1. Stephen J Nicholls MBBS PhD FRACP FACC
The Future of Imaging as a Surrogate in the Development of New Cardiovascular Drugs
Stephen J Nicholls MBBS PhD FRACP FACC
Cleveland Clinic
Heart & Vascular Institute

2. Disclosures
Honoraria from AstraZeneca, Pfizer, Merck, Roche and Takeda
Consultant for AstraZeneca, Pfizer, Merck, Roche, Takeda, Novo-Nordisk, Anthera and LipoScience
Research support from AstraZeneca, Novartis, Resverlogix, Roche and Eli-Lilly

3. Residual Clinical Risk in Statin Trials
JUPITER
WOS
AF/Tex
LIPID
CARE
HPS
2o PREVENTION
1o PREVENTION
HIGH RISK
Percent of Events
Residual Events
Prevented Events

4. Surrogate Endpoints Requirements - Logical and Statistical Criteria
Changes in the surrogate must be predictive of the relevant clinical outcome
Surrogate must fully (or nearly so) capture the effect of the intervention on the clinical outcome.
Disease
Intervention
Surrogate
Endpoint
True Clinical
Outcome
DeMets and Califf. Circulation 2002;106:746.

5. The development of a range of imaging modalities enable us to directly visualize the artery wall at different points in time. And this gives us a powerful tool to assess the impact of therapies on the natural history of plaque progression.

7. 50 Years of Coronary Angiography
And for nearly 50 years the best imaging modality for the detection and quantitation of CAD has been angiography. However, we have come to realise that while it is extremely effective in helping us to triage patients to a range of medical and revascularization strategies, angiography does not image plaque. It provides a 2-D silhouette of the vessel lumen and does not visualize the wall, the site in which plaque accumulates. In other word we see the hole in the donut but not the donut itself.

8. To Study the Disease You Need to Image the Vessel Wall

9. Ultrasound Determination of Atheroma Area
Precise Planimetry of EEM and Lumen Borders with Calculation of Atheroma Cross-sectional Area
EEM Area
Lumen Area
Our major focus over the last 10 years has been to develop IVUS to quantify plaque burden and do it in a serial fashion. Our analysts sit in a dark room all day and trace circles, the lumen and the EEM. Given the negligible thickness of the media, the area in between is regarded as plaque.
Atheroma Area

10. Beneficial Impact on Disease Progression with IVUS
Intensive lowering of LDL cholesterol
Anti-inflammatory properties of high-dose statins
Intensive lowering of blood pressure
Infusing HDL
Pioglitazone in patients with type 2 diabetes

11. Atheroma Burden and Incident Clinical Events
Change PAV
Yes No
P=0.04
Change Percent Atheroma Volume
PAV
Baseline Percent Atheroma Volume
P<0.001
Incidence of cardiovascular death, myocardial infarction, hospitalisation for unstable angina, stroke and coronary revascularisation
ILLUSTRATE (n=1180)
Nicholls AHA Scientific Sessions 2007

12. Recurrent Myocardial Infarction
Complementary Impact on Plaque Progression and Clinical Events
Change in % Atheroma Volume (%)
REVERSAL
PROVE IT - TIMI 22
Recurrent Myocardial Infarction
of Coronary Death (%)
Furthermore, when we stratified according to degree of LDL and CRP lowering we see exactly the same effect. This is an important observation for IVUS in which we see the same impact on plaque as we observe with clinical outcome.

13. Coronary Calcium Correlates with disease burden
Predicts cardiovascular events
Proposed role in risk prediction
Lack of impact of intensive lipid lowering questions utility in evaluation of new therapies

14. CT Angiography Increasing resolution with technology advances
Strength is negative predictive value
Clinical role is unknown
Uncertain whether resolution is sufficient to evaluate therapies

15. Combined CT and FDG-PET

16. Magnetic Resonance Imaging
High resolution imaging of full artery wall thickness
Potential to assess burden, composition and functionality
Early studies demonstrate benefit of statins on burden and composition
Largely limited to imaging of aorta and carotids

17. Is Ultrasonic Assessment of Plaque Composition Possible?

18. Statins and Plaque Composition
Pravastatin
Atorvastatin
% Plaque Area
Baseline
Follow-up
Fibrous Tissue
Lipidic Tissue
Pravastatin
Atorvastatin
% Plaque Area
P<0.05
P<0.05
P<0.01
P<0.01
Kawasaki J Am Coll Cardiol 2005; 45:

19. Inhibition of Lp-PLA2 Attenuates Progression of Necrotic Core
Change Volume (mm3)
P=0.012
P=0.003
Serruys Circulation 2008; 118:

20. Plaque Composition and Burden Predict Risk of Events
TCFA
PB>70% TCFA
PB>70%
MLA<4mm2
PB>70% MLA<4mm2 TCFA
P<0.0001
P<0.0001
P<0.0001
P<0.0001
P<0.0001
Stone TCT 2009

21. Functional Activity of Plaque
Plaque Burden
Plaque Composition
Functional Activity of Plaque
Arterial Remodeling
Clinical Event

22. Novel Invasive Modalities
Thermography
Palpography
Spectroscopy
Optical coherence tomography
Each require ongoing validation
Potentially provide complementary, but not comprehensive, evaluation of plaque

23. Molecular Imaging Can We Assess Plaque Activity?
FDG Metabolic Activity
Macrophage Iron Uptake
Thrombus Formation
Angiogenesis
Cathepsin Activity
Choudhury Nat Rev Drug Disc 2004;3:913-25

24. Challenges for Emerging Modalities
Resolution
Standardization of approaches
Ease of use
Increasing validation
Relationship with clinical outcome

25. Is it the Right Drug Class for Imaging?
Change PAV
ApoA-I Milano
Torcetrapib
Nissen JAMA 2003;290: ; Nissen N Engl J Med 2007;356:

26. Ultimate Objective
There is an ongoing need to develop new anti- atherosclerotic therapies
Arterial wall imaging can be employed at an early stage of clinical development to assess potential efficacy of novel agents
The ultimate fate of these therapies will be determined in large morbidity-mortality trials