With minimally invasive left-heart procedures like transcatheter aortic valve replacement becoming increasingly safe and commonplace, attention has turned to procedure-associated brain injury from showers of emboli. Several medtech start-ups are developing devices that could protect patients’ brains during not only TAVR, but also surgical aortic valve replacement, atrial fibrillation ablation and other left-heart procedures.
- Transcatheter aortic valve replacement (TAVR) could become a $7.4 billion industry by 2025, but concerns about associated brain injury or stroke are rising, with some researchers concerned that large clinical trials of TAVR greatly underreport stroke.
- TAVR and other left-heart procedures can liberate microemboli made of calcified material, thrombus or device fragments that can travel to the brain and cause injury. Such microemboli don’t necessarily cause clinically obvious stroke, but they are associated with important neurological and cognitive effects and downstream consequences nonetheless.
- Start-up companies are developing brain-protection devices with approaches that include deflecting emboli away from brain vessels and toward the periphery, catching and removing emboli from the body, and creating a pressure gradient in the blood column that diverts emboli.
- Some industry insiders say such protection will soon become standard of care – as it already is in carotid stenting – and point to the potential risk of not using such a device if clinical data show it to be effective.
With transcatheter aortic valve replacement (TAVR) becoming a mainstream procedure, worth a predicted $7.4 billion by 2025, attention is turning to the associated stroke risk. Cerebral embolic protection devices show promise in prevention, and some start-ups predict they will become standard of care for TAVR and other left-heart procedures. Some estimate a billion-dollar market potential for such ancillary devices.
Highlighting Claret Medical: Removing Emboli Entirely
Removing such debris from the body entirely is the approach taken by Claret Medical’s flagship Sentinel Cerebral Protection System. Approaching through the radial artery of the right arm with a 6F catheter, the operator inserts a pair of coneshaped polyurethane filters, deploying one in the brachiocephalic artery and the other in the left common carotid. Held against arterial walls with nitinol hoops, these filters remain in place during the TAVR procedure, catching released embolic debris, and are then are removed from the vessels afterward along with the debris. This debris can include thrombus, chunks of heart muscle, valve tissue, foreign body and calcium.
“When you can capture it effectively and remove it efficiently, why deflect [debris] to the kidneys and mesenteric arteries to create another problem downstream?” asks Claret’s Azin Parhizgar. The one-size-fits-all Sentinel also achieves good apposition to vessel walls, reducing the chance that debris will float past, according to Parhizgar, and remains out of the way of TAVR catheters and devices during the procedure to reduce any chance of interference – “a key safety differentiator,” she says.
CE marked in 2013, Sentinel is now in its fourth generation. As of November it had shipped about 2,200 devices in the EU. With respect to valve brands, it is platformagnostic, and Parhizgar says it can be used in other left-heart procedures that produce embolic showers.
Claret Medical was founded in 2009 by Randall Lashinski, an engineer and entrepreneur who had previously helmed Allure Medical and Direct Flow Medical and had been a VP at Medtronic. Neurosurgeon Leo Nelson Hopkins, MD, and interventional cardiologist Eberhard Grube, MD, PhD, provided clinical leadership by defining clinical need, according to Parhizgar. Claret closed a Series A round of $5 million in August 2009, and its Series B was announced last August for up to $18 million, from Santé Ventures, Lightstone Ventures, Easton Capital and Incept. The company has 39 employees. Parhizgar joined Claret in 2013 after co-founder Lashinski stepped down. Previously, she was chief operating officer of Conor Medsystems, which Johnson & Johnson acquired for about $1.4 billion in 2007.
As noted earlier, the Sentinel covers the brachiocephalic and the left common carotid arteries. It does not cover the left subclavian artery, the third major vessel to take off from the aortic arch. The main branch of the left subclavian feeds the left rm; a smaller one forms the left vertebral artery. The left and right vertebral arteries unite via crossover circulation at the circle of Willis at the base of the brain, where they go on to supply many regions of the brain. Because the Sentinel does protect the right vertebral artery and because of this commingling in the circulation, the left vertebral artery is partially protected, according to Parhizgar.
“A number of publications as well as internally generated data illustrate that the left vertebral artery contributes about 5% to 7% of the cerebral circulation,” Parhizgar says. As a two-vessel protector, the Sentinel CPS is a simple and quickly deliverable device with a high efficiency of debris capture that does not risk becoming entangled with or dislodged by TAVR equipment, she says.
“Everything that has been published with fluid dynamic studies with respect to the blood flow to the brain shows that the contribution of embolic debris toward the left vertebral artery is small,” Parhizgar says. “The majority of anything that goes to the left subclavian artery is going to go down the arm. For that reason also, the thought process was that leaving the left vertebral artery partially protected is not going to be significant. In fact, our pivotal European trial, CLEAN-TAVI, has demonstrated this very fact.”
“The 5% to 7% that we’re not protecting fully, we will revalidate from the Sentinel clinical studies in the US if that is significant or not,” Parhizgar adds.
The Sentinel CPS was tested in CLEAN-TAVI, a prospective randomized controlled trial of cerebral embolic protection in high-risk AS patients undergoing TAVR. One hundred patients being fitted with a Medtronic CoreValve underwent pre- and postprocedural MRI using highly sensitive 3-Tesla MRI. In patients randomized to the Sentinel, the study found a clinically significant reduction in the volume and number of DW-MRI-detected lesions shortly after TAVR. A trend toward fewer neurological events was noted in the protected group. This “compelling” trial was among the factors that attracted Santé Ventures to invest in the technology, according to James Eadie.
Claret’s multicenter double-blinded European trial, MISTRAL-C, was presented at TCT in October. This study randomized TAVR patients to Sentinel protection or no protection, with pre- and post-procedural 3-Tesla DW-MRI and neurological and neurocognitive assessments. Fifty-four patients were needed for an adequately powered trial, but only 37 received the second MRI. In those patients there were trends toward fewer new brain lesions and a lower chance of neurocognitive deterioration, according to the principal investigator, cardiologist Nicolas M. Van Mieghem, MD, PhD.
In October 2014, Claret launched its pivotal IDE trial, SENTINEL. This US multicenter randomized controlled trial will study Sentinel’s safety and efficacy in 296 patients receiving “some of the latest US approved” transcatheter valves, in Khosravi’s words, using as its primary endpoint the reduction in median new brain lesion volume as measured by two types of MRI sequences. Patients will also be clinically tested for neurological and cognitive deficits. The trial is being closely watched, not only by reimbursement bodies but also potential future innovators and investors, Khosravi says.
Eadie expects the SENTINEL study to be completed in the first half of 2016, and FDA clearance by the end of 2016.
Parhizgar says the company is working with estimates of a global TAVR market of $3.5 billion by 2020, but declines to speculate on cerebral protection’s potential degree of penetration before IDE data are in. However, she adds, if efficacy is proven, “I would say this will become a mandatory use for the device.”
She is noncommittal about potential pricing, and says Claret will consider acquisition among other possible strategies after IDE results are in, including raising a Series C round to continue as an independent company. Parhizgar is also discussing reimbursement with the Centers for Medicare and Medicaid Services, and the company plans to submit an ICD-10 application in July 2016.
Text taken from:
Cerebral Embolic Protection For TAVR: Start-Ups Compete
Autor: Jenny Blair
Published December 22, 2015