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ASTEROID

ASTEROID. A S tudy T o evaluate the E ffect of R osuvastatin O n I ntravascular ultrasound- D erived coronary atheroma burden Name Title Affiliation .

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ASTEROID

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  1. ASTEROID AStudy To evaluate the Effect of Rosuvastatin On Intravascular ultrasound-Derived coronary atheroma burden Name Title Affiliation  Reference: Nissen S et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006; 295: e-publication ahead of print (doi:10.1001/jama.295.13.jpc60002)

  2. ASTEROID • ASTEROID used intravascular ultrasound (IVUS) to evaluate the effect of rosuvastatin (CRESTOR™) on atherosclerotic disease in patients with coronary artery disease (CAD) • It investigated whether rosuvastatin can induce regression of the volume of coronary artery atheroma

  3. Angiography underestimates atherosclerotic burden Patients (n=44) with suspected CAD and normal angiograms Atheroma on IVUS No atheroma on IVUS 52% 48% CAD=coronary artery disease; IVUS=intravascular ultrasoundErbel R et al. Eur Heart J 1996; 17: 880–889

  4. LDL-C levels correlate withangiographic progression 0.06 PLAC-1 0.05 REGRESS LCAS-1 CCAIT 0.04 MLDdecrease(mm/y) PLAC-1 0.03 MARS MAAS CCAIT 0.02 MARS Treatment REGRESS Placebo LCAS 0.01 ? MAAS 0 2.1 80 3.1120 2.6100 4.1 160 4.7 180 3.6 140 LDL-C (mmol/L, mg/dL) LDL-C=low-density lipoprotein cholesterol; MLD=minimum lumen diameterr2=0.71; p=0.0005Adapted from Ballantyne CM et al. Curr Opin Lipidol 1997; 8: 354–361

  5. The IVUS coronary imaging technique Rotating transducer Normal coronary anatomy Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

  6. The IVUS technique can detect angiographically ‘silent’ atheroma Angiogram IVUS No evidence of disease Little evidence of disease Atheroma IVUS=intravascular ultrasoundNissen S, Yock P. Circulation 2001; 103: 604–616

  7. Rationale • Angiographic studies indicate that substantial LDL-C reductions (≥40%) are needed to slow progression of arterial stenosis • Although quantitative coronary angiography (QCA) is widely used to measure luminal narrowing, it may underestimate atherosclerotic burden • IVUS allows tomographic assessment of lumen area, plaque size and composition • Studies are required to assess the effects of intensive lipid lowering on progression/regression of atherosclerosis measured using IVUS

  8. Objective • The primary objective of ASTEROID was to evaluate whether long-term treatment with rosuvastatin 40 mg in CAD patients resulted in regression of coronary artery atheroma burden, as assessed by the percentage atheroma volume (PAV) in the entire segment length of the artery assessed and total atheroma volume (TAV) in the most severely diseased segment, as measured using IVUS

  9. ASTEROID – study design Patients CAD, undergoing coronary angiography Target coronary artery: ≤50% reduction in lumen diameter of ≥40 mmsegment No cholesterol entry criteria ≥18 years Rosuvastatin 40 mg (n=349 evaluated serial IVUS examinations) 2 0 3 13 4 26 5 39 6 52 7 65 8 78 9 91 10 104 1 –6 Visit: Week: Eligibilityassessment IVUSLipids Tolerability IVUSLipidsTolerability LipidsTolerability Tolerability LipidsTolerability Tolerability Tolerability CAD=coronary artery disease; PCI=percutaneous coronary intervention; IVUS=intravascular ultrasound

  10. Study endpoints Primary Dual endpoints assessed by IVUS: • change in PAV in the entire segment of coronary artery assessed • change in TAV in the most severely diseased 10mm segment of the coronary artery Secondary • change in TAV within the entire segment assessed by IVUS • percentage change from baseline in lipid and lipoprotein levels PAV = percentage atheroma volume, TAV = total atheroma volume

  11. EEM Area LumenArea (EEM area — Lumen Area) IVUS Determination of Atheroma Area Precise Planimetry of EEM and Lumen Bordersallows calculation of Atheroma Cross-sectional Area Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory EEM = External Elastic Membrane

  12. IVUS efficacy measures (EEM – Lumen)CSA EEM Area (EEM – Lumen)CSA Changein PercentAtheromaVolume   X 100 X 100 – n n = LumenArea EEMCSA EEMCSA (baseline) (Month 24) (EEM – Lumen) Most diseased contiguous10 cross-sections Normalized* Total Atheroma Volume (EEMCSA - LumenCSA) number cross-sectionsin patient’s pullback median number cross-sections for all patients x = * Normalized = adjusting for pullbacks of differing lengths thereby resulting in an equal weighting of each individual patient

  13. Major inclusion criteria • Clinical indication for cardiac catheterisation • Angiographic evidence of CAD • entire coronary circulation: ≥1 lesion in a native coronary artery has >20% reduction in lumen diameter • target coronary artery: ≤50% reduction in lumen diameter throughout a ≥40 mm segment • No cholesterol entry criteria • Men or women aged ≥18 years

  14. Major exclusion criteria • Statin naïve requirement - treatment with lipid-lowering therapy for not more than 3 months within the last 12 months • NYHA Class III or IV congestive heart failure, LVEF <0.35, recent coronary bypass surgery or clinically significant heart disease likely to require surgical intervention • Active liver disease or hepatic dysfunction (ALT, AST or bilirubin ≥1.5 x ULN) • Uncontrolled diabetes mellitus (HbA1c ≥10%) • Uncontrolled hypertension (≥200/100 mmHg) • CK >3 x ULN

  15. Baseline characteristics - demographics Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  16. Baseline characteristics – concomitant medication Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  17. Baseline characteristics - lipids *3 out of 349 patients completing the trial were missing lab data Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  18. Endpoint analysis: Change in median percentage atheroma volume - 0.79% * * p<0.001 for difference from baseline values. Wilcoxon signed rank test Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  19. Endpoint analysis: Change in key IVUS parameters - 6.8% * - 9.1% * * p<0.001 for difference from baseline. Wilcoxon signed rank test Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  20. Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print Baseline and follow-up IVUS results SD = standard deviation; IQR = interquartile range; *distribution free 97.5% confidence interval for the median #distribution free 95% confidence interval for the median ~ a Bonferroni correction (<0.025) was pre-specified and applied to correct for 2 primary efficacy endpoints; a Wilcoxon signed rank test for comparisons to baseline; NA = not applicable

  21. Number (%) of patients showing regression measured by each IVUS parameter 78 % Normalised total atheroma volume (TAV) IVUS parameter measured Atheroma volume in the most diseased 10 mm subsegment 78 % 64 % Percent atheroma volume (PAV) Percentage of patients showing regression Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  22. Example of regression of atherosclerosis with rosuvastatin in ASTEROID, measured by IVUS Baseline IVUS Atheroma Area 10.16 mm2 Lumen Area 6.19 mm2 Follow-up IVUS 24 months rosuvastatin Atheroma Area 5.81 mm2 Lumen Area 5.96 mm2 Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  23. Percentage change# in LDL-C, HDL-C, TC & LDL-C/HDL-C Ratio * 15% - 34% * - 53% * - 59% * LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TC=total cholesterol # from time weighted average throughout the duration of therapy; * p<0.001 Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  24. Progression Regression Relationship between LDL-C levels and change in percent atheroma volume for several IVUS trials 1.8 REVERSAL pravastatin R2 = 0.97 P<0.001 CAMELOT placebo 1.2 Median change in Percent Atheroma Volume(%) 0.6 REVERSAL atorvastatin A-Plus placebo 0 -0.6 ASTEROID rosuvastatin -1.2 50 80 60 70 100 110 90 120 Mean LDL-C (mg/dL) Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  25. Change in IVUS by pre-specified subgroups – demographic characteristics *Wilcoxon signed rank test for comparisons to baseline PAV = Percent Atheroma Volume Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  26. Change in IVUS by pre-specified subgroups – average on treatment LDL-C *Wilcoxon signed rank test for comparisons to baseline PAV = Percent Atheroma Volume Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  27. Change in IVUS by pre-specified subgroups – average on treatment HDL-C *Wilcoxon signed rank test for comparisons to baseline PAV = Percent Atheroma Volume Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  28. Tolerability • In ASTEROID, rosuvastatin 40mg was taken by more than 500 patients in this 2 year study. • Rosuvastatin 40mg was well tolerated with a safety profile consistent with the existing extensive safety database • Increases in ALT* were low (0.2%) • There were no clinically significant increases in CK# observed in the core laboratory and there were no cases of rhabdomyolysis • The number of clinical events in the study was too small for any meaningful analysis of the relationship between progression rate and morbidity or mortality *ALT>3xULN on two consecutive visits # CK >10 ULN Ref: Nissen S et al. JAMA 2006; 295: e-publication ahead of print

  29. Summary • ASTEROID showed that regression of atherosclerosis can be achieved with intensive statin therapy using rosuvastatin 40mg • Rosuvastatin 40mg produced significant regression of atherosclerosis for all three IVUS measures assessed • Regression occurred in 4 out of 5 patients and in virtually all subgroups evaluated, including men and women, older and younger patients and in most subgroups defined by lipid levels. • Regression of atherosclerosis was associated with a substantial reduction of LDL-C (-53%) combined with a significant increase in HDL-C (15%). • Analysis of results from ASTEROID and other previously conducted IVUS trials confirms the strong correlation between LDL-C reduction and reduction in atheroma volume • Rosuvastatin 40mg was well tolerated with a safety profile consistent with the existing extensive safety database

  30. Clinical implications • Atherosclerosis is the underlying cause of heart disease - the World’s number one killer • Rosuvastatin is the first and only statin that has been shown to reduce atheroma and reverse established atherosclerosis in a major clinical study; rosuvastatin 40 mg produced significant regression of atherosclerosis for all three IVUS measures assessed • While other statins have tried to demonstrate this effect, only rosuvastatin has produced this unprecedented reduction in plaque volume in a large clinical trial. • These landmark results, backed by established superiority in lowering LDL-C and raising HDL-C, further confirm rosuvastatin as an effective and well-tolerated product for the treatment of high cholesterol

  31. Acknowledgements • The ASTEROID Steering Committee: • S Nissen (Chairman), Cleveland, OH, USA • C Ballantyne, Houston, TX, USA • J Davignon, Montreal, Canada • R Erbel, Essen, Germany • J Fruchart, Lille, France • P Libby, Boston, MA, USA • J-C Tardif, Montreal, Canada • J Raichlen, AstraZeneca, Wilmington, DE, USA • V Cain, AstraZeneca, Wilmington, DE, USA • The ASTEROID investigators and patients participating in the study • This study was supported by AstraZeneca

  32. Supplementary slides

  33. Percentage change# in other lipid and lipoprotein levels nonHDL-C=non-high-density lipoprotein cholesterol; TG=triglycerides; Apo=apolipoprotein; #from time weighted average throughout the duration of therapy

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