The company’s cerebral protection system is being studied during TAVR procedures in three randomized trials: CLEAN-TAVI, MISTRAL-C, and SENTINEL.
CLEAN-TAVI: The First RCT to Study Cerebral Protection During TAVR
Claret Medical co-funded the landmark CLEAN-TAVI clinical trial, a prospective, blinded, 1:1 randomized controlled trial of 100 patients receiving a Medtronic CoreValve. This is the first randomized controlled trial to study the use of cerebral protection during TAVR. First results were revealed in September 2014 at the Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, D.C. as a Late Breaking Clinical Trial presentation, which demonstrated the effectiveness of the company’s cerebral protection system.
The study hypothesis was that the use of Claret Medical’s cerebral protection technology would reduce the number of cerebral emboli by 50% as evaluated by diffusion-weighted MRI two days post-procedure. Other endpoints included evaluation at 7, 30 and 365 days, neurological evaluation, neurocognitive assessment, periprocedural transcranial Doppler assessment, and histopathological analysis of captured debris.
The study met its primary endpoint and demonstrated that the use of Claret Medical technology significantly reduced the number and volume of cerebral lesions, with a 65% reduction in the total volume of new brain lesions and a 57% reduction in the number of new brain lesions 7 days after the procedure.
The patients protected by the Claret Medical technology showed a significantly lower ataxia* rate when compared to the control group (9% vs. 24%, respectively) in a “Per Protocol” analysis at 2 days post-procedure, which indicates the potential of the device to improve neurological outcomes.
Neurological deficit was observed in 28% of patients that did not receive cerebral protection during TAVR as evaluated by a neurologist 2 days post-procedure in the “Intent to Treat” analysis, demonstrating that the incidence of brain infarcts is higher than previously reported when serial neurological assessment is performed.
Of particular importance, no additional safety issues were experienced as a result of using Claret Medical’s cerebral protection system in conjunction with the TAVR procedure.
*Ataxia is a lack of coordination and steadiness of muscle movement most often associated with damage to the brain.
MISTRAL-C: The First Study to Show Definitive Neurocognitive Benefit for TAVR Patients Protected by Sentinel CPS
MISTRAL-C is a multi-center, randomized, controlled trial of 65 patients enrolled at four centers in the Netherlands that underwent TAVR using both self-expanding and balloon-expandable valves, with and without the use of the Sentinel CPS. Results were presented in October 2015 in an oral presentation at the Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in San Francisco.
The study compared the median total new lesion volume as detected by DW-MRI at five days post-procedure to pre-procedural baseline cerebral scans. It also included a detailed neurological and cognitive assessment of patients five days post-procedure.
MISTRAL-C showed encouraging cognitive benefit from use of the Sentinel™ Cerebral Protection System (CPS) during TAVR. Data show that unprotected patients have a statistically significant (p=0.017) worsening in cognition when compared to Sentinel-protected patients at five days post-TAVR, when assessed using the Mini Mental State Exam (MMSE).
MISTRAL-C also validated findings from the landmark CLEAN-TAVI study that showed the use of a Claret Medical cerebral protection system reduced the number and volume of brain lesions in TAVR patients.2 MISTRAL-C showed a 52 percent reduction in the median total new lesion volume at 5 days post-procedure as assessed using highly sensitive 3-Tesla brain MRI. None of the protected patients had National Institute of Health Stroke Scale (NIHSS) deterioration at 5 days post-procedure, while 5% of unprotected patients showed deterioration.
- van Mieghem N. MISTRAL C: MRI Investigation in TAVI with Claret. Transcatheter Cardiovascular Therapeutics (TCT). 2015
- Linke A. CLEAN-TAVI: A Prospective, Randomized Trial of Cerebral Embolic Protection in High Risk Patients with Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement. Transcatheter Cardiovascular Therapeutics (TCT). 2014
SENTINEL: The first randomized clinical trial approved by the FDA evaluating cerebral protection in TAVR
The SENTINEL clinical trial is a prospective, multi-center, randomized, controlled trial of 363 patients enrolled at 19 centers in the U.S. and Germany that underwent TAVR using all commercially available TAVR valves, with and without the use of the Sentinel CPS. Results were presented as a Late Breaking Clinical Trial presentation at the 2016 Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington DC and published in the Journal of American College of Cardiology (JACC).
The purpose of the study was to assess the safety and efficacy of the Claret Medical Sentinel CPS used with TAVR (protected TAVR) compared to unprotected TAVR.
The primary safety endpoint was the occurrence of all Major Adverse Cardiac and Cerebrovascular Events (MACCE) at 30 days compared to a historical performance goal, with MACCE defined as all death, all stroke, and all Class 3 Acute Kidney Injury (AKI).
The primary efficacy endpoint was the reduction in median total new lesion volume in protected territories between the Imaging Arms (Test and Control) as assessed by weighted magnetic resonance imaging (DW-MRI) at Day 2-7 post-procedure. The FDA mandated observational success criteria was to demonstrate the true treatment effect by showing the observed ratio of the median total new lesion volume is ≥ 30% in favor of the Test Arm having a lower median new lesion volume in the protected territories as compared to the Control Arm.
SENTINEL met its primary safety endpoint with a 30-day MACCE rate of 7.3% which is non-inferior to the performance goal of 18.3% and numerically lower than the concurrent control arm of 9.9%. Other safety outcomes showed protected TAVR reduced stroke rates by 53%* and there were no radial access complications.
An important finding from the SENTINEL trial showed there is a significant dose-response relationship between the number and volume of new cerebral infarcts and neurocognitive deterioration at 30-days. The use of Sentinel CPS showed a clinically significant 42% reduction in total new cerebral lesion volume across all valve types, which exceeded the pre-specified 30% treatment effect success criteria. This was shown to be statistically significant in a multivariable analysis which controlled for differences in baseline populations.
Cerebral debris which included valve tissue, arterial wall, calcium and thrombus material from catheters used during the TAVR procedure, was captured and retrieved in 99% of patients protected with Sentinel CPS.
Of particular importance, the adjudicated 30-day stroke rate for the control arm (unprotected TAVR) was 9.1%, and a majority of the strokes (61%) were identified within 72 hours of the TAVR procedure.
SENTINEL confirms findings from the CLEAN-TAVI1 and MISTRAL-C2 randomized trials, showing a strong treatment effect in reducing cerebral infarcts with the use of Sentinel CPS.
* SENTINEL trial was not powered for stroke
- Haussig, et al. JAMA, 2016
- Van Mieghem, et al. EuroIntervention, 2016
The Sentinel CPS has received the CE Mark and is commercially available in Europe. It is limited to investigational use in the United States.