Clinical

VERDICT (Vascular Evaluation for Revascularization: Defining the Indications for Coronary Therapy: A Pilot Study) is a prospective, global, multicenter study sponsored by Volcano to determine the correlation between fractional flow reserve (FFR) and Intravascular Ultrasound with Virtual Histology (VH-IVUS) in patients with intermediate coronary lesions. Up to 300 patients at approximately 12 sites in Europe, South Africa and U.S. will be enrolled in this study. The primary study objective is to establish the correlation between FFR and VH-IVUS-derived parameters in patients with intermediate coronary lesions (≥40% to <80% diameter stenosis, as visually assessed by angiography). Specifically, to determine the extent to which pull back, lesion length, and VH-TCFA plaque type improve the correlation between FFR and MLA. Patients will be followed for 3 years. Enrollment started in Q3 and will continue though Q2 of 2011

(VH in Carotids Observational Registry) An Investigator initiated multicenter, non-randomized prospective registry in Europe to confirm the feasibility of IVUS and VH during carotid interventions. The registry enrolled 119 patients at 10 sites in Italy, Poland . Results were presented at Late Breaking Trials at PCR 2010 by Dr. G. Sangiorgi who summarized IVUS-VH imaging is safe and feasible during CAS. Further he stated for primarily asymptomatic patients there was no correlation between lesion complexity and clinical presentation at the time of the interventions. The publication of these results is expected in the near future.

(Bifurcation Lesion Analysis and Stenting) Volcano is sponsoring the BLAST trial where we expect to demonstrate that IVUS with VH guidance leads to better post procedural outcomes when compared to angiography alone. 195 patients in approximately 11 sites in the U.S. and Europe were randomized to angiography alone or angiography with grayscale IVUS and VH to best determine the treatment of the lesion. Enrollment ended in December of 2010. Follow up will continue throughout 2 years after baseline. Results were presented at Late Breaking trials at PCR in May.

(Assessment of Dual Anti-Platelet Therapy with Drug-Eluting Stents). Volcano is excited to participate in the ADAPT-DES trial being conducted in approximately 10 sites in both the U.S. and Europe. ADAPT-DES is a prospective registry of at least 11,000 and up to 15,000 patients with coronary artery disease undergoing stent assisted intervention using DES. The objective of the study is to determine the frequency, timing and correlates (clinical and angiographic) of drug eluting stent thrombosis in the study population and the relationship of aspirin and/or clopidogrel response in this population. There is an IVUS sub-study that will include 3,000 patients to determine whether one or more IVUS parameters are independent predictors of stent thrombosis. Enrollment goal was met at the end of September 2001. Expect results early in 2011.

(Fractional Flow Reserve and Intravascular Ultrasound RelationShip Study) This is a multi-center, prospective registry of patients with intermediate coronary lesions defined as a stenosis of 40-80% by angiography. Approximately 300 patients will be enrolled into the study at sites in the United States and Europe. There will be no follow up beyond hospital discharge in this study. A sub-group of 30 patients will undergo Adenosine MRI. The objective is to evaluate the relationship between IVUS RF (Intravascular Ultrasound Radiofrequency) anatomical parameters and FFR value in patients with intermediate coronary stenoses, and to determine the IVUS RF anatomical criteria and cutoff value associated with significantly functional criteria of FFR<0.8. Enrollment started in September 2011 and will be completed by the end of Q2 2011.

(FFR Registry Freedom from Angiography Alone is Simple and Trouble-free) This is a prospective, post market registry of FFR cases in the U.S. and EU. Approximately 220 cases will be enrolled in up to 22 sites in the U.S. and EU. The objective of the FAAST Registry is to gather information on FFR use times in intermediate lesions. The information collected will include “time to answer” and “time to treatment”, and the amount of contrast and fluoroscopy/cine time.

(Canadian Atherosclerosis Imaging Network) Correlation between coronary and carotid atherosclerotic disease and links with clinical outcomes is a prospective, multi-center imaging study expecting to enroll approximately 2000 patients scheduled for clinically-indicated coronary angiography. The objectives are to compare the atherosclerosis present in the coronary vasculature with the extent of atherosclerosis present in the carotid vasculature, compare the rate of disease progression in the coronary and carotid vasculature, and to characterize the association between changes in the coronary and carotid vasculature measurements from baseline to 24 months. Patients will undergo a coronary intravascular ultrasound (IVUS) examination and a carotid ultrasound examination (the latter allowing measurements of the intimal-medial thickness and 3-D ultrasound assessment of carotid plaque burden). Following a 24-month follow-up period, patients will then undergo repeat coronary intravascular ultrasonography and standard invasive coronary angiography as well as carotid ultrasound examination Patients will also be contacted by phone on an annual basis for 5 years to collect cardiovascular and cerebrovascular events.

(Aliskiren QUantitative Atherosclerosis Regression Intravascular Ultrasound Study, is a randomized, double blind study to evaluate the efficacy and safety of aliskiren on the progression of atherosclerosis in patients with coronary artery disease in addition to optimal background therapy. The study is sponsored by Novartis. It will be conducted in approximately 10 countries and will enroll approximately 600 patients. The primary objective is to measure the change in the progression of coronary atherosclerosis (defined as change from baseline in percent atheroma volume) as assessed by IVUS. Approximately 50 of the sites will be using Volcano s5™ IVUS systems to obtain the images. Enrollment has started and expects to be complete next year. The trial will conclude in 2013.

(Study of LoSmapimod Treatment on Inflammation and InfarCt SizE ) sponsored by GlaxoSmithKline is a randomized, double-blind, placebo-controlled study to evaluate the safety of 12 weeks of dosing with GW856553 and its effects on inflammatory markers, infarct size, and cardiac function in subjects with myocardial infarction without ST-segment elevation. This is a randomized, double-blind, placebo-controlled, parallel group, multi-center study to evaluate initial safety and efficacy in subjects with NSTEMI. Up to approximately 500 subjects in the U.S., Australia, Canada and Europe will be randomized to complete 12 weeks of dosing. Approximately 70 of the randomized subjects will also participate in a coronary flow and pressure sub-study. All subjects will continue to receive the local standard of care for the duration of the study.

The primary objectives of this study is to assess the safety of GW856553 in subjects with NSTEMI, assess the effects of GW856553 on biomarkers of inflammation in subjects with NSTEMI over the 12 weeks of treatment and to assess the effects of GW856553 on infarct size and cardiac function during the peri-infarct period and during the ensuing 12 weeks of treatment.

The PROSPECT data was recently published in the New England Journal of Medicine. PROSPECT is the first and only natural history study that tracked the clinical outcomes, hospital readmissions, and subsequent coronary events in 700 patients with acute coronary syndrome (ACS) over three years. The investigators assessed these patients' coronary arteries by taking very detailed measurements and interior images of all 3 arteries. The PROSPECT Trial showed that of the 55 different parameters measured, IVUS and VH IVUS measurements were the only 3 parameters that could statistically predict lesion risk. The investigators found that lesions with certain high-risk characteristics relatively small lumen area, a large amount of plaque, and a lot of dead tissue or necrosis near the lumen as identified by VH IVUS, had an almost 20% risk of a cardiac event within three years. These lesions were classified as „predictive‟ by the investigators. Conversely, certain low-risk lesions where that same necrotic tissue was not present in the study had a significantly lower event rate of only 0.6% out to three years. These lesions were termed „protective‟ by the PROSPECT team.

The detailed analysis that was performed using both angiographic and IVUS data points from the patients that were enrolled showed that of the 55 imaging parameters measured, grayscale IVUS and VH® IVUS identified the only individual parameters that could statistically predict lesion risk for future clinical events. Based on detailed core lab analysis, these three lesion level factors were presence of VH-TCFA, MLA <4mm2, and Plaque Burden >70%.

The combination of large plaque burden (IVUS) and a large necrotic core without a visible cap (VH-TCFA) identify lesions which are at especially high risk for future adverse cardiovascular events.

In addition to these three positive predictors, the study also revealed a negative predictor in Pathological Intimal Thickening, or PIT, lesions. A PIT lesion does not contain VH TCFA. In the 960 PIT lesions that were deferred based on VH® IVUS and PROSPECT data there were only six events at 3.4 years (0.2%). These predictors were not detectable by angiography; they were only identified by IVUS and VH® IVUS. With these lesion characteristics, the PROSPECT investigators were able to classify over 2,000 lesions into two categories: High-risk non-culprit lesions and Low-risk non-culprit lesions. Being able to define a high-risk non-culprit lesion with IVUS and VH® IVUS could allow the physician to implement the proper therapy based the lesion‟s prospective risk.

The more we can understand about the disease we are treating, the further we can advance as a cardiology community. PROSPECT has provided an important step forward by showing that we can see a difference in lesions, supported by clinical evidence. Understanding a problem is the first step to solving it. Our knowledge is increasing, as IVUS is now used in approximately 16% of U.S. procedures and VH® IVUS tissue characterization has been studied in more than 10,000 patients globally.