Lindsay and Choudhury, Nature Reviews: Drug Discovery 2008, 7: 517-29

Imaging the vessel wall in atherosclerosis

@12 Months

Vessel wall areaAorta decrease ~ 8%Carotid decrease ~ 15%

Lumen AreaAorta unchangedCarotid unchanged

Max ThicknessAorta decrease ~ 9%Carotid decrease ~ 11%

Corti R et al. Circulation, 2001;104: 249-2525

Atherosclerosis regression on statins – wall imaging with MRI

Underhill et al. AHJ, 2008;155:584:e1-8

T1W ToF PDW T2W

t = 0

t = 0

t = 2y

~40 patients with US-defined carotid artery stenosis. Randomised to rosuvastatin 5mg vs 20-40 mg / dayNo change in overall plaque burden BUTIn patients (n=16) with lipid rich core – regression of core over 24 months

Plaque composition analysis

SCREENINGINDIVIDUAL

PARTICIPATIONCOMPLETED

Established atherosclerosis and HDL-c < 1mmol/LAll treated with statins

Randomised to placebo or Niaspan375mg for 1wk > 500mg for 1 wk > 750mg for 1 wk > 1000mg for 4 wks >

1500mg 4 wks > 2000mg maintenancePrimary end point = change in carotid wall area at 12 months

6 MONTH REVIEWMRI

FASTING BLOODS

12 MONTH REVIEWMRI

FASTING BLOODS

Week 7LFTs, CK

Week 15LFTs, CK

BASELINEMRI

FASTING BLOODS

Effect of nicotinic acid on atherosclerosis progression when added to statin therapy

Placebo Nicotinic acid

Cha

nge

in c

arot

id w

all a

rea

(mm

2 ) *

*p=0.03 (mixed effect model adjusted for baseline covariates)estimated treatment difference [95% CI] = −1.64 mm2 [−3.12, −0.16]

Lee JMS et al; J Am Coll Cardiol, 2009;54:1787-94

Effect of nicotinic acid on atherosclerosis progression

TBR >1.6-inflammation

presentby a central

core lab

• A double-blind, randomized, placebo (S.O.C.)- controlled, parallel group,multi-center (11 sites) study in 130 patients with CHD or CHD equivalent

Fayad ZA et al. Am Heart J. 2011

130 Treated (1:1 allocation)189 patients screened

Recruitmentn=189 subjects

screened

Double-blind treatment periodSubjects allocated to dalcetrapib 600 mg/day

(n=64) or placebo (n=66) for 24 months

24-month MRI*6-month MRI

3-month PET/CT

Baseline PET/CT at screening

*Primary Endpoints

24 months -3 months

First patient screened Feb 2008Last patient randomised Nov 2008

Change in arterial wall 18F-FDG uptake (target to background ratio) within the index vessel (left/right carotid or ascending aorta) after 6 months

Structural changes in the arterial wall (total vessel area, wall area, wall thickness, normalised wall index) based on the average of the right and left carotids after 24 months*

6-month PET/CT*

Baseline MRI 2 wk before randomisation

0 months 6 months

rand

omis

atio

n

12-month MRI

12 months

Dal-PLAQUE: design

“Failure of Torcetrapib”

VariablePlacebo

(N=65)Dalcetrapib

(N=63)Absolute change vs placebo (90%

CI)P

valueNo-harm

boundary**

MRI, mean* (SE)†

Total vessel area, mm2 5.72 (1.45) 1.71 (1.43) -4.01

(-7.23, -0.80) 0.04 2.0

Wall area, mm2 2.69 (1.05) 0.49 (1.04) -2.20(-4.54, 0.13) 0.12 3.0

Wall thickness, mm 0.05 (0.03) 0.02 (0.03) -0.03(-0.11, 0.04) 0.45 0.02

Normalized wall index, % -0.40 (0.80) 0.30 (0.80) 0.60

(-1.20, 2.50) 0.57 4.00

PET/CT, mean* (SE)‡

Most diseased segment mean of maximum TBR

-0.26 (0.08) -0.19 (0.08) 0.07(-0.11, 0.25) 0.51 0.27

SE = standard error *After adjustment for baseline and centre†Total number of patients with MRI vessel parameter measurements was 56 for placebo and 58 for dalcetrapib‡Total number of patients with target-to-background ratio measurements was 56 for placebo and 56 for dalcetrapib.**For upper limit of 90% CI for placebo-corrected change from baselineNominal P-values

Dal-PLAQUE: MRI (24 months) and PET (6 months) outcomes