Lesion Preparation Using Diamondback 360 OAS Shown to Enhance Paclitaxel Distribution in Calcified PAD
September 11, 2017—CBSET announced that its scientists have published data and analyses regarding the barrier effects of calcified plaque on drug delivery and the treatment success of adjunctive lesion preparation therapy in the treatment of peripheral atherosclerosis. CBSET is a not-for-profit preclinical research institute dedicated to translational research, education, and advancement of medical technologies.
According to CBSET, these data demonstrated enhanced paclitaxel distribution in calcified human arteries after lesion treatment using the Diamondback 360 orbital atherectomy system (OAS; Cardiovascular Systems, Inc.) in a cadaver model with simulated flow and are published by Abraham R. Tzafriri, PhD, et al online in Journal of Controlled Release.
The study's Lead Investigator, Elazer Edelman, MD, who is Chairman and Co-Founder of CBSET, commented in the announcement, “The data are exciting in that they suggest that subtle modification to the plaque surface can have profound effects on drug penetration. Massive debulking may be a relic of the past, and a more muted approach may extend endovascular intervention for peripheral artery disease treatment into vessels even below the knee. This paradigm shift, which relies on quantitative studies, creates an opportunity for the medical device industry to optimize drug-delivery therapies to complex lesions.”
Dr. Tzafriri, who is Director of Research and Innovation at CBSET, added, “CBSET is committed to the development of novel experimental and computational models for defining the barrier effects of tissue components on drugs of interest and evaluating novel endovascular therapies. Quantification of the barrier effects of calcified plaque through computational modeling of arterial drug distribution experiments provides a framework by which to evaluate and optimize a range of emerging drug delivery and lesion preparation therapies for peripheral artery disease.”
As summarized in Journal of Controlled Release, the CBSET investigators evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque.
Diagnostic angiography and three-dimensional rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using the OAS under simulated blood flow and fluoroscopy.
The investigators conducted either histomorphometric assessment of effect or tracking of 14-C-labeled or fluorescent-labeled paclitaxel of explanted arterial segments. Radiolabeled drug-quantified bulk delivery and fluorescent label established penetration of the drug over finer spatial domain in serial microscopic sections. Results were interpreted using a mathematical model of binding-diffusion mediated arterial drug distribution.
In Journal of Controlled Release, the investigators reported that lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate-constant of 14-C labeled, declining 5.5-fold per calcified quadrant (P = .05; n = 7).
Compared to controls, OAS-treated femoropopliteal segments exhibited 180 μm thinner intima (P < .001), 45% less plaque calcification, and two log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls due to a 70% increase in diffusivity (P < .001).
These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries, concluded the investigators in Journal of Controlled Release.
In CBSET's press release, Michael R. Jaff, DO, commented, "These data suggest that clinical association of diminished efficacy of antirestenotic drugs in severely calcified arteries is at least partly due to limitations in drug absorption.” Additionally, Dr. Jaff stated, "This preclinical demonstration of the hindrance of drug distribution by calcified tissue and improved drug delivery after modification of calcified atherosclerotic plaque could have significant clinical implications.” Dr. Jaff is President of Newton-Wellesley Hospital, and Professor of medicine, Harvard Medical School in Boston, Massachusetts. He has no formal financial relationship with CSI or CBSET, noted the announcement.