology 2007;1(6):583-592.

  17. LDL and HDL Particle Subclasses Predict Coronary Events and are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT) Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara J, Bloomfield HE, Robins SJ Circulation 2006;113:1556-63

  18. Alternative Measures of LDL as Predictors of CHD Events in VA-HIT p<0.001 Odds Ratio per 1-SD Increment of on-trial value p=0.17 p=0.25 LDL-C Non-HDL-C LDL-P Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Circulation 2006;113:1556-63

  19. Alternative Measures of HDL as Predictors of CHD Events in VA-HIT p<0.001 Odds Ratio per 1-SD Decrement of on-trial value p=0.42 HDL-C HDL-P Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Circulation 2006;113:1556-63

  20. ADA/ACC Consensus StatementA need for better lipoprotein Management

  21. Lipoprotein abnormalities are common findings in patients with CMR. Measurement of LDL cholesterol may not accurately reflect the true burden of atherogenic LDL particles, especially in those with typical lipoprotein abnormalities of CMR. Even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual CVD risk. Treatment targets and the best approach for CVD risk reduction in this population need to be better defined. Some have advocated that assessment of other lipoprotein parameters might be more helpful than assessment limited to LDL-C or non-HDL cholesterol in these populations. ADA/ACC Consensus StatementA need for better lipoprotein management

  22. “A more accurate way to capture the risk posed by LDL may be to measure the number of LDL particles directly using nuclear magnetic resonance (NMR).” “Measurements of apoB or LDL particle number by NMR may more closely quantitate the atherogenic lipoprotein load. “ApoB and LDL particle number also appear to be more discriminating measures of the adequacy of LDL lowering therapy than are LDL cholesterol or non-HDL cholesterol.” ADA/ACC Consensus StatementKey Findings on LDL-P by NMR

  23. Step 1: Assess clinical CHD risk: Very-High, High, Moderate-High Risk Step 2: Establish targets of therapy appropriate for degree of clinical risk present Very-High and High Risk LDL-P < 1000 nmol/L Moderately-High Risk LDL-P NMR < 1300 nmol/L Step 3: Laboratory evaluation Step 4: Clinical intervention as indicated to achieve targets: Primary target: LDL Secondary targets: HDL and TG Step 5: Assess response to therapy and modify intervention as indicated to achieve LDL-P target Approach to Clinical Utilization of NMR LDL-P

  24. Conclusions • 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. • Achievement of LDL-P treatment goals ensures that the patient has achieved adequate LDL reduction. • LDL size (“quality”) does not contribute to risk once LDL particle number is taken into account. • The weight of clinical and scientific evidence should lead us to coverage of LDL-P (CPT 83704)

  25. New Evidence Supporting the use of LDL-P and HDL-P

  26. Outcome • 3026 Major Coronary Events (MI, coronary death, revascularization) during 5-yr follow-up. Heart Protection Study (confidential results) • Randomized trial of simvastatin vs placebo in >20,000 high-risk adults. • NMR analyses of stored plasma samples: 10,085 on statin; 10,057 on placebo. Confidential; unpublished data

  27. Prediction of Major Coronary Events in HPS by LDL-Related Variables LDL-C Non-HDL-C Apo B LDL-P Improvement in Model Fit (2) From Cox regression models predicting 3026 MCEs (MI, coronary death, revascularization), adjusted for age, sex, smoking, SBP, prior disease, eGFR, and treatment allocation. Confidential; unpublished data

  28. Prediction of Major Coronary Events in HPS by HDL-Related Variables HDL-C Adjusted for LDL-P Apo A1 HDL-P Improvement in Model Fit (2) From Cox regression models predicting 3026 MCEs (MI, coronary death, revascularization), adjusted for age, sex, smoking, SBP, prior disease, eGFR, and treatment allocation. Confidential; unpublished data

  29. Prediction of Major Coronary Events in HPS by LDL + HDL-Related Variables LDL-C + HDL-C Apo B + Apo A1 LDL-P + HDL-P Improvement in Model Fit (2) From Cox regression models predicting 3026 MCEs (MI, coronary death, revascularization), adjusted for age, sex, smoking, SBP, prior disease, eGFR, and treatment allocation. Confidential; unpublished data

  30. Multi-Ethnic Study of Atherosclerosis (MESA) • Large NHLBI observational study of the pathogenesis and progression of subclinical atherosclerosis. • Baseline NMR measurements of entire cohort. Outcomes • 319 CVD events during 5.5-yr follow-up (n=5,598). Confidential; unpublished data

  31. Cumulative Incidence of CVD Events in MESA in Subgroups with Low LDL-C, Low LDL-P, or Both From proportional hazards regression analyses adjusted for age, sex, race, SBP, smoking, hypertension rx, BMI, and diabetes. Confidential; unpublished data

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