Five Considerations When Embarking on an Embolic Protection Device Trial

The TAVR Market

An estimated 300,000 patients worldwide have received transcatheter aortic valve replacement (TAVR) for severe aortic stenosis. TAVR is a minimally invasive, equally safe alternative to surgical replacement of the affected valve. The commercial market for TAVR is poised to grow to $7.45 billion by 2025­­­­­­1 as EU and US regulatory authorities have recently expanded indications to include patients with intermediate risk of death or complications. TAVR itself, however, is not without its own set of risks. The procedure can dislodge micro-debris that can cause cerebral embolization and lead to risks of stroke, cerebral lesions, and neurological complications.2 Embolic protection devices (EPDs), which deflect the debris into the descending aorta away from the three cerebral arteries or collect debris before it can enter these arteries, may reduce the incidence and severity of this risk.

The medical device community has noted the market potential of EPDs, too. As of March 2017, more than a dozen companies are developing the technology. Three devices have EU market clearance for use with TAVR, and one has received an FDA advisory panel recommendation for US approval. If EPDs become standard for TAVR and other interventional cardiac procedures, their commercial market could reach $1 billion.1

To understand the impact of EPDs on patients’ stroke risk, sponsors must first understand how to measure stroke. In just the past few years, the use of clinical imaging has increased the diagnosis of stroke to include silent strokes. Current EPD trials use silent strokes/brain lesions as a surrogate marker for disease, even though the clinical relevance of such lesions for TAVR patients is not firmly established due to mixed results.

With vast experience helping sponsors progress along the 510(k) pathway for cardiovascular medical devices, Novella provides sponsors exploring different EPD designs with a complimentary resource titled “Clinical Trial Considerations in Cerebral Protection for TAVR Patients.” Here is a summary of the five crucial factors described when designing a trial protocol:

1. The right patient populations

EPD/TAVR study patients must have stable health for 30 days before the procedure, and must undergo assessments of the valve severity, comorbidities, and mortality risk, which can challenge recruitment procedures compared to other cardiac device trials.

2. Strong site teams

Sponsors should select sites with a track record of commitment to strong patient enrollment and retention. They must also coordinate with sites for more time and resources than are usually expected with other device studies. In addition to a core team of a heart failure/valve cardiologist, an interventional cardiologist, and cardiovascular surgeons and imaging specialists, Novella recommends including geriatricians and potentially also heart failure experts, stroke neurologists, electrophysiologists, anesthesiologists, and behavioral specialists to the team. A committed, organized and multidisciplinary interventional and surgical heart team can help a sponsor achieve the best patient outcomes, both in study settings as well as in post-approval commercial use of the devices.

3. Careful definition of endpoints

EPD trial endpoints must cover many aspects of safety and efficacy. To best understand complications, sponsors of EPD trials should ensure their protocols include standardized definitions and criteria for the known and probable clinical, neurological and cognitive symptoms of overall health, stroke and brain lesions. Novella also recommends that endpoints should fall within existing and anticipated regulatory requirements, whether for the internal review board of an individual site, or for national marketing clearance criteria.

4. Accurate stroke definition and assessment

In a document updating the definition of stroke to account for advances in science and technology, the American Heart Association/American Stroke Association recommended that stroke definitions “should always reflect the goals of a given research study and should be carefully specified before initiating the trial.”3 AHA/ASA guidance also makes provisions for how to address the inclusion of clinically silent brain lesions as endpoints, and how to accommodate changes in imaging technology.

5. Superior detection modality

MRI with diffusion-weighted imaging is considered the gold standard for detecting and quantifying brain ischemia related to cardiovascular procedures such as TAVR.4 Novella Clinical and Medical Metrics recommend requiring the use of baseline and post-procedure MRI data for endpoints in EDP-related clinical research to locate, count and quantify volumes of lesions.

For more information on this topic, download our webinar, Clinical Trial Considerations in Cerebral Protection for TAVR Patients

 

References:

  1. Blair, J. Cerebral Embolic Protection For TAVR: Start Ups Compete. Pharma & MedTech Business Intelligence. December 30, 2015. http://lightstonevc.com/sites/all/files/press/Document.pdf
  2. Lansky, A.J., et al. Neurologic Complications of Unprotected Transcatheter Aortic Valve Implantation (from the Neuro-TAVI Trial). Am J Cardiol. 2016 Aug 23. pii: S0002-9149(16)31373-X. doi: 10.1016/j.amjcard.2016.08.013. https://www.ncbi.nlm.nih.gov/pubmed/27645761
  3. Sacco, R., et al. An Updated Definition of Stroke for the 21st Century. 2013;44:2064-2089. http://stroke.ahajournals.org/content/44/7/2064
  4. Lansky AJ, et al. A prospective randomized evaluation of the TriGuard HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J 2015;36:2070e2078.
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