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

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):1556-65.

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)

Rotating transducer Normal coronary anatomy

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

IVUS Coronary Imaging Technique

Nissen S, Yock P. Circulation 2001;103:604–16.

Angiogram IVUS

Little evidence of disease

Atheroma

No evidence of disease

The IVUS Technique Can Detect Angiographically “Silent” Atheroma

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):1556-65.

• 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

Objectives

Adapted from Nissen et al. JAMA 2006;295(13):1556-65, Ballantyne et al. Circulation 2008;in press.

Rosuvastatin 40 mg (n=349 for IVUS analysis; n=292 for QCA analysis)

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

Visit:Week:

Lipids LipidsTolerability

IVUSQCA

LipidsTolerability

LipidsTolerability

TolerabilityTolerability Tolerability

1–6

20

313

426

539

652

765

878

991

10104

Eligibilityassessment

ASTEROID: Study Design

IVUSQCA

Lipids

Study End Points

• Dual primary 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


ASTEROID

IVUS Analysis

IVUS Determination of Atheroma Area

Precise planimetry of EEM and lumen bordersallows calculation of atheroma cross-sectional area

EEM=external elastic membrane

EEM Area

LumenArea

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

(EEM area — Lumen Area)

IVUS Efficacy Measures

LumenArea

(EEM – Lumen)

EEM Area

(EEMCSA - LumenCSA)

Number cross-sectionsin patient’s pullback

Normalized*Total

AtheromaVolume

=Median number cross-sections for all patientsx

Most diseasedcontiguous

10 cross-sections

Changein Per CentAtheromaVolume

n

EEMCSA

= n

(EEM – Lumen)CSA

EEMCSA

–

(Month 24) (Baseline)

(EEM – Lumen)CSA

X 100 X 100

*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


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


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


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


Baseline level (mmol/L)

Baseline level (mg/dL)

N=346

1.143.1HDL-C

1.7152.2TG

5.3204.0TC

3.4130.4LDL-C

Mean Baseline Lipid Levels


End Point Analysis: Change in Median PAV

*P<0.001 for difference from baseline values. Wilcoxon signed rank test

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0Median PAV

Chang

e f

rom

base

line

(%

)

- 0.79%

*

n=349


*P<0.001 for difference from baseline. Wilcoxon signed rank test

-10-9-8-7-6-5-4-3-2-10

Median atheroma volume in themost diseased 10-mm

subsegmentMedian normalized TAV

Chang

e f

rom

base

line (

%)

- 9.1%*

*- 6.8%

End Point Analysis: Change in Key IVUS Parameters

n=319 n=346


0 10 20 30 40 50 60 70 80 90 100

Percentage of patients showing regression

IVUS parameter measured

PAV

Atheroma volume in the most diseased 10-mm subsegment

Normalized TAV

78%

78%

64%

Number (%) of Patients Showing Regression Measured by Each IVUS Parameter


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; 73:937-944.

Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.

-60

-50

-40

-30

-20

-10

0

10

20

30LDL-C HDL-C TC LDL-C/HDL-C

*P<0.001

**From time-weighted average throughout the duration of therapy

- 53%

15%

- 34%

*

*

*

- 59%*

Percentage Change** in LDL-C, HDL-C, TC & LDL-C/HDL-C Ratio

Media

n c

hange f

rom

base

line (

%)

n=346

n=346

n=346 n=346


Change in Per Cent Diameter Stenosis vs. On-Treatment LDL-C in QCA Trials

ASTEROID - rosuvastatin; MAAS - simvastatin; CCAIT - lovastatin; MARS – lovastatin; LCAS - fluvastatin; PLAC I - pravastatin

Chang

e in %

ste

nos i

s pe

r year

40 60 80 100 120 140 160 180

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

MARS MAAS

PLAC ILCAS

PLAC ICCAIT

LCASMAAS

MARS

ASTEROID

On-treatment LDL-C (mg/dL)

CCAITPlacebo

Statin

Adapted from Ballantyne et al. Circulation 2008; in press.

-60

-50

-40

-30

-20

-10

0

10

20

30

TG=triglycerides

*P<0.001

**From time-weighted average throughout the duration of therapy

- 47%- 42%

** - 46%

*

non-HDL-C TG ApoB ApoB/ApoA1ApoA1

- 15%*

9%*

Percentage Change** in Other Lipids and Lipoproteins

Media

n c

hange f

rom

base

line (

%)

n=346 n=346 n=346 n=346n=346


-1

-0.8

-0.6

-0.4

-0.2

0

Media

n c

hange f

rom

base

line (

%)

Change in PAV by Pre-specified Subgroups: Demographic Characteristics

-0.8%

* *

Age ≤ median (n=180)

Age > median (n=169)

Male

(n=245)

Female (n=104)

BMI ≤ median (n=174)

BMI > median (n=173)

History of diabetes (n=46)

No history of diabetes (n=303)

-0.9%

-0.7%

-0.9%

-0.7%

-0.6%

-0.8% -0.8%

*

*

*

*

**

*Wilcoxon signed rank test for comparisons to baseline


-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

LDL-C ≤ mean (n=192)

LDL-C > mean

(n=157)

LDL-C <

1.81 mmol/L

(n=254)

LDL-C 1.8-2.6 mmol/L (n=78)

LDL-C >

2.6 mmol/L (n=17)

-1.1%

-0.6%

-0.9%

-0.3%

-0.2%

*

*

*Media

n c

hange f

rom

base

line (

%)

Change in PAV by Pre-specified Subgroups – Average On-Treatment LDL-C



-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

HDL-C ≤ mean

(n=197)

HDL-C > mean

(n=152)

HDL-C > 1.1mmol/L (n=205)

HDL-C < 0.9 mmol/L

(n=34)

HDL-C > 0.9 mmol/L (n=315)

HDL-C ≤ 1.1mmol/L (n=144)

HDL-C > 1.1 mmol/L

(n=269)

HDL-C < 1.1mmol/L

(n=80)

-1.3%

-0.9%

-0.7% -0.7%-0.8%

-0.7%

-1.5%

-0.7%

*

* **

*

*

*

*

Media

n c

hange f

rom

base

line (

%)

Change in PAV by Pre-specified Subgroups: Average On-treatment HDL-C



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

Summary: IVUS Results


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 Analysis

ASTEROID: QCA Efficacy Measures

Reference diameter

MLDVessel wall

Vessel wall

Reference diameter - MLD

Reference diameterX 100%DS =

Change from baseline in %DS for all lesions with >25% stenosis severity

Change from baseline in the MLD within all measured coronary segments

#On-treatment and per cent change from baseline were based on time-weighted average throughout the duration of therapy

Percentage Change* in LDL-C, HDL-C, TC & LDL-C/HDL-C Ratio

-70

-60

-50

-40

-30

-20

-10

0

10

20

LDL-C HDL-C TC LDL-C/HDL-C

Mean

ch

an

ge f

rom

base

line (

%)

- 53%

13.8%

- 58%

- 34%

n=292 n=292 n=292

n=292


%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%(26.0-73.0)

End of study

36.0% (10.1) 34.5%(8.0-74.0)

-1.3% (8.00)

-0.50% (-4.0-2.0)

P<0.001*

QCA ResultsBaseline change in %DS during treatment, analyzed by patient

*Wilcoxon signed rank testQ1=25th percentile; Q3=75th percentile

Adapted from Ballantyne et al. Circulation 2008;in press

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(0.56-2.65)

End of study

1.68 mm(0.38)

1.67 mm(0.76-2.77)

+0.03 mm (0.20)

+0.02 mm (-0.04-0.11)

P<0.001*

*Wilcoxon signed rank testQ1=25th percentile; Q3=75th percentile


QCA ResultsBaseline and Change in MLD During Treatment, 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%

QCA ResultsProgression vs. regression in per cent diameter stenosis 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%

QCA ResultsProgression vs. regression of MLD during treatment analyzed by patient


-1

-0.5

0

0.5

1

1.5

2

50 60 70 80 90 100 110 120

ASTEROID rosuvastatin

A-Plus placebo

ACTIVATE placebo

CAMELOT placebo

REVERSAL pravastatin

REVERSAL atorvastatin

Mean LDL-C (mg/dL)

Change in Progression of IVUS PAV Volume vs.LDL-C in IVUS Trials

C

hange in P

AV

(%

)

Adapted from JAMA 2006;295:1556-65, Cleve Clin J Med 2006;73:937-44.

r2=0.95P<0.001

On-treatment LDL-C (mg/dL)

Relationship Between On-treatment LDL-C and % Change in LDL-C and Change in %DS and MLD in Statin Angiography Studies

40 60 80 100 120 140 160 180

-1-0.8-0.6-0.4-0.2

00.20.40.60.81

1.21.4

MARS

PLAC ILCAS

PLAC ICCAIT

LCASMAAS

MARS

ASTEROID

CCAIT

MARS MAAS

PLAC ILCAS

PLAC I

CCAIT

LCASMAAS

MARS

ASTEROID

CCAIT

0-70 -60 -50 -40 -30 -20 -10 10

Change in %

ste

nosi

s/year

On-treatment LDL-C (mg/dL) Per cent change in LDL-C

On-treatment LDL-C (mg/dL) Per cent change in LDL-C ASTEROID

-0.06

-0.04

-0.02

0

0.02

0.04

MARS MAAS

CCAITPLAC I

LCASPLAC I

CCAIT

REGRESS

LCAS MAASMARS

REGRESS

MARS MAAS

REGRESSPLAC I

LCAS

PLAC ICCAIT

REGRESSLCAS

MAAS

MARS

ASTEROID

CCAIT

Change in M

LD (

mm

/year)

40 60 80 100 120 140 160 180 0-70 -60 -50 -40 -30 -20 -10 10

MAAS


Change in Per Cent Diameter Stenosis vs.On-treatment HDL-C in QCA Trials

Placebo

Statin

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

MARS MAAS

PLAC I LCAS

PLAC ICCAIT

LCASMAAS

MARS

ASTEROID

On-treatment HDL-C (mg/dL)

CCAIT

40 45 50

Chang

e in %

ste

nos i

s/year


-1-0.8-0.6-0.4-0.20

0.20.40.60.81

1.21.4

MARS MAAS

PLAC I LCAS

PLAC ICCAIT

LCASMAAS

MARS

ASTEROID

CCAIT

40 45 50On-treatment HDL-C (mg/dL)

MARS MAAS

PLAC ILCAS

PLAC I

CCAIT

LCASMAAS

MARS

ASTEROID

CCAIT

-5 0 5 10 15 20Per cent change in HDL-C

Change in %

ste

nosi

s/year

-0.06

-0.04

-0.02

0

0.02

0.04

35 40 45 50 55

MARS

MAAS

REGRESS PLAC I

LCASCCAIT

PLAC I

CCAIT

REGRESSLCAS

MAAS

MARS

ASTEROID

On-treatment HDL-C (mg/dL)-5 0 5 10 15 20

MARS MAAS

REGRESS PLAC I

LCASCCAIT

PLAC ICCAIT

REGRESS

LCASMAAS

MARS

ASTEROID

Per cent Change in HDL-C

Change in M

LD (

mm

/year)

Relationship Between On-treatment HDL-C and % Change in HDL-C and Change in %DS and MLD in Statin Angiography Studies


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

Summary: QCA results


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


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% to61 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


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

Clinical Perspective

Documents

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