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Confirmation of Lipid Hypothesis in SEAS: Ischemic Morbidity Risk Stratification without Lipids?

This presentation discusses the confirmation of the lipid hypothesis in the SEAS trial and explores the relationship between lipoprotein components and ischemic cardiovascular events. The aim is to assess the risk stratification of ICE and develop a prognostic model for these events.

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Confirmation of Lipid Hypothesis in SEAS: Ischemic Morbidity Risk Stratification without Lipids?

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  1. MasterClassLipidInnovations Prague, Czech Republic May 27-28, 2011 The concept of Diabetes & CV risk:A lifetime risk challenge Presentation topic Confirmation of lipid hypothesis in SEAS: Ischemic morbidity risk stratification without lipids? Slide lecture prepared and held by: Prof. Ingar Holme PhD, Oslo University Hospital Ulleval Center for Preventive Medicine Oslo, Norway

  2. Randomized double-blind multicentre trial Comparison S+E (40 + 10 mg) vs. placebo 1873 patients with asymptomatic aortic stenosis Endpoints: Aortic valve replacement and cardiovascular clinical events

  3. LDL-Cholesterol Intention to Treat Population 4 150 Placebo 125 3 100 mmol/L 2 75 Mean (mg/dL) ±SE 50 EZ/Simva 10/40 mg 1 25 0 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Year N Engl J Med 2008;359:1343-56.

  4. Lipid-changes in SEAS at Year 1 Intention-to-Treat Population Non– HDL-C Placebo LDL-C Total-C HDL-C TG E/S 10/40 mg * * Mean % Change from Baseline * * * *P<0.001 vs placebo N Engl J Med 2008;359:1343-56.

  5. Proportional Reduction in MCE by Mean Reduction in LDL-C: CTT- Analysis 50 40 30 % 20 10 0 0,5 1.0 1.5 2.0 Reduction in LDL cholesterol (mmol/L) CTT Collaborators. Lancet 2005;366:1267-78

  6. Intention to Treat Population 50 Placebo 40 Hazard ratio: 0.96, p=0.591 30 Percentage of Patients With First Event EZ/Simva 10/40 mg 20 10 0 0 1 2 3 4 5 Years in Study No. at Risk EZ/Simva 10/40 mg 906 817 713 618 53 Placebo 884 791 696 586 56 Primary EndpointMajor Cardiovascular Events N Engl J Med 2008;359:1343-56.

  7. 50 Intention to Treat Population 40 Placebo Hazard ratio: 1.00, p=0.968 30 Percentage of Patients With First Event 20 EZ/Simva 10/40 mg 10 0 0 1 2 3 4 5 Years in Study No. at risk EZ/Simva 10/40 mg 915 837 734 640 55 Placebo 896 816 728 618 61 Aortic Valve Replacement N Engl J Med 2008;359:1343-56.

  8. 30 Intention to Treat Population Hazard ratio: 0.78, p=0.024 Placebo 20 EZ/Simva 10/40 mg 10 0 0 1 2 3 4 5 Years in Study 2nd EP:Ischemic CV Events (ICE) Percentage of Patients With First Event No. at risk EZ/Simva 10/40 mg 917 867 823 769 76 Placebo 898 838 788 729 76 N Engl J Med 2008;359:1343-56.

  9. Intention to Treat Population Hazard ratio: 0.68, p=0.015 20 Percentage of Patients With First Event Placebo 10 EZ/Simva 10/40 mg 0 0 1 2 3 4 5 Years in Study No. at risk EZ/Simva 10/40 mg 925 887 848 797 80 Placebo 909 862 819 761 80 Coronary Artery Bypass Grafting (CABG) 30 N Engl J Med 2008;359:1343-56.

  10. # of Events Placebo EZ/Simva 355 333 56 47 278 267 23 25 26 17 100 69* 17 8 8 5 29 33 Primary events - Components ITT Population Hazard Ratio (95% CI) Endpoints Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Non hem. Stroke *p=0.02 vs Placebo 0.1 1.0 10.0 Favors EZ/Simva 10/40 mg Favors Placebo N Engl J Med 2008;359:1343-56.

  11. Aims • Explore relationships between on-treatment lipoprotein components (LC) and ICE risk in SEAS, and by severity of AS at baseline • ICE risk reduction predicted (estimated) from reductions in atherogenic LC compared to observed risk within SEAS • AS severity assessed by baseline peak transaortic jet velocity (JV) categorized into thirds • To explore if risk stratification of ICE is possible • By developing a prognostic model for ICE American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  12. Lipid Components (LC) and Ischemic Cardiovascular Event relationship • Analysis of 1,570 SEAS patients • Complete baseline JV data • Baseline and 1-year LDL-C, HDL-C, and ApoB • No ICE during first year • Baseline JV thirds with split points of 2.79 and 3.33 m/sec • Relationship between Year-1 LC measurements (combined treatment groups) and time-to-ICE (dependent variable) assessed totally and in JV thirds by Cox models with time-fixed and time-varying LC covariate • Mean treatment group differences in Year 1 LC were calculated to approximate observed average difference in LC exposure (for time fixed estimations) American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  13. Characteristics by thirds • Variable Third 1 Third 2 Third 3 • n= 534 n=514 n=522 • Jet Vel. Range (m/s) < 2.8 2.8 – 3.3 > 3.3 • Jet Vel. Mean (m/s) 2.50 3.06 3.72 • Age Mean (years) 66.9 67.4 67.3 American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  14. Mean LDL-C Levels at Baseline and Year 1: Combined Treatment Groups mmol/L American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  15. Incidence of ischemic events by baseline AS severity % HR=1.10 p=0.80 HR=0.63 HR=0.54 p=0.033 p=0.004 Aortic jet velocity m/sec American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  16. Endpoint Incidence from Year 1 onwards % American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  17. Distribution of first ICE % American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  18. Hazard Ratios for ICE per SD Increase in Lipid Component at Year 1 American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  19. Estimated and Observed Hazard Ratios for ICE Risk at Year 1 Third 1 LDL-C 0.51 (0.33 – 0.77) Non-HDL-C 0.45 (0.29 – 0.69) ApoB 0.46 (0.31 – 0.68) TC/HDL-C 0.54 (0.40 – 0.73) Observed 0.53 (0.31 – 0.92) 0.25 0.50 0.75 1.00 1.25 1.50 Reduced Risk Increased Risk American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  20. Estimated and Observed Hazard Ratios for ICE Risk at Year 1 Third 2 LDL-C 0.65 (0.45 – 0.96) Non-HDL-C 0.65 (0.45 – 0.94) ApoB 0.62 (0.43 – 0.89) TC/HDL-C 0.72 (0.54 – 0.97) Observed 0.64 (0.38 – 1.06) 0.25 0.50 0.75 1.00 1.25 1.50 Reduced Risk Increased Risk American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010 .

  21. Estimated and Observed Hazard Ratios for ICE Risk at Year 1 Third 3 LDL-C 0.93 (0.70 – 1.24) Non-HDL-C 0.95 (0.72 – 1.27) ApoB 0.89 (0.68 – 1.16) TC/HDL-C 0.95 (0.75 – 1.21) Observed 1.02 (0.71 – 1.46) 0.25 0.50 0.75 1.00 1.25 1.50 Reduced Risk Increased Risk American Journal of Cardiology Volume 105, Issue 12 , Pages 1802-1808, 2010

  22. ICE Reduction by LDL-C Lowering: SEAS vs CTT SEAS T1 SEAS T2 Proportional Reduction in Vascular Event Rate (SE) SEAS T3 Reduction in LDL-C (mmol/L)

  23. LIMITATIONS • Internal validations • Post hoc • Subgroup analysis • Limited statistical power • External validations • Meta analysis based on non-AS populations • Higher risk populations

  24. Part CONCLUSION • Changes in lipid components predicted reductions in ICE as observed when patients with mild AS were treated with S+E • Changes in lipid components were not predictive of ICE in patients with severe AS, probably due to • confounding of aortic valve related endpoints • shorter exposure to therapy before endpoint • There is no indication that lipid lowering with S+E is less efficient per mmol/l reduction on ICE than S alone, given the limitations

  25. Prognostic model for ICE • Potential baseline RF searched for among • Echo cardiographic • Biochemical • Anthropometric • Physiological • Requirement • Age, sex, smoking, TRT group forced into model • All with P<0.01 in univariate analysis • No pairs should be highly correlated (r<0.70)

  26. Risk stratification by prognostic function • Risk in Third 1 of estimated probability of ICE: 25 (10.4 %) • Risk in Third 2 of estimated probability of ICE : 46 (19.2 %) • Risk in Third 3 of estimated probability of ICE : 73 (30.4 %) • Prognostic function indicates a tripling of risk in upper as compared to lower third • Calibration statistics by deciles of estimated probability of ICE: Hosmer-Lemeshow Chi square = 14.5 (P=0.106)

  27. Why is TRT effective, while not prognostic? • Treatment effectiveness measured on relative scale by OR or HR between TRT groups • Prognostic model seeks to estimate and explain the individual variation in absolute risk: • Mean: 14.2 % with SD=14.5 % • Variation in estimated absolute risk: 0-70 % • Absolute reduction in ICE risk due to 1 SD reduction in apoB: 14.2*(1-0.755) %= 3.5 %. • This is a sizeable clinical reduction, but explains only 3.5/14.5*100 = 24 % of the individual usual between-person variation in absolute risk.

  28. Conclusions • Baseline LC did not associate strongly to ICE • Discrimination ability was moderately high for the selected factors. • The ICE risk was tripled from lower to upper third of estimated risk. • In-trial apoB associated strongly to ICE and was clearly the strongest among LC. • Added discrimination ability of apoB showed some added value (placebo), but less than regarded as clinically significant (>=0.02 area units) • Although 1 SD apoB reduction predicts a sizeable clinical effect, it would explain relatively little of the between person variability of the probability of ICE.

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