regression of atherosclerosis and related cv diseases

Regression of atherosclerosisand related CV diseases

Regression of atherosclerosisand related CV diseases

Jean-Claude Tardif MD, FRCPC, FACC, FCAHSDirector, MHI Research Center

Professor of MedicineUdeM Endowed Research Chair in Atherosclerosis

Montreal Heart InstituteUniversité de Montréal

Jean-Claude Tardif MD, FRCPC, FACC, FCAHSDirector, MHI Research Center

Professor of MedicineUdeM Endowed Research Chair in Atherosclerosis

Montreal Heart InstituteUniversité de Montréal

Change in atheroma volume in 6 weeks in statin-naïve patients

Change in atheroma volume in 6 weeks in statin-naïve patients

-5-5

-4.5-4.5

-4-4

-3.5-3.5

-3-3

-2.5-2.5

-2-2

-1.5-1.5

-1-1

-0.5-0.5

00

-10-10

-8-8

-6-6

-4-4

-2-2

00

22

-0.54 ± 0.89

-4.71 ± 0.96

1.21

-9.10

Relative changeRelative change Nominal changeNominal change

P = 0.003P = 0.003

Chronic statin therapy

prior to ACS(n = 38)



Newly initiated statin therapyfollowing ACS

(n = 36)


(n = 36)

Ad

just

ed m

ean

± S

EA

dju

sted

mea

n ±

SE

Med

ian

(IQ

R)

Med

ian

(IQ

R)






(n = 36)


(n = 36)

P = 0.002P = 0.002

Rodes J and Tardif JC, Am J Cardiol 2009;104:750-7Rodes J and Tardif JC, Am J Cardiol 2009;104:750-7Rodes J and Tardif JC, Am J Cardiol 2009;104:750-7Rodes J and Tardif JC, Am J Cardiol 2009;104:750-7

Substantial Risk of CHD Events Remains for Many Patients on Statin Therapy

Substantial Risk of CHD Events Remains for Many Patients on Statin Therapy

Trial (N) Statin treatment

Clinical eventsa

Risk reduction vs placebo

WOSCOPSb (6595) Pravastatin 40 mg 31%

AFCAPS/TexCAPSb (6605) Lovastatin 20 or 40 mg 37%

ASCOT-LLAb (10,305) Atorvastatin 10 mg 36%

4Sb (4444) Simvastatin 20 mg 26%

CAREc (4159) Pravastatin 40 mg 24%

LIPIDc (9014) Pravastatin 40 mg 24%

HPSc (20,536) Simvastatin 40 mg 27%

PROSPERc (5804) Pravastatin 40 mg 19%

aNonfatal myocardial infarction and coronary heart death; bPrimary prevention trial; cSecondary prevention trial

WOSCOPS=West of Scotland Coronary Prevention Study; AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; LIPID=Long-Term Intervention with Pravastatin in Ischemic Disease; HPS=Heart Protection Study; PROSPER=Prospective Study of Pravastatin in the Elderly at Risk

Adapted from Mahley RW, Bersot TP. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division, 2006:933–966; Bays HE. Expert Rev Cardiovasc Ther. 2004;2:485–501; Shepherd J et al. N Engl J Med. 1995;333:1301–1307; Downs JR et al. JAMA. 1998;279:1615–1622; Sever PS et al. Lancet. 2003;361:1149–1158; Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383–1389; Sacks FM et al. N Engl J Med. 1996;335:1001–1009; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Eng J Med. 1998;339:1349–1357; Heart Protection Study Collaborative Group. Lancet. 2002;360:7–22; Shepherd J et al. Lancet. 2002;360:1623–1630.

Remaining risk

69%

63%

64%

74%

76%

76%

73%

81%

Risk of death according to presence of metabolic syndrome

Risk of death according to presence of metabolic syndrome

Nigam A, Bourassa MG, Fortier A, Guertin MC, Tardif JC. Am Heart J 2006; 151: 514-21Nigam A, Bourassa MG, Fortier A, Guertin MC, Tardif JC. Am Heart J 2006; 151: 514-21

1.01.0

0.750.75

0.500.50

0.250.25

00

1.01.0

0.750.75

0.500.50

0.250.25

00

00 55 1010 1515 2020

238131078

238131078

20796877

20796877

17854673

17854673

10978388

10978388

No at riskNo MSMS

No at riskNo MSMS

00 55 1010 1515 2020

231221054

231221054

20110853

20110853

17233651

17233651

10611376

10611376

No WHO metabolic syndromeWHO metabolic syndrome

p < 0.0001 p < 0.0001

Survival (all-cause) Survival (CV)

Time (years)Time (years) Time (years)Time (years)

No WHO metabolic syndromeWHO metabolic syndrome

Lipoprotein metabolismLipoprotein metabolism

CD36SR-A

ABC1

MacrophageMacrophage

NascentHDL

NascentHDLHDLHDL

LiverLiver

CETPCETP

A-1A-1 A-1A-1LCATLCAT

LDLLDL

OxidationOxidationB

LPLLPL

IDLIDL

VLDLVLDL

B

BC-II

C-II

EE

LPLLPL

Cholesterolpool

FC CEACAT

HLHL

PL TPPL TP

FC CEACAT MTP

ApoB27-hydroxylase

ABCG1

LDLreceptor

LDLreceptor

IntestineIntestine

AC

AT

AC

AT

FC

FC

CE

CE IBATIBAT

BileBile

Change in plaque volumeChange in plaque volume

30-mm segment, intent-to-treat population30-mm segment, intent-to-treat population

-4-4

-2-2

00

22

44

66

PlaceboPlacebo50 mg

(n = 108)50 mg

(n = 108)250 mg(n = 98)250 mg(n = 98)

750 mg(n = 117)750 mg

(n = 117)

Avasimibe Avasimibe AvasimibeAvasimibe Avasimibe Avasimibe

-2.5 ± 26.6

5.1 ± 30.0

1.2 ± 24.2

1.9 ± 33.1

p = 0.058 (unadjusted)p = 0.17 (adjusted)

Mea

n c

han

ge (

±SD

)M

ean

ch

ange

(±S

D)

A+

(n=109)(n=109)

mm3mm3

Tardif et al Circulation 2004; 110:3372-7Tardif et al Circulation 2004; 110:3372-7

-0.10-0.10

-0.08-0.08

-0.06-0.06

-0.04-0.04

-0.02-0.02

00

Coronary change scoreCoronary change score

(mm

)(m

m)

(mm

)(m

m)

p = 0.35

0000

5555

10101010

15151515

20202020

New lesionsNew lesions Diseaseprogression

Diseaseprogression

(% o

f pa

tien

ts)

(% o

f pa

tien

ts)

(% o

f pa

tien

ts)

(% o

f pa

tien

ts)

p = 0.84*

p = 0.27*

Instrumented (IVUS-relatedInstrumented (IVUS-related arteries arteries))Instrumented (IVUS-relatedInstrumented (IVUS-related arteries arteries))

Non-instrumented (Non-instrumented (Non-IVUS arteriesNon-IVUS arteries))Non-instrumented (Non-instrumented (Non-IVUS arteriesNon-IVUS arteries))

Long-Term Safety of Intravascular Ultrasound

Long-Term Safety of Intravascular Ultrasound

A+

J Am Coll Cardiol 2005;45:559-564

IVUS assessment - Atherosclerosis regressionIVUS assessment - Atherosclerosis regression20% reduction in plaque burden20% reduction in plaque burden

Plaque volume (mm3): 272.9EEM volume (mm3): 609.5Plaque volume (mm3): 272.9EEM volume (mm3): 609.5

Plaque volume (mm3): 197.3EEM volume (mm3): 445.9Plaque volume (mm3): 197.3EEM volume (mm3): 445.9

BaselineBaseline Follow-upFollow-up

Correlations between changes in plaque, vessel and lumen areas in pts with regression

Correlations between changes in plaque, vessel and lumen areas in pts with regression

n = 227r = 0.64p < 0.0001

-6-6

-4-4

-2-2

00

22

44

66

-4-4 -3.5-3.5 -3-3 -2.5-2.5 -2-2 -1.5-1.5 -1-1 -.5-.5 00

Change in mean plaque area (mm2)Change in mean plaque area (mm2)

-6-6

-4-4

-2-2

00

22

44

66

-4-4 -3.5-3.5 -3-3 -2.5-2.5 -2-2 -1.5-1.5 -1-1 -.5-.5 00

n = 227r = 0.20p = 0.0030

Change in mean plaque area (mm2)Change in mean plaque area (mm2)

Mean lumen area (mm2) Mean lumen area (mm2) Mean vessel area (mm2) Mean vessel area (mm2)

Tardif et al. Am J Cardiol 2006;98-23-7Tardif et al. Am J Cardiol 2006;98-23-7

IVUS results in patients with angiographic progression vs no progression by QCA in the IVUS-related artery

IVUS results in patients with angiographic progression vs no progression by QCA in the IVUS-related artery

150150

175175

200200

225225

250250

BaselineBaseline Follow-upFollow-up

ProgressionNo progression

217.2

72.1

197.1

73.6

226.8

69.9

196.0

71.3

p = 0.05

p = 0.0089

Mea

n p

laq

ue v

olu

me

(mm

3 )M

ean

pla

que

vol

um

e (m

m3 )

P-value for mean change in plaque volume: 0.0283P-value for mean change in plaque volume: 0.0283 CirculationCirculation 2007;115:1851-72007;115:1851-7CirculationCirculation 2007;115:1851-72007;115:1851-7

Prognostic significance of angiographic progression of coronary atherosclerosisPrognostic significance of angiographic progression of coronary atherosclerosis

Circulation 1993; 87: 1067-75Circulation 1993; 87: 1067-75

00 2020 4040 6060 8080MonthsMonths

Non progressors

Progressors

Any coronary event ( n = 112)Any coronary event ( n = 112)1.01.0

0.750.75

0.500.50

0.250.25

Pro

port

ion

even

t fr

eeP

ropo

rtio

n ev

ent

free

00 2020 4040 6060 8080MonthsMonths

Non progressors

Progressors

Death or MI (n = 40)Death or MI (n = 40)1.01.0

0.750.75

0.500.50

0.250.25P

ropo

rtio

n ev

ent

free

Pro

port

ion

even

t fr

ee(N = 260) (N = 137) (N = 0) (N = 0) (N = 309) (N = 192) (N = 5) (N = 1)

p < 0.001 p < 0.001

Canadian Atherosclerosis Imaging NetworkClinical Translation and Practice

Canadian Atherosclerosis Imaging NetworkClinical Translation and Practice

Correlation of coronary and carotid atherosclerosis and their changes over time and links with clinical outcomes 2000 patients undergoing coronary angiography, IVUS (with

virtual histology) and carotid ultrasound (IMT and plaques) at baseline and 24 months

5-year follow-up for cardio/cerebrovascular events NIRS, PET/CT, MRI and microvascular substudies Genomic (including miRNAs) and biomarker biobanks Proteomic and metabolomic analyses

Application of this knowledge and framework in clinical trials of novel anti-atherosclerotic agents





Beyond statin-induced LDL-C reductionBeyond statin-induced LDL-C reduction

Tardif JC, Heinonen T. Nature Clin Pract CV Med 2006;3:366-7Tardif JC, Heinonen T. Nature Clin Pract CV Med 2006;3:366-7

CETP inhibitors

HDL infusions/mimetics

5-LO/FLAP inhibitors

PLA2 inhibitors

Serpins

Heart rate reduction?

Adhesion Molecule

Monocyte

LDL

LDLMCP-1

Macrophage

Cytokines

Foam Cell

HDL PROMOTES CHOLESTEROL EFFLUXHDL PROMOTES CHOLESTEROL EFFLUX

HDL INHIBITS ADHESION MOLECULE EXPRESSIONHDL INHIBITS ADHESION MOLECULE EXPRESSION

MODIFIED LDL

HDL INHIBITSHDL INHIBITSOXIDATION OF LDLOXIDATION OF LDL

HDL INHIBITS MCP-1 EXPRESSIONHDL INHIBITS MCP-1 EXPRESSION

INHIBITION OF ATHEROSCLEROSIS BY HDL

Effects of rApo-A1 Milano on coronary atherosclerosisEffects of rApo-A1 Milano on coronary atherosclerosis

JAMA 2003; 290:2292-2300JAMA 2003; 290:2292-2300

-20-20

-16-16

-12-12

-8-8

-4-4

00

-2-2

-1-1

00

11

mm3mm3 %%

Change in atheroma volumeChange in atheroma volume Change in % atheroma volumeChange in % atheroma volume

Placebo(n = 11)Placebo(n = 11)

15 mg/kg(n = 21)

15 mg/kg(n = 21)

45 mg/kg(n = 15)

45 mg/kg(n = 15)

Combined(n = 36)

Combined(n = 36)

ETC-216ETC-216


15 mg/kg(n = 21)

15 mg/kg(n = 21)

45 mg/kg(n = 15)

45 mg/kg(n = 15)

Combined(n = 36)

Combined(n = 36)

ETC-216ETC-216

p = 0.97p = 0.97 p = 0.02p = 0.02 p = 0.007p = 0.007 p < 0.001p < 0.001

-2.9 ± 23.3

-15.1 ± 50.6

-12.6 ± 15.3-14.1 ± 39.5

0.14 ± 3.09

-1.29 ± 3.48

-0.73 ± 2.75

-1.06 ± 3.17

p = 0.03p = 0.03 p = 0.45p = 0.45 p = 0.02p = 0.02

Change in atheroma volume on IVUSChange in atheroma volume on IVUS

Plaque volume at baseline: 146.0 mm3 for CSL-111, 151.4 mm3 for placebo Interval between IVUS examinations : 43 ± 6 days in both groups

Plaque volume at baseline: 146.0 mm3 for CSL-111, 151.4 mm3 for placebo Interval between IVUS examinations : 43 ± 6 days in both groups

-4-4

-3.5-3.5

-3-3

-2.5-2.5

-2-2

-1.5-1.5

-1-1

-0.5-0.5

00

-6-6

-5-5

-4-4

-3-3

-2-2

-1-1

00

CSL-111(n = 89)

CSL-111(n = 89)


CSL-111(n = 89)

CSL-111(n = 89)


p=NS p=NS

p < 0.0001

p = 0.07

p < 0.0001

P=0.04

-3.41

-1.62

-5.34

-2.33

Median percent changeMedian percent change Median nominal changeMedian nominal change

%% mm3mm3

The ERASE trial

Tardif et al. JAMATardif et al. JAMA 2007;297:1675-822007;297:1675-82Tardif et al. JAMATardif et al. JAMA 2007;297:1675-822007;297:1675-82

Changes in plaque characterization indexesChanges in plaque characterization indexes

-0.02-0.02

-0.01-0.01

00

0.010.01

0.020.02

-0.02-0.02

-0.01-0.01

00

0.010.01

0.020.02

CSL-111CSL-111 PlaceboPlacebo CSL-111CSL-111 PlaceboPlacebo

Arc indexArc index Inner perimeter indexInner perimeter index

-0.0083

0.0137

-0.0097

0.0128

p = 0.01p = 0.01 p = 0.01p = 0.01

The ERASE trialL

east

squ

are

mea

nsL

east

squ

are

mea

ns

Lea

st s

quar

e m

eans

Lea

st s

quar

e m

eans

Tardif et al. JAMATardif et al. JAMA 2007;297:1675-822007;297:1675-82Tardif et al. JAMATardif et al. JAMA 2007;297:1675-822007;297:1675-82

Changes in coronary score on QCAChanges in coronary score on QCA

-0.08-0.08

-0.06-0.06

-0.04-0.04

-0.02-0.02

00

1.76 mm1st quartile

1.76 mm1st quartile

2.00 mmMedian2.00 mmMedian

2.26 mm3rd quartile

2.26 mm3rd quartile

There was a significant interaction between study treatment and baseline coronary score

(p = 0.03)

Placebo

CSL-111 40 mg/kg

p = 0.03

Coronary score at baselineCoronary score at baseline

The ERASE trial

Lea

st s

quar

e m

eans

(m

m)

Lea

st s

quar

e m

eans

(m

m)

JAMAJAMA 2007;297:1675-822007;297:1675-82JAMAJAMA 2007;297:1675-822007;297:1675-82

Lipoprotein metabolismLipoprotein metabolism

CD36SR-A

ABC1

MacrophageMacrophage

NascentHDL

NascentHDLHDLHDL

LiverLiver

CETPCETP

A-1A-1 A-1A-1LCATLCAT

LDLLDL

OxidationOxidationB

LPLLPL

IDLIDL

VLDLVLDL

B

BC-II

C-II

EE

LPLLPL

Cholesterolpool

FC CEACAT

HLHL

PL TPPL TP

FC CEACAT MTP

ApoB27-hydroxylase

ABCG1

LDLreceptor

LDLreceptor

IntestineIntestine

AC

AT

AC

AT

FC

FC

CE

CE IBATIBAT

BileBile

ILLUSTRATE – Primary endpoint

Change in Percent Atheroma Volume

ILLUSTRATE – Primary endpoint

Change in Percent Atheroma Volume

0,19

0,12

0

0,05

0,1

0,15

0,2

0,25

0,3

0,35

Changein percentatheromavolume

†p value from ANCOVA

Atorvastatinmonotherapy

Torcetrapib-atorvastatin

*LS Mean change

p = 0.72†

Nissen, Tardif, et al. N Engl J Med 2007; 356:1304-16Nissen, Tardif, et al. N Engl J Med 2007; 356:1304-16

ILLUMINATE - Primary Endpoint Time to First MCVE*: Kaplan-Meier Plot

*Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable *Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable anginaangina

00 9090 180180 270270 360360 450450 540540 630630 720720 810810

Days from RandomizationDays from Randomization

Event

Free (

%)

Event

Free (

%)

9090

9292

9494

9696

9898

100100

Atorvastatin (A) events = 373Atorvastatin (A) events = 373

Torcetrapib/Atorvastatin (T/A) events = 464Torcetrapib/Atorvastatin (T/A) events = 464

P=0.001

Hazard Ratio 1.25

NEJM 2007;357:2109-2122NEJM 2007;357:2109-2122

Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with missing month 3 Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with missing month 3 HDL-C. Preliminary analysis initiated and authorised by P Barter and conducted by PfizerHDL-C. Preliminary analysis initiated and authorised by P Barter and conducted by Pfizer

Hazard ratios for CHD Death or Non-Fatal MI Hazard ratios for CHD Death or Non-Fatal MI by quintile of on-trialby quintile of on-trial HDL-C HDL-C

(referent group is HDL-C < 60 mg/dL stratum)(referent group is HDL-C < 60 mg/dL stratum)

1.001.00

0.670.67

0.470.470.570.57

0.430.43

00

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

CH

D D

eath

or

No

n-F

ata

l MI

CH

D D

eath

or

No

n-F

ata

l MI

(Ha

zard

Ra

tio)

(Ha

zard

Ra

tio)

<60<60 60-7060-70 71-8071-80 81-9381-93 >93>93Quintiles of HDL-C (mg/dL) at Month 3Quintiles of HDL-C (mg/dL) at Month 3

*P<0.05*P<0.05

****

**

Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin GroupGroup

Lack of Effect of Dalcetrapib vs Torcetrapib on Aldosterone Secretion

0

100

200

300

400

500

600

700

0 0,001 0,005 0,01 0,025 0,1 1 2,5 5 7,5 10 AngII100 nM

Concentration of Torcetrapib or RO4607381 (µM)

Ald

oste

ron

e

fmo

le/µ

g p

rote

in

RO4607381

Torcetrapib

The dal-HEART Program tests a novel hypothesis: enhancing HDL efficacy through CETP modulation treats the underlying disease of atherosclerosis and will attenuate CV risk

dal-OUTCOMES1

15,600 patients recently hospitalizedfor ACSTo evaluate the effect of dalcetrapib on CVoutcomesRECRUITMENTCOMPLETE

dal-VESSEL2

450 patients withCHD or CHD riskequivalentTo evaluate the effect of dalcetrapib onendothelial function and blood pressure, measured by FMD and ABPMRECRUITMENT COMPLETE

dal-PLAQUE3

130 patients withCHDTo evaluate the effect of dalcetrapib oninflammation, plaque size and burden, measured by PET/CT and MRIRECRUITMENT COMPLETE

The dal-HEART Programdalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport

1Schwartz et al. Am Heart J 2009;158:896-901; 2http://clinicaltrials.gov/ct2/show/NCT00655538 Accessed April 1st 2010;3http://clinicaltrials.gov/ct2/show/NCT00655473 Accessed April 1st 2010; 4http://clinicaltrials.gov/ct2/show/NCT01059682 Accessed April 1st 2010.

dal-PLAQUE-24

900 patients withCADTo evaluate the effect of dalcetrapib onatherosclerotic disease progression, assessed by IVUS and carotid B-mode ultrasoundRECRUITING

http://clinicaltrials.gov/ct2/show/NCT01059682

DAL-OUTCOMES Study DesignA double-blind, randomized, placebo-controlled, parallel group, multi-centre study in 15,600 patients recently hospitalized for ACS

Visit 1 Visit 2 Visit 3randomization

1 : 1

Double-blind

Single-blind Placebo Run-in

4-12 Weeks

Until 1600 events

occur but at least a minimum

of2 years

Until 1600 events

occur but at least a minimum

of2 years

Follow up1st year: every 3 months

Following years: every 4 months

Dalcetrapib 600 mg

Placebo

dal-PLAQUE-2: Study Design

• Objective: to assess the effect of dalcetrapib versus placebo on atherosclerotic disease progression in patients with CAD

• A double-blind, randomized, placebo-controlled, parallel-group multicenter study in 900 patients with CAD

dalcetrapib 600 mg

placebo

Randomization 24 months

Primary endpoints: IVUS and CIMT at 24 monthsOther assessments: CIMT at 6+12 months; QCA at 24 months

Pre-rando phase

Screening phase up to 8 weeksBaseline IVUS, QCA and CIMT

Double-blind

Background of contemporary evidence-basedtherapy for CAD and CV risk factors

dal-PLAQUE-2Primary endpoints

Co-primary endpoints

• Nominal change from baseline to study end in coronary percent atheroma volume (PAV) for all anatomically comparable slices in a 30-mm segment of the target coronary artery assessed by IVUS

• Rate of change from baseline to study end in intima-media thickness (IMT), defined as the per scan average of the far wall MEAN IMT values of the right and left common carotid, carotid bulb and internal carotid arterial segments as assessed by carotid B-mode ultrasound

British Journal of Pharmacology 2008; 154:765-773British Journal of Pharmacology 2008; 154:765-773

29

17

18

19

20

21

22

23

24

25

26

0 5 10 15

Aortic valve area during treatment

Stop cholesterol diet + Vit D2

Start ApoA-I mimetic peptide treatment

Ao

rtic

val

ve a

rea

(mm

2)

Days

*** * *p<0.05

**p<0.01

Control

Treated

Br J Pharmacol 2008;154:765-773

BC22140 Investigator Meeting

The dual PPAR agonist aleglitazar and change in HDL-C

%

Δ B

L

of

HD

L -

C

0

5

10

15

20

25

30

35

n54 54 54 53 54 57

Placebo 0.05 0.15 0.3 0.6 Pioglitazone

p=0.0312

p< 0.0001p< 0.0001 p< 0.0001

p<0.0014

Aleglitazar 150 μg Provides Beneficial Effects onCardiovascular Biomarkers

Placebo Aleglitazar 150 µg

Pioglitazone 45 mg

Fibrinogen baseline (mg/dL) 337.25 342.92 328.67

hsCRP baseline (mg/dL) 4.97 3.85 4.00

PAI-1 baseline (μg/mL) 22.26 22.67 22.30

1,1

-35,4

9

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

Me

an

Ab

so

lute

Ch

an

ge

Fro

m B

ase

line

Placebo Aleglitazar 150 μg Pioglitazone 45 mg

1,1

-35,4

9

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

Me

an

Ab

so

lute

Ch

an

ge

Fro

m B

ase

line

Placebo Aleglitazar 150 μg Pioglitazone 45 mg

PAI-1 (μg/mL)hsCRP (mg/dL)Fibrinogen (mg/dL)

-0,1

-1,6-1,7

-3

-2

-1

0

1

-3,7

-5

-7,3

-10

-5

0

BC22140 Investigator Meeting

Aleglitazar 150 µg

Placebo

Treatment Periodat least 2.5 years

Run-in Period2–6 (+ 6) weeks

Follow-upFollow-up

ALECARDIO Study DesignS

cree

ned

Pat

ient

s

Standard of care (diabetes and other CV risk factors)

4 weeks

Inde

x A

CS

Eve

nt

Potential therapeutic targets in CV diseasesPotential therapeutic targets in CV diseases

****

**0.00

20,000.00

40,000.00

60,000.00

80,000.00

100,000.00

120,000.00

140,000.00

160,000.00

-2 0 2 4 6 8 10 12 14

Study Weeks

Mea

n L

TB

4 P

rod

uct

ion

[p

g/m

l]VIA-2291 Decreases ex Vivo Whole Blood LTB4 Production from Baseline through Week 12

** p < 0.0001 ANCOVA Change from Baseline

Error Bars represent 95% CI

Placebo 25mg 50mg 100mg

Tardif et al. Circulation Cardiovasc Imaging 2010;3:298-307

Significant Decrease in hs-CRP in VIA-2291 100 mg Group versus Placebo at 24 Weeks

Change in non-calcified plaque volume and patients with new plaque lesions on serial coronary CT scans in the VIA-2291

groups versus placebo at 24 Weeks

Plaque volume (mm3)

-5

-3

-1

1

3

5

7

Placebo All VIA-22910

5

10

15

20

25

30

Placebo All VIA-2291

Pts with new plaques (%)

p < 0.01 p < 0.01

Tardif et al. Circulation Cardiovasc Imaging 2010;3:298-307

37

1

2

3

4

5

6

7

Predose 8 hr 16 hr 24 hr 48 hr 54 hr Day 14 Day 28

Placebo

5 µg/kg Dose

15 µg/kg Dose

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Predose 8 hr 16 hr 24 hr 48 hr 54 hr Day 14 Day 28

Placebo

5 µg/kg Dose

15 µg/kg Dose

Dose-dependent reduction in biomarkers of cardiac damage observed in the first 24 hours

VT VT VTVT VT VT

=statistically significant (p<0.05 vs control) VT = timing of doses

Tro

po

nin

I (n

g/m

l)

CK

-MB

(n

g/m

l)

Troponin I: Adjusted Geometric Mean CK-MB: Adjusted Geometric Mean

Serp-1 Phase 2a Results: Myocardial Enzymes

Tardif et al. Circulation Cardiovasc Interventions 2010 (in press)

Mortality by resting heart rateMortality by resting heart rate

Adjusted for age, gender, hypertension, diabetes, smoking, NDCV, ejection fraction, recreational activity, medications including -blockers, plus BMI for CV mortalityAdjusted for age, gender, hypertension, diabetes, smoking, NDCV, ejection fraction, recreational activity, medications including -blockers, plus BMI for CV mortality

Overall mortalityOverall mortality CV mortalityCV mortality

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

00 55 1010 1515 2020Years after enrolmentYears after enrolment

Cu

mul

ativ

e su

rviv

alC

um

ulat

ive

surv

ival

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

00 55 1010 1515 2020Years after enrolmentYears after enrolment

62 bpm63 - 70 bpm71 - 76 bpm77 - 82 bpm≥ 83 bpm

RHR in quintiles

Diaz A, Bourassa MG, Guertin MC, Tardif JC. Eur Heart J 2005; 26: 967-74Diaz A, Bourassa MG, Guertin MC, Tardif JC. Eur Heart J 2005; 26: 967-74

WT

DL

DL + IVA

100100

8080

6060

4040

2020

00

9090

7070

5050

3030

1010

WT

DL

DL + IVA

Dila

tion

(% o

f max

imal

dila

tion)

Dila

tion

(% o

f max

imal

dila

tion)

6060

00

5050

4040

3030

2020

1010

Dila

tion

(% o

f max

imal

dila

tion)

Dila

tion

(% o

f max

imal

dila

tion)

0.0010.001 0.010.01 0.10.1 11 1010

ACh (M)ACh (M)

0.00010.0001 0.0010.001 0.010.01 0.10.1 11 1010

ACh (M)ACh (M)

*

#

‡

#

‡

Emax: ‡ P < 0.05 vs. to WT; # P < 0.05 vs. to DLEmax: ‡ P < 0.05 vs. to WT; # P < 0.05 vs. to DL pD2: * P < 0.05 vs. WT and DLpD2: * P < 0.05 vs. WT and DL

RENALRENAL CEREBRALCEREBRAL

Drouin et al. Br J Pharmacol. 2008;154:749-757.

Wild type

Dyslipidemia

DL+Ivabradine

Wild type

Dyslipidemia

DL+Ivabradine

Ivabradine prevents endothelial dysfunction Ivabradine prevents endothelial dysfunction associated with dyslipidemia in miceassociated with dyslipidemia in mice

*

#

‡

#

‡

TED at trough of drug activityTED at trough of drug activityIvabradine vs atenololIvabradine vs atenolol

Equivalence interval Equivalence interval- 35 sec- 35 sec + 35 sec+ 35 sec00

IVA 5 mg bidvs ATE 50 mg od

at M1


at M1

595286595286

IVA 7.5 mg bidvs ATE 100 mg od

at M4

IVA 7.5 mg bidvs ATE 100 mg od

at M4

300286300286


at M4


at M4

298286298286

nn Favors ATEFavors ATE Favors IVAFavors IVA

6.7 (-7.4; 20.8)p < 0.0001

6.7 (-7.4; 20.8)p < 0.0001

10.3 (-8.3; 28.8)p < 0.0001

10.3 (-8.3; 28.8)p < 0.0001

15.7 (-2.9; 34.3)p < 0.0001

15.7 (-2.9; 34.3)p < 0.0001

E (95% CI)P for non inferiority

E (95% CI)P for non inferiority

Tardif JC et al. Eur Heart J 2005; 26:2529-36Tardif JC et al. Eur Heart J 2005; 26:2529-36

INITIATIVE

Ivabradine + atenolol

Placebo + atenolol

0

10

20

30

40

50

60

Total exercise durationTotal exercise duration Time to limiting angina

Time to limiting angina

Time to angina onsetTime to angina onset Time to 1mm ST segment depression

Time to 1mm ST segment depression

Cha

nge

in E

TT

cri t

eri a

* (

s )

at 4

mo n

ths

P<0.001P<0.001 P<0.001P<0.001

P<0.001P<0.001 P<0.001P<0.001

Ivabradine increases all ETT parameters in patients already receiving beta-blockers

*Evaluated at trough of drug activity

889 stable angina patients, 20 countries

Tardif JC, et al. Eur Heart J. 2009;30:540-548.

Effect of Ivabradine on hospitalisationEffect of Ivabradine on hospitalisationfor fatal and non-fatal MI for fatal and non-fatal MI (HR (HR ≥≥ 70 bpm) 70 bpm)

Placebo

IvabradineIvabradine

P = 0.001

Hazard ratio = 0.64 (0.49 – 0.84)

RR = -36%

Years

0.5 1 1.5 2

% with hospitalisation for fatal and non-fatal MI

00

8

0

4

6

2

Lancet Online August 31, 2008.

43

0 6 12 18 24 30

40

30

20

10

0

Primary composite endpoint (CV death or hospital admission for worsening HF)

18%

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

Placebo

Ivabradine

HR = 0.82 (0.75–0.90) P < 0.0001

Swedberg K, et al. Lancet. 2010;online August 29.MonthsMonths

Ivabradine Starting dose 7.5 mg bid

Placebo bid

Run in2 - 4 weeks

M006M003M000 Every 6 months

Target HR: 55-60 bpm

MethodsEvents: 4.5% per year in the placebo group 1070 primary composite endpoints (cardiovascular death and non fatal MI N = 11 330, mean follow up = 2.5 years; RRR = 18%, α bilateral 5%, power 90%

PopulationOutpatients with stable CAD without LVSD (EF > 40%) or clinical signs of HF, with appropriate CV medication

Canadian Atherosclerosis Imaging Network“Hearts and Minds”

Canadian Atherosclerosis Imaging Network“Hearts and Minds”

Stems from CIHR’s 2007 consensus conference on imaging

Five-year (2008-2013) 10M$ operating grant from CIHR

Infrastructure grant 25M$ from CFI in June 2009

Unique network combining in vivo imaging of vessel wall disease, end-organ disease, clinical and pathological endpoints

Enables cross-sectional and longitudinal clinical studies of coronary, carotid and peripheral vascular beds

International resource for studying the natural history of atherosclerosis and novel therapeutic interventions

Stems from CIHR’s 2007 consensus conference on imaging

Five-year (2008-2013) 10M$ operating grant from CIHR

Infrastructure grant 25M$ from CFI in June 2009

Unique network combining in vivo imaging of vessel wall disease, end-organ disease, clinical and pathological endpoints

Enables cross-sectional and longitudinal clinical studies of coronary, carotid and peripheral vascular beds

International resource for studying the natural history of atherosclerosis and novel therapeutic interventions

Canadian Atherosclerosis Imaging NetworkCanadian Atherosclerosis Imaging Network

Imaging Core Analysis Laboratories (vascular)

IVUS, 3-D US, QCA, MDCT, MRI, PET/CT, SPECT

Imaging Core Analysis Laboratories (end-organ)

Pan-canadian network of 45 partner sites

Data coordinating and image repository center (MHICC)

Genetic, pharmacogenomic and biomarker biobanks

Proteomic and metabolomic analyses

Tissue samples

CAIN – one imaging network for one entire countryCAIN – one imaging network for one entire country

CAIN

Research themes

CAIN

Research themes

Vascular biology of atherosclerotic plaque

Vascular imaging technology development and assessment

Translation to clinical research and clinical practice

Vascular biology of atherosclerotic plaque

Vascular imaging technology development and assessment

Translation to clinical research and clinical practice

Hearts and

Minds

Canadian Atherosclerosis Imaging Network1- Vascular Biology of Atherosclerotic PlaqueCanadian Atherosclerosis Imaging Network

1- Vascular Biology of Atherosclerotic Plaque

Assess natural history of the plaque from 3 time points (MRI): Plaque initiation, progression and complication

Evaluate inflammation, neovascularization and hemorrhage

Determine the role of stimuli such as Db and hyperlipidemia

Study the genetics of atheroma

Assess the role of hypertension, hemodynamics and the interaction with blood constituents at the site of plaque rupture

Assess natural history of the plaque from 3 time points (MRI): Plaque initiation, progression and complication

Evaluate inflammation, neovascularization and hemorrhage

Determine the role of stimuli such as Db and hyperlipidemia

Study the genetics of atheroma

Assess the role of hypertension, hemodynamics and the interaction with blood constituents at the site of plaque rupture

Canadian Atherosclerosis Imaging Network2- Vascular Imaging Technology

Development and Assessment

Canadian Atherosclerosis Imaging Network2- Vascular Imaging Technology

Development and Assessment

Validation of developing technologies through quantitative histological examination of surgical specimens

Includes: Carotid ultrasound - surface morphology, plaque vulnerability

and plaque volume 18FDG-PET – metabolic activity and inflammation Ultrasound microbubbles – plaque neovascularity

Validation of developing technologies through quantitative histological examination of surgical specimens

Includes: Carotid ultrasound - surface morphology, plaque vulnerability

and plaque volume 18FDG-PET – metabolic activity and inflammation Ultrasound microbubbles – plaque neovascularity

Canadian Atherosclerosis Imaging Network3- Translation to Clinical Research/PracticeCanadian Atherosclerosis Imaging Network3- Translation to Clinical Research/Practice









Canadian Atherosclerosis Imaging NetworkCanadian Atherosclerosis Imaging Network

www.canadianimagingnetwork.org

[email protected]

CAIN – one imaging network for one entire countryCAIN – one imaging network for one entire country

http://www.canadianimagingnetwork.org/

52

www.gainresearch.net

regression of atherosclerosis and related cv diseases

Documents

heart j

j cardiol

shepherd j

n engl j

rodes j

n eng j

statinnave patients

avasimibe avasimibe