1. Treating arteries instead of treating risk factors
J. David Spence
Stroke Prevention & Atherosclerosis Research Centre
Robarts Research Institute
London, Canada

2. 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

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

4. 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.

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

6. 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:

7. 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.

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

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

10. 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 (similar to R2 for coronary events)
Stenosis (Doppler velocity) R2 is 0.132
1. O’Leary DH, et al Stroke 1996; 27:
2. Spence JD, Hegele RA Stroke 2004; 35:

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

12. 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:
Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol Nov;24(11):e188

13. Plaque is more closely related to coronary artery disease than IMT
Ebrahim S, et al. Stroke 1999; 30:
Chan SY et al. J Am Coll Cardiol. 2003;42:
 Brook R et. al. ATVB 2006;26:
Johnsen, SH et al. Stroke 2007;38;
Inaba Y, et al. Atherosclerosis. 2011;220:

14. 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

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

16. Carotid Plaque Area as predictor of events
1,686 patients in our Atherosclerosis Prevention Clinic followed up to 5years
During mean followup of 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:

17. 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:

18. 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

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

20. 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;

21. 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;

22. 10-year stroke risk more strongly predicted by plaque area in Tromsø Study
Hazard ratio 1.73 for men(p=0.004), for women (p=0.03)
No differences for quartiles of IMT
Total plaque area
Mathiesen ES et al. Stroke online Feb 10

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

24. 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:

25. 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

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

27. 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 *
  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)

28. 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 ( ) (4.1-79)
p<0.0001
Spence JD et al. Stroke 2005; 36:

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

30. 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%

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

32. 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

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

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

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

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

37. 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

38. 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

39. 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.

40. 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: patients /group x 2 years2
3-D plaque volume: ?
Bots M et al, Stroke 2003;34:
Hackam DG et al Am J Hypertens 2000;13:

41. Disk segmentation for measurement of plaque volume

42. Disk segmentation method

43. First measurement of carotid plaque volume 1994

44. Rendered plaque volume

45. Plaque volume fixed at bifurcation

46. Plaque volume fixed at bifurcation
Stroke 2005; 35:

47. 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:

48. Rate of plaque volume progression on placebo vs Atorvastatin 80mg
In 3 months: Placebo Atorvastatin mm mm3 (p<0.0001)
Stroke 2005; 35:

49. 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:

50. Sample size for change in progression of plaque volume
To show treatment effect in 3 months
placebo progression mm3

51. 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 mm3
Stroke 2005; 35:

52. 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 Jun;33(6):

53. 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 Jul 31.

54. 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:

55. Annual change cannot be measured within patients by IMT
Resolution of carotid ultrasound is ~ 0.3mm
Mean rate of change of IMT is only for mean and for maximum IMT1
Large groups required to show changes for groups, not individuals
Mean change in TPA is 11mm2; can easily be measured.
mm2
Bots ML, et a. Stroke 2003 Dec;34(12):
Spence JD. Can J Cardiol 2008; 24 (Suppl C): 61C-64C.

56. 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.

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

58. 3D Volume Analysis
Enable Imaging Technologies Beijing
Measurement of plaque volume at baseline, and change over time

59. 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

60. 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

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