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

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

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

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.

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.

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.

To Study the Disease You Need to Image the Vessel Wall

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

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

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

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.

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

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

Combined CT and FDG-PET

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

Is Ultrasonic Assessment of Plaque Composition Possible?

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; 45:1946-53

Inhibition of Lp-PLA2 Attenuates Progression of Necrotic Core Change Volume (mm3) P=0.012 P=0.003 Serruys Circulation 2008; 118:1172-82

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

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

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

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

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

Is it the Right Drug Class for Imaging? Change PAV ApoA-I Milano Torcetrapib Nissen JAMA 2003;290:2292-2300; Nissen N Engl J Med 2007;356:1304-16

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