Treating arteries instead of treating risk factors J. David Spence Stroke Prevention & Atherosclerosis Research Centre Robarts Research Institute London, Canada dspence@robarts.ca www.robarts.ca/sparc

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

Post-prandial oxidative stress and inflammation* * ROS, inflammatory mediators, oxidized LDL: not fasting Chol/Trig/HDL

Composite drawing of all plaques in extracranial carotids Large artery strokes Not just stenosis: also high plaque burden Plaque measurement very useful 79 yo woman 72 yo man Composite drawing of all plaques in extracranial carotids Bogiatzi C…Spence JD SPARKLE classification Neuroepidemiology 2014;42:243–251.

Ischemic stroke subtypes are changing Better BP control More statins Bogiatzi C ….Spence JD. Stroke. 2014 Sep 11

Ischemic stroke subtypes are changing Before 2005 After 2009 Cardioembolic strokes more common, large artery strokes less common Bogiatzi C ….Spence JD. Stroke. 2014;45:3208-13.

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 IMT Spence JD. Atherosclerosis. 2012;220:34-5.

Ultrasound measurement of “Atherosclerosis” It is important to recognize biological differences among Intima-media thickness - with and without plaque thickness Plaque Stenosis

Carotid Intima-Media Thickness (IMT) Mannheim consensus conference Site : common carotid artery , far wall , Quality Index > 0.50 Cerebrovascular Diseases 2007;23:75-80

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.

Measurement of IMT, plaque area and volume Al-Shali et al. Atherosclerosis 2005; 178: 319–325

Phenotypes of atherosclerosis Thus 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 distinct IMT: mainly hypertensive medial hypertrophy Plaque: reflects endothelial dysfunction, oxidative stress, lipids Stenosis: consequence of plaque rupture and thrombosis – reflects plaque instability, inflammation, MMP, thrombosis, impaired fibrinolysis Spence 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

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.

IMT isn’t atherosclerosis Correlation Between Carotid Intimal/Medial Thickness (IMT) and Atherosclerosis: A Point of View from Pathology Finn AV, Kolodgie FD, Virmani R. ATVB 2009 online

Measurement of 2-D Plaque area* * Invented in our lab in 1990 by Maria DiCicco, R.V.T.

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.

Baseline Carotid plaque area as a predictor of events Baseline Carotid plaque area as a predictor of events Stroke, MI, Death (after adjustment for risk factors*) *Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BP Stroke 2002; 33:2916-2922.

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

TPA increases AUC in ROC Romanens M, Spence JD et al. Cardiovasc. Med. 2011;14:53–57

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

5-year MI risk by Total Plaque Area Tertile Men Women IMT in the CCA was not predictive Johnsen, SH et al. Stroke 2007;38;2873-2880

10-year stroke risk more strongly predicted by plaque area in Tromsø Study 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 Mathiesen ES et al. Stroke 2011 online Feb 10

Distribution of carotid plaque area by age groups and sex Spence JD. Nature Clinical Practice Neurology 2006;2: 611-619.

Plaque progression despite therapy doubles the risk* Medical treatment was failing in half the cases, and they were at double the risk: we needed to do better! *Adjusted for Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BP Stroke 2002; 33:2916-2922.

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

Treating arteries without measuring plaque is like treating hypertension without measuring blood pressure

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 therapy 1.Barnett HJM. CMAJ 2004;171: 473-4 The high number needed to treat is entirely predicated on a low (3%) surgical risk in clinical trials; there would be no benefit expected with real-world surgical risk (see next slide)

TCD microembolus detection 319 ACS patients between 2000 and 2004 10% had microemboli 1-year Stroke Risk No 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.

Stroke risk over 2 years by baseline microembolic status Spence JD et al. Stroke 2005;36:2373-2378

Decline of microemboli with more intensive medical therapy < 5% of ACS patients can now benefit from carotid endarterectomy or stenting Spence JD et al. Arch Neurol. 2010;67:180-6 P<0.001 11% 2.2%

Annual rate of plaque progression in ACS patients before and since 2003 Spence JD et al. Arch Neurol. 2010;67:180-6

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

Plaque area by age group and clinic pop. age by year Spence JD, Hackam DG. Stroke 2010 Jun;41(6):1193-9

Average rate of plaque progression by year among all patients in clinic

Effects of more intensive therapy on plasma lipids in clinic population n=4,328

Rates of progression and LDL by year Spence JD, Hackam DG. Stroke 2010 Jun;41(6):1193-9

Decline in events in ACS with more intensive medical therapy No emboli n=431 Microemboli n=37 p Before 2003 n=199 Since n=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 3.2% 0.394 2.7% 0.104 Death in year 1 2.8% 0.069 4.4%% 2.4% 0.386 Death in year 2 2.1% 3.7% 0.477 3.8% 0.044 CEA year 1 12.9% 0.003 1.9% 0.739 CEA year 2 0.3% 0.146 1.1% 0.499 Stroke, death or CEA 1st 2 years 6.5% 32.4% <0.0001 14.1% 4.5% Stroke, death, MI or CEA 1st 2 years 8.6% 17.6% 5.2% Events declined markedly among patients with asymptomatic carotid stenosis after the paradigm change in 2003, though microemboli on transcranial Doppler remained strong predictors of risk. Spence JD et al. Arch Neurol. 2010;67:180-6

Carotid plaque measurement Summary Plaque measurement is useful for: Managing patients Stratifying risk Managing resources Encouraging patients to follow regimen Monitoring success of therapy Genetic research Quantitative traits for linkage studies Studying effects of new therapies Much smaller sample size x duration Proof of concept studies in human subjects Dose-finding studies

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.

Sample size x duration required To show a 30% reduction in rate of progression Power 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: ? Bots M et al, Stroke 2003;34:2985-2994 Hackam DG et al Am J Hypertens 2000;13:105-10.

Disk segmentation for measurement of plaque volume

Disk segmentation method

First measurement of carotid plaque volume 1994

Rendered plaque volume

Plaque volume fixed at bifurcation

Plaque volume fixed at bifurcation Stroke 2005; 35: 1904-1909.

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.

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.

3-month progression of carotid plaque volume with placebo vs 3-month progression of carotid plaque volume with placebo vs. atorvastatin 80mg P<0.0001 Stroke 2005; 35:1904-1909.

Sample size for change in progression of plaque volume To show treatment effect in 3 months placebo progression 16.81 + 80 mm3

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 Stroke 2005; 35:1904-1909.

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.

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.

DIRECT 3D Ultrasound Study Atherosclerosis regression on all 3 diets, proportional to BP reduction and weight loss Shai I, Spence JD, Parraga A, Mallette C, Fenster JD et al. Circ 2010;121:1200-1208.

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. 11+ 34 mm2 Bots ML, et a. Stroke 2003 Dec;34(12):2985-94. Spence JD. Can J Cardiol 2008; 24 (Suppl C): 61C-64C.

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.

Treating arteries without measuring plaque is like treating hypertension without measuring blood pressure

3D Volume Analysis Enable Imaging Technologies Beijing Measurement of plaque volume at baseline, and change over time

Acknowledgements 3-D Ultrasound technology Genetics Drs. Aaron Fenster, Grace Parraga Dr. Rob Hegele Measurements Lab Manager 2-D : Maria DiCicco RVT Tisha Mabb 3-D: Craig Ainsworth, Funding Anthony Landry, Chris Blake, NINDS Micaela 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 Awad TCD Study Dr. Arturo Tamayo MRI Dr. Claudio Munoz Dr. Brian Rutt Scanning PET/CT Maria DiCicco RVT Dr. Jean-Luc Urbain Janine Desroches RVT Dr. Ting Lee

Acknowledgements Maria DiCicco R.V.T. Plaque area Aaron Fenster Ph.D. Plaque volume Plaque roughness, texture 3D U/S Grace Parraga Ph.D. Vessel wall volume

http://www.robarts.ca/sparc dspence@robarts.ca