Major Revisions

• 1.0 - 17 Aug 2008 - Craig Bonsignore - First draft, based on Stent Summit 2008 conversations with Jen Goode, Donna Lochner, Paul Bishop, Chris Cheng, Alan Pelton.
  

Title

ASPECT-I:  Assessment of plaque composition, dynamic biomechanics, and therapeutic outcomes in subjects with implanted vascular devices.

Background

[Atherosclerosis / PAD background]
[Clinical intervention options, including medical, surgical, endovascular]
[Role of stents; off label issues] Stents are commonly used as an adjunct to percutaneous transluminal angioplasty (PTA), and have been demonstrated to improve outcomes relative to PTA alone in some cases [Ref Schillinger NEJM].

Motivation

Device designers lack fundamental boundary condition data to create realistic bench tests and simulations that adequately represent dynamic loading experienced by devices in a diseased population [Ref (unwritten) synopsis of Computational Methods workshop].  Animal models can not represent the lengths, diameters, and musculoskeletal relationships of human vasculature, and the mechanical properties of their healthy vessels are significantly different from  artherosclerotic plaques typical of human subjects.  Cheng [ref] has demonstrated human vascular deformations in healthy subjects, but such data is not representative of a diseased population, and does not include the influence of the implanted device. Nikanorov [ref] has studied vascular deformation of implants in cadavers, but such data lacks the influences of acute and chronic physiological conditions and biological response to the implant with time.   Several investigators have reported device fractures in various clinical studies [Duda, Scheinert, etc], and Jaff [ref] has proposed standards for reporting such fractures in future SFA/Proximal Popliteal studies. Rocha-Singh [ref] has proposed clinical trial guidance for investigational trials of stents for PAD in the femoropopliteal vessels.  These studies provide data of great interest to device designers, but the mechanical deformation data is limited to very small non-diseased or non-stented populations provide limited data in tabular form, and the clinical fracture data is collected at inconsistent time points, and are therefore of limited utility in building realistic models of diseased vessels.

None of these studies have been designed to provide engineers with direct and complete information required to accurately model vascular composition, deformation and loading, as it relates to an implant during its service life, in the setting of symptomatic peripheral arterial disease.  Because this data has been lacking, device manufactures have not been able to develop appropriate testing or simulation strategies, regulators have not had adequate information to anticipate device failures, clinicians have not had data with which to choose appropriate devices for specific disease presentations, and devices have experienced unanticipated high fracture rates in clinical use. 

The present study aims to correct the shortcomings of previous efforts by collecting extensive imaging of target vasculature before, during, and after device implantation.  The techniques described here will provide complete and detailed vessel morphology, plaque composition, and dynamic deformation data that can be used directly by engineers to create realistic models of symptomatic peripheral vascular disease.  This information will lead to more realistic bench tests with more accurately predictive results, less reliance on unrepresentative animal testing, ultimately less reliance on human clinical testing, and more durable and effective medical implants.  The techniques described in this pilot study can also be extended to investigate alternative devices and other therapeutic options.

Objective

The objectives of this study are to:

1. prospectively collect clinically relevant biomechanics boundary condition data, including plaque morphology and in situ deformation for specific cardiovascular disease states before and after intervention with implantable devices
2. make complete raw data and selected analyses available to the academic and commercial communities for research purposes to better inform selection, design, development, and analysis, and selection of vascular implants.
3. provide methodologies and infrastructure to encourage productive and direct collaboration between investigators, clinicians, regulators, and implant design engineers for this and future studies.
   

Specifically, we propose beginning with a focus on peripheral vascular disease of the superficial femoral artery (SFA) in a limited pilot study, enrolling 10-20 patients.  This pilot study is intended to demonstrate feasibility of selected imaging modalities, data collection, sharing, and storage, network collaboration strategies, and methods of analysis and reporting. Future studies will expand upon the methodologies developed here to include a more broad range of therapeutic options and clinical indications.

Study Design

The proposed SFA pilot study may include the following elements, though this is just a “straw-man” at this point, and will need input from clinical advisors. The least ambitious incarnation of this study could be a simple registry that is limited to a single imaging modality (i.e. flat plate digital x-ray), that captures only straight and flexed limb images at a single time point.  What I've described here is the most ambitious incarnation, involving multiple imaging modalities and multiple time points.  We'll need to discuss best approach in terms of cost/benefit and funding.

• Study Type

• Inclusion criteria
• Select for challenging cases: limbs with angiographically defined lesion length greater than 10cm, Rutherford class 3 or 4. QUESTION (jlg):  Need to also consider treatment of inflow/outflow disease as well, and what will be allowed in the study.
• For pilot study, limit enrollment to cases with failed PTA and elected stent implantation, because imaging modalities will depend on presence of a metallic implant to assess dynamic biomechanics of treated vessel.  (What are implications of fact that most stents are “off label” in USA?) NOTE (jlg):  If the stent manufacturer is willing to provide a letter of reference to FDA submission(s) that include pre-clinical testing information to demonstrate the safety of the device, then this might be sufficient to initiate an IDE from FDA's perspective.  If this letter of reference is not available, then detailed safety information on clinical use may be acceptable (might require going back through pt records which could be time consuming and costly). OBSERVATION (cb):  Hmmmm, this would suggest that the inclusion of any off-label device (most/all) would require the participation / involvement / support of its manufacturer, which could be time consuming / difficult... Is this a deal killer for a US based trial?  Would we then focus on a single manufacturer (perhaps ev3, since they have a limited approval for everflex)  COMMENT (jlg 9-26-08):  FDA could internally discuss what minimum clinical data might be needed to support use of a stent that is commonly used in practice of medicine. 

QUESTION (jlg 9-26-08):  Is it better to look at all patients (with variable disease) with a single stent, or to get data across both a range of stents and patient disease status?

QUESTION (jlg):  Is stenting after sub-optimal PTA the common clinical approach for R3-R4 pts?  I'm not sure it is.  It may be that PTA/cryo/laser/thrombectomy is all done to optimize channel prior to stenting, but I'm pretty sure that not everyone does this the same way.  If the pilot study is conducted at a single center, the lesion pre-treatment approach (prior to stenting) should be carefully captured (at a minimum).  In addition, the team should consider whether the pre-treatment approach is unique (from a clinical practice perspective), or common across the general practicing population.

• Time points and follow-up
• Pre-operative
• Intraoperative
• Follow-up at some combination of {1, 2, 6 ,12, 24} months.
  
  
• Imaging Modalities
• Computed Tomography:  Pre-operative CT angiography with contrast, and possibly follow-up CT with or without contrast at one or more of the follow-up points.
• Digital flat plate X-Ray: Straight and flexed positions
• IVUS preoperative: quantify and characterize plaque type, composition and volume as function of position.
• IVUS (Optional) Follow-up: If patient returns for diagnositic angio/intervention, IVUS exact segment imaged at treatment.
• 3D Rotational Angiography:  with contrast (and possibly also without, if possible), before and after stent implantation, and ideally with a straight and flexed limb. (CT may be redundant if 3DRA is available) QUESTION (jlg):  Should we consider 3DCT (w/o contrast) instead of 3DRA (I'm not sure what 3DRA gets us)?  From a conversation I had with Alex Nikanorov on Friday, it sounds to me like digital X-ray won't give the resolution needed in the tibials, but non-contrast 3DCT will give both strut fracture resolution and calcification location through the vessel wall.  If we want to set this SFA/Proximal Popliteal data set up to allow for quick follow-up data collection in the tibial bed, it might help to use the imaging modality that we expect might work (based on pictures Alex presented on Thursday). RESPONSE (cb): Good question for a clinical specialist that's familiar with pros/cons of each.  My rationale for 3DRA is based on an assumption that it allows for flexed limb imaging (does it?), which I don't think is possible with CT.  Maybe its a tossup.  
  
  
• Other diagnostics [Ref Rocha-Singh 2007]
• Duplex ultrasound at specified follow-up times to assess patency
• ABI
• Pedometer regimen at selected time points to collect quantitative data on patient mobility. [Ref Iida 2006]

Proposed Analysis: t=0 data

• Calcium map

• Deformation map, pre-stent

• 3DRA#1: Straight limb, with contrast
• 3DRA#2: Flexed limb, with contrast

• Deformation map, post-stent

• 3DRA#3: Straight limb, with contrast
• 3DRA#4: Flexed limb, with contrast

QUESTION (jlg):  could we collect access anatomy (across the aortoiliac arch) with this study?  We don't have great tracking models for iliofemoral indications and it would be great to make this kind of information publically available. Great suggestion.  Probably depends on the imaging modality - with angio type imaging, the field of view is typically such that the upper leg has to be divided into two or more imaging fields, so including the bifucation, iliacs, femorals, pop, tibials, etc would require an unreasonable number of imaging runs (can't to a moving 'follow-the-bolus' type of run and expect to get useful engineering data from it --- the I-I needs to be stationary).  Might be more practical to capture this type of anatomical data with CT.  May have an impact on the amount of contrast and radiation, but the experts will have to comment there.

Proposed Analysis: t=0,1,6,12,24m data

• Implant deformation map

Data Management

The intention of the study is to collect and store all imaging and other patient data such that it can be anonymized appropriately and shared as completely as possible with the clinical, academic, and commercial community, pursuant to the requirements of HIPAA and related privacy and ethics standards.   It is anticipated that a core lab will be used to collect, store, and analyze all imaging and patient data, and will also likely provide the IT infrastructure to share this data live via an internet site, and/or by request for a nominal fee on physical media.

Other Considerations

• Interested parties / stakeholders:  Clinicians; Societies; Commercial device manufacturers, large and small; Regulators. Alex Nikanorov.  Charley Taylor.  VIVA Physicians Inc has been active in this area – we should run this by them at some point.

• Sponsor: Several options for the entity that sponsors this study.  Sponsor raises the funds, and thus controls the direction of the study.  Want to be unbiased, independent of industry and “conflicted” interests as possible.

• Academic/Clinical Institution:  i.e. Cleveland Clinic Foundation (has all clinical, infrastructure, analysis resources under one roof)
• Physician Group: i.e. VIVA Physicians Inc (established nonprofit focused in this clinical space)
• Independent Foundation: i.e. Open Medsystems Foundation (founded explicitly to promote open sharing and collaboration in medical device community)
• Government: NIH or FDA (complicated)
• Commercial: (tried that, not a great idea)

• Funding: Estimate $10-15k/patient, for a total of $100k - $300k for a 10-20 patient pilot study. Industry contributions are least desirable, unless they are completely unrestricted (donate devices?).  Government grants are best, but likely to take time... Need advice there.  Foundation or private grant?

• Principal Investigator: Clinician to represent the cause.  Kashyap @ CCF?  One of the VIVA physicians?

• Resources:  Bonsignore, Cheng, Goode will be active contributors within bounds allowed by day jobs.  FDA Critical Path Initiative – possible to fund an analyst for some time if beneficial. NIH?  CCF has core lab, docs, clinical trial infrastructure, etc.  Ideally: sponsor gets funding, then hires someone to run the trial.

Some useful citations, in no particular order

• Jaff 2007.  Catheter Cardiovasc Interv. 2007 Sep;70(3):460-2. Standardized evaluation and reporting of stent fractures in clinical trials of noncoronary devices.
• Rocha-Singh 2007.  Catheter Cardiovasc Interv. 2007 May 1;69(6):910-9. Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease
• Nikanorov 2008. J Vasc Surg. 2008 Aug;48(2):435-40. Epub 2008 May 16. Fracture of self-expanding nitinol stents stressed in vitro under simulated intravascular conditions.    
• Bishop 2008.  Ann Vasc Surg. 2008 Jul 18. [Epub ahead of print]. Arterial Calcification Increases in Distal Arteries in Patients with Peripheral Arterial Disease   
  
• Rits 2008. Eur J Vasc Endovasc Surg. 2008 Jul 3. [Epub ahead of print]. The Incidence of Arterial Stent Fractures with Exclusion of Coronary, Aortic, and Non-arterial Settings     (Review to Feb 08)
• Schillinger 2006. N Engl J Med. 2006 May 4;354(18):1879-88. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery  
  
• Iida 2006.  Am J Cardiol. 2006 Jul 15;98(2):272-4. Epub 2006 Jun 6. Effect of exercise on frequency of stent fracture in the superficial femoral artery  
  
• Cheng 2006.  J Vasc Interv Radiol. 2006 Jun;17(6):979-87. In vivo MR angiographic quantification of axial and twisting deformations of the superficial femoral artery resulting from maximum hip and knee flexion   
  
• Scheinert 2005.  J Am Coll Cardiol. 2005 Jan 18;45(2):312-5. Prevalence and clinical impact of stent fractures after femoropopliteal stenting
  
• Goode 2007.  Catheter Cardiovasc Interv. 2007 May 1;69(6):920-1. FDA perspective on clinical trial design for femoropopliteal stent correction of peripheral vascular insufficiency cardiovascular devices.
  
• Duda 2006.  J Endovasc Ther. 2006 Dec;13(6):701-10. Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial