ASTEROID A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden References Nissen et al. Effect.

ASTEROID A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden References Nissen et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006;295(13): Ballantyne et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography in ASTEROID. Circulation 2008;in press.

ASTEROID Use of intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA) to evaluate the effect of rosuvastatin on atherosclerotic disease in patients with coronary artery disease (CAD)

IVUS Coronary Imaging Technique
Rotating transducer Normal coronary anatomy Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

The IVUS Technique Can Detect Angiographically “Silent” Atheroma
Angiogram IVUS No evidence of disease Little evidence of disease Atheroma Nissen S, Yock P. Circulation 2001;103:604–16.

Rationale Angiographic studies indicate that substantial LDL-C reductions (≥40%) are needed to slow progression of arterial stenosis Although QCA has been used to measure luminal narrowing, it may underestimate atherosclerotic burden IVUS enables measurement of the volume of atheroma within the wall of the arteries by combining a series of cross-sectional images of the vessel over a predefined length IVUS has emerged as the most sensitive measure of the progression of coronary disease and an appropriate method to assess the effects of intensive lipid lowering on progression/regression of atherosclerosis Adapted from Nissen et al. JAMA 2006;295(13):

Objectives 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 by IVUS Secondary objectives included to determine whether long- term treatment with rosuvastatin 40 mg results in regression of (i) coronary atheroma burden, as assessed by TAV in the total segment as measured by IVUS and (ii) CAD, as measured by QCA Adapted from Nissen et al. JAMA 2006;295(13): , Ballantyne et al. Circulation 2008;in press.

ASTEROID: Study Design
Patients (≥18 years) CAD, undergoing coronary angiography Target coronary artery: ≤50% reduction in lumen diameter of ≥40 mm segment Target segment for QCA: all segments >25% at baseline No cholesterol entry criteria Rosuvastatin 40 mg (n=349 for IVUS analysis; n=292 for QCA analysis) Visit: Week: 1 –6 2 3 13 4 26 5 39 6 52 7 65 8 78 9 91 10 104 IVUS QCA Lipids Eligibility assessment Lipids Lipids Tolerability Tolerability Lipids Tolerability Tolerability Tolerability IVUS QCA Lipids Tolerability

Study End Points Dual primary end points: Secondary end points:
Change in PAV in the entire segment of coronary artery assessed by IVUS Change in TAV in the most severely diseased 10-mm segment of the coronary artery assessed by IVUS Secondary end points: Change in TAV within the entire segment assessed by IVUS Change in per cent diameter stenosis (%DS) for all lesions with >25% stenosis severity as measured by QCA Change in the minimal lumen diameter (MLD) within all measured coronary segments as measured by QCA Percentage change from baseline in lipid and lipoprotein levels Tolerability Adapted from Nissen et al. JAMA 2006;295(13): , Ballantyne et al. Circulation 2008;in press.

ASTEROID IVUS Analysis

IVUS Determination of Atheroma Area
Precise planimetry of EEM and lumen borders allows calculation of atheroma cross-sectional area EEM Area Lumen Area Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory (EEM area — Lumen Area) EEM=external elastic membrane

IVUS Efficacy Measures
Lumen Area (EEM – Lumen) EEM Area Change in Per Cent Atheroma Volume  n EEMCSA = (EEM – Lumen)CSA – (Month 24) (Baseline) X 100 Most diseased contiguous 10 cross-sections (EEMCSA - LumenCSA) Number cross-sections in patient’s pullback Normalized* Total Atheroma Volume = 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

Major Inclusion Criteria
Patients requiring coronary angiography for a clinical indication Angiographic evidence of CAD Entire coronary circulation: ≥1 lesion with >20% reduction in lumen diameter in any coronary artery Target coronary artery for IVUS: ≤50% reduction in lumen diameter throughout a target segment with a minimum length of 40 mm Target segment for QCA: all segments >25% at baseline No cholesterol entry criteria Men or women aged ≥18 years, statin-naïve Adapted from Nissen et al. JAMA 2006;295(13): , Ballantyne et al. Circulation 2008;in press.

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 triglyceride levels (≥500 mg/dL [5.7 mmol/L]) Uncontrolled diabetes mellitus (HbA1c ≥10%) Uncontrolled hypertension (≥200/100 mm Hg) CK >3 x ULN Adapted from Nissen et al. JAMA 2006;295(13):

Baseline Characteristics
Mean age of patients was 58.5 years 70% of patients were male 97% were white Median body mass index was 28.4 96% of patients had a history of hypertension 13% of patients had a history of diabetes 17% of patients had a history of acute coronary syndrome 25% of patients had history of myocardial infarction Adapted from Nissen et al. JAMA 2006;295(13):

Concomitant Medications
84% of patients were taking ASA 53% of patients were taking ACE inhibitors 18% of patients were taking angiotensin receptor blockers 85% of patients were taking organic nitrates 84% of patients were taking beta-blockers Adapted from Nissen et al. JAMA 2006;295(13):

Mean Baseline Lipid Levels
Baseline level (mg/dL) Baseline level (mmol/L) LDL-C 130.4 3.4 TC 204.0 5.3 TG 152.2 1.7 HDL-C 43.1 1.1 Adapted from Nissen et al. JAMA 2006;295(13):

End Point Analysis: Change in Median PAV
n=349 -0.1 -0.2 -0.3 -0.4 Change from baseline (%) -0.5 -0.6 -0.7 -0.8 - 0.79% -0.9 * *P<0.001 for difference from baseline values. Wilcoxon signed rank test Adapted from Nissen et al. JAMA 2006;295(13):

Change in Key IVUS Parameters
End Point Analysis: Change in Key IVUS Parameters Median atheroma volume in the most diseased 10-mm Median normalized TAV subsegment n=319 n=346 -1 -2 -3 -4 Change from baseline (%) -5 -6 -7 - 6.8% -8 * -9 - 9.1% -10 * *P<0.001 for difference from baseline. Wilcoxon signed rank test Adapted from Nissen et al. JAMA 2006;295(13):

Number (%) of Patients Showing Regression Measured by Each IVUS Parameter
Normalized TAV 78% IVUS parameter measured Atheroma volume in the most diseased 10-mm subsegment 78% PAV 64% 10 20 30 40 50 60 70 80 90 100 Percentage of patients showing regression Adapted from Nissen et al. JAMA 2006;295(13):

Example of Regression of Atherosclerosis with Rosuvastatin in ASTEROID (measured by IVUS)
Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73: Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.

Percentage Change** in LDL-C, HDL-C, TC & LDL-C/HDL-C Ratio
30 * 20 15% 10 n=346 n=346 n=346 n=346 -10 Median change from baseline (%) -20 -30 - 34% -40 * -50 - 53% -60 * - 59% * *P<0.001 **From time-weighted average throughout the duration of therapy Adapted from Nissen et al. JAMA 2006;295(13):

Change in Per Cent Diameter Stenosis vs.
On-Treatment LDL-C in QCA Trials CCAIT -1 -0.8 -0.6 -0.4 -0.2 0.2 0.4 0.6 0.8 1 1.2 1.4 Placebo Statin LCAS PLAC I MARS MAAS CCAIT MARS PLAC I Change in % stenosis per year MAAS LCAS On-treatment LDL-C (mg/dL) ASTEROID ASTEROID - rosuvastatin; MAAS - simvastatin; CCAIT - lovastatin; MARS – lovastatin; LCAS - fluvastatin; PLAC I - pravastatin Adapted from Ballantyne et al. Circulation 2008; in press.

Percentage Change** in Other Lipids and Lipoproteins
non-HDL-C TG ApoB ApoA1 ApoB/ApoA1 30 20 * 9% 10 n=346 n=346 n=346 n=346 n=346 -10 Median change from baseline (%) -20 - 15% * -30 -40 - 42% -50 - 47% - 46% * * * -60 TG=triglycerides *P<0.001 **From time-weighted average throughout the duration of therapy Adapted from Nissen et al. JAMA 2006;295(13):

Change in PAV by Pre-specified Subgroups: Demographic Characteristics
Age ≤ median (n=180) Age > median (n=169) BMI ≤ median (n=174) BMI > median (n=173) History of diabetes (n=46) No history of diabetes (n=303) Male (n=245) Female (n=104) -0.2 -0.4 Median change from baseline (%) -0.6 -0.6% * -0.7% -0.7% -0.8 * * -0.8% -0.8% -0.8% * * * -0.9% -0.9% -1 * * *Wilcoxon signed rank test for comparisons to baseline Adapted from Nissen et al. JAMA 2006;295(13):

Median change from baseline (%)
Change in PAV by Pre-specified Subgroups – Average On-Treatment LDL-C LDL-C ≤ mean (n=192) LDL-C > mean (n=157) LDL-C < 1.81 mmol/L (n=254) LDL-C mmol/L (n=78) LDL-C > 2.6 mmol/L (n=17) -0.2 -0.2% -0.3% -0.4 Median change from baseline (%) -0.6 -0.6% * -0.8 -0.9% -1 * -1.1% -1.2 * *Wilcoxon signed rank test for comparisons to baseline Adapted from Nissen et al. JAMA 2006;295(13):

Median change from baseline (%)
Change in PAV by Pre-specified Subgroups: Average On-treatment HDL-C HDL-C ≤ mean (n=197) HDL-C > mean (n=152) HDL-C > 1.1mmol/L (n=205) HDL-C ≤ 1.1mmol/L (n=144) HDL-C < 1.1mmol/L (n=80) HDL-C > 1.1 mmol/L (n=269) HDL-C < 0.9 mmol/L (n=34) HDL-C > 0.9 mmol/L (n=315) -0.2 -0.4 -0.6 Median change from baseline (%) -0.8 -0.7% -0.7% -0.7% -0.7% * * -0.8% * * -1 -0.9% * * -1.2 -1.4 -1.3% * -1.6 -1.5% * *Wilcoxon signed rank test for comparisons to baseline Adapted from Nissen et al. JAMA 2006;295(13):

Summary: IVUS Results ASTEROID showed that in patients with CAD, regression of coronary atherosclerosis can be achieved with intensive statin therapy using rosuvastatin 40 mg Rosuvastatin 40 mg 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 Adapted from Nissen et al. JAMA 2006;295(13):

ASTEROID QCA Analysis

ASTEROID: QCA Analysis
The effect of rosuvastatin on coronary stenoses by QCA was a secondary end point in ASTEROID 507 patients with coronary disease received rosuvastatin 40 mg for 24 months Blinded QCA analyses of %DS and MLD was performed for up to 10 segments of coronary arteries and major branches with >25% diameter stenosis at baseline 379 patients had baseline and follow-up angiography 292 patients had 1 or more segments with >25% stenosis at baseline Adapted from Ballantyne et al. Circulation 2008;in press.

ASTEROID: QCA Analysis
By providing lumen information throughout the coronary tree, QCA provides a more “global measure” of coronary atheroma and complements the detailed imaging data provided by IVUS for larger vessels

ASTEROID: QCA Efficacy Measures
Change from baseline in %DS for all lesions with >25% stenosis severity Change from baseline in the MLD within all measured coronary segments Reference diameter MLD Vessel wall Reference diameter - MLD X 100 %DS =

Percentage Change* in LDL-C, HDL-C, TC & LDL-C/HDL-C Ratio
-70 -60 -50 -40 -30 -20 -10 10 20 LDL-C HDL-C TC LDL-C/HDL-C Mean change from baseline (%) - 53% 13.8% - 58% - 34% n=292 #On-treatment and per cent change from baseline were based on time-weighted average throughout the duration of therapy Adapted from Ballantyne et al. Circulation 2008;in press.

QCA Results Baseline change in %DS during treatment, analyzed by patient
%DS (n=292) Mean (SD) Median (range) Mean change from baseline (SD) Median change from baseline (Q1 to Q3) Baseline 37.3% (8.4) 35.7% ( ) End of study 36.0% (10.1) 34.5% ( ) -1.3% (8.00) -0.50% ( ) P<0.001* *Wilcoxon signed rank test Q1=25th percentile; Q3=75th percentile Adapted from Ballantyne et al. Circulation 2008;in press

QCA Results Baseline and Change in MLD During Treatment, Analyzed by Patient
MLD (n=281) Mean (SD) Median (range) Mean change from baseline (SD) Median change from baseline (Q1 to Q3) Baseline 1.65 mm (0.36) 1.62 mm ( ) End of study 1.68 mm (0.38) 1.67 mm ( ) +0.03 mm (0.20) +0.02 mm ( ) P<0.001* *Wilcoxon signed rank test Q1=25th percentile; Q3=75th percentile Adapted from Ballantyne et al. Circulation 2008;in press.

QCA Results Progression vs
QCA Results Progression vs. regression in per cent diameter stenosis analyzed by patient Total (N=292) Per cent of total Stenosis reduced (regression) 156 53.4% No change 17 5.8% Stenosis increased (progression) 119 40.8% Stenosis reduced by >10% (regression) 22 7.5% Stenosis changed by <10% 261 89.4% Stenosis increased by >10% (progression) 9 3.1% Adapted from Ballantyne et al. Circulation 2008;in press.

QCA Results Progression vs
QCA Results Progression vs. regression of MLD during treatment analyzed by patient Total (N=281) Per cent of total MLD larger (regression) 155 55.2% No change 12 4.3% MLD smaller (progression) 114 40.6% MLD larger by >0.2 mm (regression) 34 12.1% Change <0.2 mm 230 81.9% MLD smaller by >0.2 mm (progression) 17 6.0% Adapted from Ballantyne et al. Circulation 2008;in press.

Change in Progression of IVUS PAV Volume vs. LDL-C in IVUS Trials
2 REVERSAL pravastatin 1.5 CAMELOT placebo 1 ACTIVATE placebo Change in PAV (%) 0.5 REVERSAL atorvastatin A-Plus placebo 50 60 70 80 90 100 110 120 Mean LDL-C (mg/dL) -0.5 -1 ASTEROID rosuvastatin r2=0.95 P<0.001 On-treatment LDL-C (mg/dL) Adapted from JAMA 2006;295: , Cleve Clin J Med 2006;73:

Relationship Between On-treatment LDL-C and % Change in LDL-C and Change in %DS and MLD in Statin Angiography Studies -1 -0.8 -0.6 -0.4 -0.2 0.2 0.4 0.6 0.8 1 1.2 1.4 CCAIT CCAIT LCAS PLAC I LCAS PLAC I MAAS MARS CCAIT MARS CCAIT MAAS MARS PLAC I MARS Change in % stenosis/year PLAC I MAAS MAAS LCAS LCAS -70 -60 -50 -40 -30 -20 -10 10 Per cent change in LDL-C On-treatment LDL-C (mg/dL) ASTEROID ASTEROID -0.06 -0.04 -0.02 0.02 0.04 PLAC I PLAC I CCAIT CCAIT REGRESS LCAS REGRESS LCAS PLAC I MAAS MAAS MARS PLAC I CCAIT MARS CCAIT Change in MLD (mm/year) MARS REGRESS MARS REGRESS MAAS LCAS LCAS MAAS -70 -60 -50 -40 -30 -20 -10 10 On-treatment LDL-C (mg/dL) Per cent change in LDL-C ASTEROID ASTEROID Adapted from Ballantyne et al. Circulation 2008;in press.

Change in % stenosis/year
Change in Per Cent Diameter Stenosis vs. On-treatment HDL-C in QCA Trials CCAIT -1 -0.8 -0.6 -0.4 -0.2 0.2 0.4 0.6 0.8 1 1.2 1.4 Placebo Statin PLAC I LCAS MARS MAAS CCAIT MARS PLAC I Change in % stenosis/year MAAS LCAS On-treatment HDL-C (mg/dL) ASTEROID Adapted from Ballantyne et al. Circulation 2008;in press.

Relationship Between On-treatment HDL-C and % Change in HDL-C and Change in %DS and MLD in Statin Angiography Studies -1 -0.8 -0.6 -0.4 -0.2 0.2 0.4 0.6 0.8 1 1.2 1.4 CCAIT CCAIT LCAS PLAC I LCAS PLAC I MARS MAAS MAAS MARS CCAIT CCAIT MARS MARS Change in % stenosis/year PLAC I PLAC I MAAS LCAS MAAS LCAS On-treatment HDL-C (mg/dL) Per cent change in HDL-C ASTEROID ASTEROID -0.06 -0.04 -0.02 0.02 0.04 REGRESS PLAC I REGRESS PLAC I CCAIT CCAIT MAAS LCAS LCAS MAAS PLAC I PLAC I MARS CCAIT MARS CCAIT MARS MARS REGRESS Change in MLD (mm/year) REGRESS MAAS MAAS LCAS LCAS On-treatment HDL-C (mg/dL) Per cent Change in HDL-C ASTEROID ASTEROID Adapted from Ballantyne et al. Circulation 2008;in press.

Summary: QCA results ASTEROID QCA analysis showed that in patients with CAD, regression of coronary atherosclerosis can be achieved with intensive therapy using rosuvastatin 40 mg Rosuvastatin 40 mg produced significant regression of atherosclerosis in terms of both reducing %DS and increasing MLD This regression of atherosclerosis was associated with a substantial reduction of LDL-C (-53%) to 61 mg/dL (1.58 mmol/L) together with a significant increase in HDL-C (+13.8%) to 48.3 mg/dL (1.25 mmol/L). An analysis of the ASTEROID QCA results and previous statin angiographic trials shows a similar association between the change in %DS and change in MLD with on-treatment and per cent change for both LDL-C and HDL-C Adapted from Ballantyne et al. Circulation 2008;in press.

Tolerability In ASTEROID, rosuvastatin 40 mg was taken by more than 500 patients in this two-year study Rosuvastatin 40 mg 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 *Alanine aminotransferase (ALT) >3xULN on two consecutive visits **Creatine kinase (CK) >10 ULN Adapted from Nissen et al. JAMA 2006;295(13):

ASTEROID Overall Summary
ASTEROID showed that in statin-naïve patients with CAD, regression of coronary atherosclerosis can be achieved with intensive statin therapy with rosuvastatin 40 mg: Reducing all three IVUS measures of coronary atheroma volume Reducing %DS and increasing MLD as measured by QCA Rosuvastatin 40 mg significantly reduced LDL-C by 53% to 61 mg/dL (1.58 mmol/L) and significantly raised HDL-C by 14.7% to 49 mg/dL (1.27 mmol/L) Rosuvastatin 40 mg was well tolerated with a safety profile consistent with the existing extensive safety database Adapted from Nissen et al. JAMA 2006;295(13): , Ballantyne et al. Circulation 2008;in press.

Clinical Perspective Atherosclerosis is the underlying cause of heart disease, the world’s number one killer Rosuvastatin is the only statin to show regression of coronary atherosclerosis in a major clinical study In ASTEROID, two imaging modalities that measure different parameters and focus on different segments of the coronary arteries have demonstrated concordant improvements in both IVUS measurements of atheroma volume and angiographic measurements of lumen dimension consistent with regression of atherosclerosis with intensive rosuvastatin therapy Rosuvastatin, which provides significant reductions in LDL-C and increases in HDL-C, has demonstrated a significant impact on atherosclerosis across the spectrum of the disease; with METEOR, in subjects with early disease and low coronary heart disease (CHD) risk; and with ASTEROID in patients with established disease and a high risk of CHD events

ASTEROID A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden References Nissen et al. Effect.

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ASTEROID A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden References Nissen et al. Effect.

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Presentation on theme: "ASTEROID A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden References Nissen et al. Effect."— Presentation transcript:

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