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Treating arteries instead of treating risk factors
J. David Spence Stroke Prevention & Atherosclerosis Research Centre
Robarts Research InstituteLondon, Canada
[email protected] www.robarts.ca/sparc
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Disclosures• Grants for research from HSF, NIH, CIHR• Grants for research from Pfizer, Merck, Pan
American Labs• Lecture fees from Pfizer, AstraZeneca, Merck,
Novartis, Boehringer-Ingelheim• Consulting fees from Novartis, Boehringer-
Ingelheim• Interest in www.vascularis.com
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Post-prandial oxidative stress and inflammation*
* ROS, inflammatory mediators, oxidized LDL: not fasting Chol/Trig/HDL
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Large artery strokes• Not just stenosis: also high plaque burden• Plaque measurement very useful
79 yo woman
Composite drawing of all plaques in extracranial carotidsBogiatzi C…Spence JD SPARKLE classification Neuroepidemiology 2014;42:243–251.
72 yo man
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Ischemic stroke subtypes are changing• Better BP control• More statins
Bogiatzi C ….Spence JD. Stroke. 2014 Sep 11
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Ischemic stroke subtypes are changing
Bogiatzi C ….Spence JD. Stroke. 2014;45:3208-13.
Cardioembolic strokes more common, large artery strokes less common
Before 2005 After 2009
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Measurement of subclinical atherosclerosis
• There are 2 distinct kinds of IMT• IMT isn’t atherosclerosis• Plaque predicts events better than IMT• Plaque measurement can be used for treatment• Plaque measurement is more sensitive to effects
of therapy• Plaque measurement is superior to IMTSpence JD. Atherosclerosis. 2012;220:34-5.
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Ultrasound measurement of “Atherosclerosis”
It is important to recognize biological differences among
•Intima-media thickness - with and without plaque thickness•Plaque•Stenosis
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Carotid Intima-Media Thickness (IMT)Mannheim consensus conference– Site : common carotid artery , far wall ,– Quality Index > 0.50
Cerebrovascular Diseases 2007;23:75-80
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Phenotypes of atherosclerosis
Traditional coronary risk factors as predictors of ultrasound phenotype:
In multivariable regression: • IMT R2 is 0.15 for internal, 0.17 for common carotid1
• Plaque area R2 is 0.522 (similar to R2 for coronary events)• Stenosis (Doppler velocity) R2 is 0.132
1. O’Leary DH, et al Stroke 1996; 27: 224-231.2. Spence JD, Hegele RA Stroke 2004; 35: 649 - 653.
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Scannning and plaque area measured by Maria DiCicco RVT; IMT by Andrew House M.D., plaque volume by Khalid Al-Shali M.D.
IMT=0.95 mm PA=0.38 cm2 PV=297 mm3
IMT=1.01 mm PA=0.19 cm2 PV=24 mm3
Measurement of IMT, plaque area and volume
Scannning and plaque area measured by Maria DiCicco RVT; IMT by Andrew House M.D., plaque volume by Khalid Al-Shali M.D.
IMT=0.95 mm PA=0.38 cm2 PV=297 mm3
IMT=1.01 mm PA=0.19 cm2 PV=24 mm3
Al-Shali et al. Atherosclerosis 2005; 178: 319–325
Scannning and plaque area measured by Maria DiCicco RVT; IMT by Andrew House M.D., plaque volume by Khalid Al-Shali M.D.
IMT=0.95 mm PA=0.38 cm2 PV=297 mm3
IMT=1.01 mm PA=0.19 cm2 PV=24 mm3
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Phenotypes of atherosclerosisThus Intima-media thickness (IMT), plaque and stenosis must be
regarded as distinct phenotypes, with distinct biologies and determinants. Therapies would also be expected to differentially affect these distinct manifestations of atherosclerosis.
Biologies of IMT, plaque and stenosis are distinctIMT: mainly hypertensive medial hypertrophyPlaque: reflects endothelial dysfunction, oxidative stress, lipidsStenosis: consequence of plaque rupture and thrombosis – reflects plaque instability, inflammation, MMP, thrombosis, impaired
fibrinolysisSpence JD, Hegele RA Noninvasive Phenotypes of Atherosclerosis: Similar Windows but Different Views Stroke
2004; 35: 649 - 653.Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol. 2004
Nov;24(11):e188
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Plaque is more closely related to coronary artery disease than IMT
• Ebrahim S, et al. Stroke 1999; 30:841-850.
• Chan SY et al. J Am Coll Cardiol. 2003;42:1037-43.
• Brook R et. al. ATVB 2006;26:656-62.
• Johnsen, SH et al. Stroke 2007;38;2873-2880
• Inaba Y, et al. Atherosclerosis. 2011;220:128-33.
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IMT isn’t atherosclerosisCorrelation Between Carotid Intimal/Medial Thickness (IMT) and
Atherosclerosis: A Point of View from Pathology Finn AV, Kolodgie FD, Virmani R. ATVB 2009 online
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Measurement of 2-D Plaque area*
* Invented in our lab in 1990 by Maria DiCicco, R.V.T.
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Carotid Plaque Area as predictor of events
1,686 patients in our Atherosclerosis Prevention Clinic followed up to 5years
During mean followup of 2.5 + 1.3 years:94 MI, 45 strokes, 44 deaths (27 vascular).
Spence JD, Eliasziw M, DiCicco M et al. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke. 2002;33:2916-2922.
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Baseline Carotid plaque area as a predictor of eventsStroke, MI, Death (after adjustment for risk factors*)
*Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BPStroke 2002; 33:2916-2922.
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Prediction of outcomes
Plaque measurement is a stronger predictor of outcomes than EBCT, presence of plaque, and somewhat more predictive than IMT, particularly for myocardial infarction
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TPA increases AUC in ROC
Romanens M, Spence JD et al. Cardiovasc. Med. 2011;14:53–57
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Tromsø Study
6226 men and women aged 25 to 84 6 year followup: • MI in 6.6% of men and 3.0% of women. • TPA: RR (95% CI) 1.56 (1.04 to 2.36) in men 3.95 (2.16 to 7.19) in women• IMT RR (95% CI) 1.73 (0.98 to 3.06) in men
2.86 (1.07 to 7.65) in women• When bulb IMT was excluded from analyses, IMT
did not predict MI in either sex.Johnsen, SH et al. Stroke 2007;38;2873-2880
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5-year MI risk by Total Plaque Area Tertile
Johnsen, SH et al. Stroke 2007;38;2873-2880
Men Women
IMT in the CCA was not predictive
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10-year stroke risk more strongly predicted by plaque area in Tromsø Study
Mathiesen ES et al. Stroke 2011 online Feb 10
Hazard ratio 1.73 for men(p=0.004), 1.63 for women (p=0.03)No differences for quartiles of IMT
Total plaque area
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Distribution of carotid plaque area by age groups and sex
Spence JD. Nature Clinical Practice Neurology 2006;2: 611-619.
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Plaque progression despite therapy doubles the risk*
*Adjusted for Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BPStroke 2002; 33:2916-2922.
Medical treatment was failing in half the cases, and they were at double the risk: we needed to do better!
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Paradigm change:Treating arteries, not risk factors
Instead of treating risk factors to target, since 2003 we treat patients more intensively if their plaque is progressing , regardless of their level
of LDL or other risk factors
i.e. – since 2003 our target is now plaque regression
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Treating arteries without measuring plaque is like
treating hypertension without measuring blood pressure
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Benefit of carotid endarterectomy
Symptomatic severe stenosis: 2-yr reduction of stroke death from 26% to 9%Asymptomatic: 5-yr risk reduction 10% to 5% NNT to prevent 1 stroke in 2 years1:
NNT
Symptomatic severe >70% age<75 6
Symptomatic severe >70% age>75 3
Symptomatic moderate 50-69% 15
Asymptomatic 67-83* Predicated on 3% surgical risk, and historical medical therapy1.Barnett HJM. CMAJ 2004;171: 473-4
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TCD microembolus detection
319 ACS patients between 2000 and 2004
10% had microemboli
1-year Stroke RiskNo Emboli Emboli 1% 15.6%
95% CI (1.01 -1.36) (4.1-79)
p<0.0001
Spence JD et al. Stroke 2005; 36:2373-2378.
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Stroke risk over 2 years by baseline microembolic status
0 200 400 600 800
Days to event
0.0
0.2
0.4
0.6
0.8
1.0
Su
rviv
al fr
ee
of
str
ok
eEmboli at baseline
No
Yes
0-censored
1-censored
Spence JD et al. Stroke 2005;36:2373-2378
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11%
2.2%
P<0.001
Spence JD et al. Arch Neurol. 2010;67:180-6
Decline of microemboli with more intensive medical therapy
< 5% of ACS patients can now benefit from carotid endarterectomy or stenting
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Annual rate of plaque progression in ACS patients before and since 2003
Spence JD et al. Arch Neurol. 2010;67:180-6
n= 346P<0.0001
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Kaplan-Meier Survival free of stroke, death, MI
logrank test p<0.0001 logrank test p<0.0001
Spence JD et al. Arch Neurol. 2010;67:180-6
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Plaque area by age group and clinic pop. age by year
n= 4,328Spence JD, Hackam DG. Stroke 2010 Jun;41(6):1193-9
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n= 4,328
Average rate of plaque progression by year among all patients in clinic
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Effectsof
more intensivetherapy
on plasma
lipidsin clinic
populationn=4,328
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Rates of progression and LDL by year
1997- 1998
1998- 1999
1999-2000
2000- 2001
2001-2002
2002-2003
2003-2004
2004-2005
2005-2006
2006-2007
Age at first year (SD)
50.45 (11.34)
54.96 (13.24)
57.43 (13.09)
60.54 (12.37)
61.33 (12.37)
62.88 (13.05)
63.50 (12.74)
63.70 (12.51)
64.02 (13.13)
64.72 (13.50)
Progression 28.2% 33% 48.1% 61.7% 55.4% 46.1% 41.9% 40.6% 26.8% 28.4% Stable 35.9% 28% 23.3% 18.1% 18.5% 20.4% 20.1% 25.6% 23.1% 31% Regression 35.9% 38.7% 28.6% 19.6% 26.1% 33.4% 38% 33.9% 50.1% 40.5%
LDL 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Progression 3.61 (2.33)
2.45 (0.95)
2.29 (0.77)
2.43 (0.81)
2.35 (0.82)
2.34 (0.73)
2.32 (0.81)
2.22 (0.55)
2.14 (0.83)
1.84 (0.74)
Stable 2.93 (0.74)
2.61 (0.57)
2.21 (0.79)
2.58 (0.74)
2.41 (0.89)
2.51 (0.98)
2.34 (0.74)
2.35 (0.89)
2.12 (0.81)
2.25 (0.93)
Regression 2.63 (1.02)
2.20 (0.32)
2.18 (0.93)
2.37 (0.77)
2.38 (0.76)
2.42 (0.95)
2.25 (0.64)
2.01* (0.61
1.94 (0.83)
1.87 (0.78)**
Spence JD, Hackam DG. Stroke 2010 Jun;41(6):1193-9
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Decline in events in ACS with more intensive medical therapy
No embolin=431
Microembolin=37
pBefore 2003n=199
Since 2003n=269
p*
Stroke in year 1 1.4% 10.3% 0.016 3.3% 1% 0.155
Stroke in year 2 1.8% 18.5% 0.001 5.5% 0% 0.006
MI in year 1 2.2% 6.9% 0.165 4.9% 0.5% 0.007
MI in year 2 1.4% 3.2% 0.394 2.7% 0.5% 0.104
Death in year 1 2.8% 10.3% 0.069 4.4%% 2.4% 0.386
Death in year 2 2.1% 3.7% 0.477 3.8% 0% 0.044
CEA year 1 1.4% 12.9% 0.003 2.7% 1.9% 0.739
CEA year 2 0.3% 3.7% 0.146 1.1% 0% 0.499
Stroke, death or CEA 1st 2 years
6.5% 32.4% <0.0001 14.1% 4.5% <0.0001
Stroke, death, MI or CEA 1st 2 years
8.6% 32.4% <0.0001 17.6% 5.2% <0.0001
Spence JD et al. Arch Neurol. 2010;67:180-6
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Carotid plaque measurementSummaryPlaque measurement is useful for:
Managing patientsStratifying riskManaging resourcesEncouraging patients to follow regimenMonitoring success of therapy
Genetic researchQuantitative traits for linkage studies
Studying effects of new therapiesMuch smaller sample size x durationProof of concept studies in human subjectsDose-finding studies
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Plaque measurement to study effects of new therapies• New therapies being developed for atherosclerosis - effective in animal models - no effect on blood pressure or lipids• It will be necessary to measure plaque - for dose finding studies - to demonstrate efficacy before committing to
very expensive events –based studies
Eg: inhibitors ACAT CETP, Leukotriene B4, etc.
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Sample size x duration required
To show a 30% reduction in rate of progressionPower 80%, p<0.05
IMT: 468 patients/group x 2 years1
(less with automated edge detection)
Plaque area: 75-100 patients /group x 2 years2
3-D plaque volume: ?1. Bots M et al, Stroke 2003;34:2985-2994 2. Hackam DG et al Am J Hypertens 2000;13:105-10.
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Disk segmentation
for measurement
of plaque volume
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Disk segmentation method
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First measurement of carotid plaque volume 1994
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Rendered plaque volume
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Plaque volume fixed at bifurcation
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Stroke 2005; 35: 1904-1909.
Plaque volume fixed at bifurcation
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3-D ultrasound carotid plaque volume: a tool for quickly measuring effects of treatment on atherosclerosis
38 patients with carotid stenosis >60% age 68 ± 6.6 years, 15 female, randomly assigned to atorvastatin 80mg daily
(n=17) vs placebo (n=21)
Stroke 2005; 35:1904-1909.
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Rate of plaque volume progression on placebo vs Atorvastatin 80mg
In 3 months:Placebo Atorvastatin 16.8 + 74.1 mm3 -90.24 + 85.12
mm3 (p<0.0001)
Stroke 2005; 35:1904-1909.
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Placebo Atorvastatin
Treatment group
-100.00
-50.00
0.00
Ch
an
ge in
pla
qu
e v
olu
me (
mm
3)
+-
SE
P<0.0001
Stroke 2005; 35:1904-1909.
3-month progression of carotid plaque volume with placebo vs. atorvastatin 80mg
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To show treatment effect in 3 months placebo progression 16.81 + 80 mm3
Sample size for change in progression of plaque volume
Power Effect size (% of atorva)
Regression in mm3
Sample size Per group
.9 10% -9 203
.9 25% -23 86
.9 50% -45 36
.9 75% -68 20
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Sample size for change in progression of plaque volume
To show treatment effect in 6 months assuming linear progression on placebo and regression on
active treatment; placebo progression 33.62 + 80 mm3
Power Effect size (% of atorva)
Regression in mm3
Sample size Per group
.9 10% -18 51
.9 25% -45 22
.9 50% -90 9
.9 75% -135 6
Stroke 2005; 35:1904-1909.
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Vessel Wall Volume
Egger M, Spence JD, Fenster A, Parraga G. Validation of 3D Ultrasound Vessel Wall Volume: An Imaging Phenotype of Carotid Atherosclerosis. Ultrasound Med Biol. 2007 Jun;33(6):905-14.
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Atorvastatin 80 vs placebo on VWV
VWV Placebo Atorvastatin p
+70 ± 140 mm3 -30 ± 110 mm3 <0.05
(14.9 ± 10.3%) (-1.4 ± 7.7%)
Krasinski A, Chiu B, Spence JD, Fenster A, Parraga G. Ultrasound Med Biol. 2009 Jul 31.
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DIRECT 3D Ultrasound Study
Shai I, Spence JD, Parraga A, Mallette C, Fenster JD et al. Circ 2010;121:1200-1208.
Atherosclerosis regression on all 3 diets, proportional to BP reduction and weight loss
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Annual change cannot be measured within patients by IMT
Resolution of carotid ultrasound is ~ 0.3mm
Mean rate of change of IMT is only 0.0147 for mean and 0.0176 for maximum IMT1
Large groups required to show changes for groups, not individuals
Mean change in TPA is 11mm2; can easily be measured.
1. Bots ML, et a. Stroke 2003 Dec;34(12):2985-94.2. Spence JD. Can J Cardiol 2008; 24 (Suppl C): 61C-64C.
11+ 34 mm2
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Plaque measurement is superior to IMT
• Greater dynamic range (~ 100-fold)• More predictive of stroke and MI• More sensitive to effects of therapy
Spence JD. Plaque measurement is superior to IMT. Atherosclerosis 2011.
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Treating arteries without measuring plaque is like
treating hypertension without measuring blood pressure
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3D Volume Analysis
Measurement of plaque volume at baseline, and change over time
Enable Imaging Technologies Beijing
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Acknowledgements3-D Ultrasound technology GeneticsDrs. Aaron Fenster, Grace Parraga Dr. Rob Hegele Measurements Lab Manager2-D : Maria DiCicco RVT Tisha Mabb3-D: Craig Ainsworth, Funding Anthony Landry, Chris Blake, NINDSMicaela Egger, Christiane Mallet, Silvia Riccio HSF Ontario Bernard Chiu, Shayna McKay, Adam Krasinsky CHRI Ulcers Dr. Vadim Beletsky, Jeremy Mason Plaque composition Jeremy Mason, Dr. Joseph AwadTCD Study Dr. Arturo Tamayo MRIDr. Claudio Munoz Dr. Brian RuttScanning PET/CTMaria DiCicco RVT Dr. Jean-Luc Urbain Janine Desroches RVT Dr. Ting Lee
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Acknowledgements
Maria DiCiccoR.V.T.Plaque area
Aaron FensterPh.D.Plaque volumePlaque roughness, texture3D U/S
Grace ParragaPh.D.Vessel wall volume
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http://www.robarts.ca/sparc [email protected]