Correlation Between Coronary and Carotid Atherosclerotic Disease and Links With Clinical Outcomes

Global Observational Study to Evaluate the Correlation Between Coronary and Carotid Atherosclerotic Disease (CAD) and Links With Clinical Outcomes

The relationship of the natural history of atherosclerosis between different vascular beds has not been well characterized. Determination and comparison of the relative rates of progression and extents of atherosclerosis in the coronary and carotid arterial trees may have major impacts on clinical research and clinical practice. Correlation between findings in the carotid and coronary circulations is an important scientific and clinical topic to address. Results from a well design study incorporating imaging technologies that currently represent the gold standards for the assessment of coronary and carotid artery plaque burden, will have potentially impact on clinical research and clinical practice.

The CAIN-003 study was a prospective observational multi-center imaging study of subjects scheduled for clinically-indicated coronary angiography. CAIN-003 provided for the collection of baseline coronary angiography and IVUS imaging data along with baseline carotid ultrasound imaging. CAIN-003 study participants underwent follow-up coronary and carotid imaging at 2-years, and were then contacted by phone on an annual basis for an additional 3 years for the collection of cardiovascular and cerebrovascular clinical endpoints.

MHICC-31052012 was a prospective, observational, multi-center study of subjects who had successfully undergone baseline imaging in the dal-PLAQUE 2 study (A multicenter, double-blind, randomized, placebo-controlled study, evaluating the effect of treatment with dalcetrapib 600 mg on atherosclerosis disease). The dal-PLAQUE 2 study, which provided for the collection of baseline and 2-year follow-up coronary angiography, coronary IVUS and carotid ultrasound imaging data, was terminated by the sponsor prior to completion due to the discontinuation of the dalcetrapib drug development program. The MHICC-31052012 study allowed for the collection of follow-up imaging and clinical endpoint data from subjects who had successfully undergone baseline IVUS imaging in dal-PLAQUE 2.

Data from CAIN-003 and MHICC-31052012 was pooled to support the objective of determining the correlation and clinical relevance of these imaging endpoints.

The objectives of the CAIN-003 and MHICC-31052012 study were:

• To compare the extent of atherosclerosis present in the coronary vasculature with the extent of atherosclerosis present in the carotid vasculature at a single point in time.
• To compare the associations of atherosclerosis burden with coronary risk factors in the coronary arteries and carotid arteries, in multivariable regression.
• To compare the rate of atherosclerosis progression or regression in the coronary vasculature with the rate of atherosclerosis progression or regression in the carotid vasculature over a 2-year period.
• To determine the correlation between imaging biomarkers and cardiovascular outcomes over a 5-year period.

Inclusion Criteria:

1. Male and female patients over the age of 18 years.

2. Patients scheduled for clinically indicated coronary angiography and possible ad hoc percutaneous coronary intervention (PCI) will be evaluated before their scheduled procedure.

3. Written informed consent (approved by the Institutional Review Board [IRB]/Independent Ethics Committee [IEC]) obtained prior to any study specific procedures.

4. Patients considered to be stable at enrollment (at the discretion of the investigator) are eligible provided they meet all other entry criteria.

5. Angiographic inclusion criteria:

   • Entire Coronary Circulation: The patient must have angiographic evidence of coronary artery disease as defined by at least one lesion in any of the three major native coronary arteries that has >20% reduction in lumen diameter by angiographic visual estimation or prior history of PCI. This vessel does not need to be the target coronary artery for IVUS. Any vessel with previous PCI may not be used as the target coronary artery.
   • Left Main Coronary Artery: The patient must not have > 50% reduction in lumen diameter by visual angiographic estimation.
   • Target Coronary Artery: Patient will be required to have one "target" coronary artery for IVUS that has not undergone prior PCI, that is not a candidate to undergo PCI presently or in the next 24 months, and that has not been the cause of a recent myocardial infarction. The proximal 4 cm of the "target" artery in which

IVUS examination will be performed at baseline:

• Must have a diameter stenosis < 50% lumen diameter by visual assessment of the angiogram;
• Must have a reference diameter > 2.5 mm;
• Must be free of filling defects suggestive of thrombus;
• Must not present any anatomical characteristic (such as but not limited to severe tortuosity or calcification) that would impede IVUS interrogation at baseline or follow-up
• Note: a lesion of up to 60% stenosis is permitted, distal to the target segment. A side branch of the target coronary artery for IVUS may not be a target for PCI.

Exclusion Criteria:

Subjects presenting with any of the following will not be included in the study:

1. Women of childbearing potential (women who are not surgically sterile or postmenopausal defined as amenorrhea for >12 months) who refuse to undergo a urine or serum pregnancy test immediately prior to baseline and repeat imaging evaluations The urine or serum pregnancy test must be negative prior to imaging evaluations.
2. Previous coronary artery bypass graft (CABG) surgery or probable need for CABG in the next 24 months.
3. Patients who have symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class III or IV) at baseline.
4. Patients with clinically significant valvular heart disease likely to require surgical repair or replacement during the treatment period of the study
5. Any clinically significant medical condition or presence of any laboratory abnormality that is considered by the investigator to be clinically important and could interfere with the conduct of the study.
6. The presence of severe liver disease as defined by the presence of cirrhosis, chronic active hepatitis, or chronic jaundice with hyperbilirubinemia,
7. Patients with eGFR < 45 ml/min prior to baseline imaging procedures, or with nephrotic syndrome
8. Patients with a life expectancy less than 2 years.
9. History of malignancy (except for curatively treated basal cell or squamous cell carcinoma of the skin) during the 3 years prior to the screening.
10. Unable or unwilling to comply with protocol requirements, or deemed by the investigator to be unfit for the study.