Neuron Specific Enolase in TAVI (NSE TAVI)
Research type
Research Study
Full title
The Influence of Cerebral Protection on Neuron Specific Enolase Levels Following Transcatheter Aortic Valve Implantation
IRAS ID
313486
Contact name
Sandeep Arunothayaraj
Contact email
Sponsor organisation
University Hospitals Sussex NHS Trust
Duration of Study in the UK
1 years, 0 months, 1 days
Research summary
Severe aortic stenosis is a common heart condition affecting elderly patients. Degeneration of the aortic valve (one-way valve between the heart and the aorta) causes high resistence to blood flow, resulting in strain on the heart and the potential for heart failure and death. Treatment of aortic stenosis has traditionally been with open heart surgery. A new procedure called transcatheter aortic valve implantation (TAVI) allows new aortic valves to be implanted through the femoral arteries, resulting in equivalent outcomes to open surgery with a more rapid recovery. Some complications remain present however, including the risk of debris released during the valve implantation being carried by the blood stream into the brain. This may lead to strokes and a loss of mental capacity. Devices that filter the blood stream and capture this debris have now been developed but are of uncertain benefit. We plan to investigate patients undergoing TAVI who have been randomly assigned to filter versus no filter to see if there is any difference in neuronal injury. This will be assessed through the use of the biomarker neuron specific enolase (NSE).
Patients who are enrolled in the ongoing BHF PROTECT-TAVI trial will be invited to partcipate in this separate trial. They will have already been randomly assigned to TAVI with or without cerebral filter use. NSE levels will be measured on blood samples routinely collected pre- and 1 day post-TAVI. There is no change to standard patient care. Biomarker testing should provide valuable insight into the performance and role of the cerebral filter for TAVI patients in the future.Summary of Results
Background and study set up
The Influence of Cerebral Protection on Neuron Specific Enolase Following Transcatheter Aortic Valve Implantation (NSE TAVI)Introduction
NSE TAVI was an observational study conducted at the Royal Sussex County Hospital in Brighton, United Kingdom. The Chief Investigator was Dr Sandeep Arunothayaraj and the Sponsor was University Hospitals Sussex NHS Foundation Trust. Funding was provided by Terumo Medical Corporation and The Australian Government Research Training Program Scholarship. There were no competing interests by any of the investigators involved in the study and there was no patient involvement in the study design, although they had been involved in the design of the Patient Information Sheet.Background
The aortic valve is responsible for stopping blood from flowing back into the heart from the main vessel (the aorta) that carries blood from the heart to circulate around the body. Failure of this valve to work properly affects around 1.5 million people over the age of 65 in the UK.
Transcatheter aortic valve implantation, or TAVI for short, is a procedure in which a new aortic valve is inserted into the body through a blood vessel. This is required when a patient’s aortic valve is diseased, and either does not open easily, or has a large leak. TAVI places the body under less stress than the traditional method of valve surgery through a large chest incision. The recovery from the procedure is also much quicker. These are important factors as the people who require a new aortic valve are often elderly and may not tolerate major surgery. Currently around 6,000 TAVI procedures are conducted in the UK each year.Despite these benefits, TAVI still carries some risks, such as stroke. Stroke occurs due to acute brain damage, leading to problems such as loss of control of an arm or leg, inability to understand or speak and loss of vision. Studies have shown that for every 100 patients who undergo a TAVI, approximately 2-3 will experience a stroke at the time of the procedure, or shortly after. About half of these patients will have permanent limitations following a stroke.
Stroke after TAVI is mostly caused by small fragments of calcium and blood clots being dislodged from the diseased aortic valve. Debris that enters the blood stream can travel to the brain and block the blood supply to important areas. If this debris can be trapped and removed from the blood stream before it reaches the brain, it is hoped that the chance of stroke will be greatly reduced. The Sentinel device is manufactured by Boston Scientific for this purpose. It consists of two filter baskets that can be placed in blood vessels that supply the brain. When fully deployed, approximately 75% of the brain is protected by this device. In almost every use, microscopic debris is captured within the baskets. Whether this means that the risk of stroke is reduced, and by how much, is still uncertain.
The BHF PROTECT-TAVI study was designed to answer this question. Patients who chose to participate are randomly assigned to standard TAVI with no filter use, or TAVI with the Sentinel device. The rate of stroke after the procedure is determined for both groups, to see if there is a benefit with use of the Sentinel device. Because stroke is rare, a very large number of people need to participate in this study to detect a reduction. This means the study will take many years to complete.
Another method to determine benefit from the use of Sentinel is to assess for changes in neuronal biomarkers. A biomarker (indicator) refers to a substance in the blood that can be measured to indicate the health of a body system. A biomarker exists for brain tissue called neuron specific enolase (NSE). This is normally found within brain cells and may be released into the blood following brain injury. Levels of NSE have been shown to rise within 24 hours of stroke. Elevations of NSE are also rarely seen in some tumours, with breaking down of red bloods cells and with renal failure. We believe that NSE could be used to measure brain damage after TAVI and detect any protective effect of the Sentinel device. A benefit of using a biomarker is that measurement should be reproducible between different laboratories. This contrasts with clinical outcomes like stroke where there can be disagreement when judging a diagnosis. This study was therefore designed to assess if.
- the use of the Sentinel device affected the levels of NSE that were present after the procedure and therefore,
- assess if NSE could act as a biomarker predictor in patients who undergo TAVI procedures.Study design
For the NSE TAVI study, we planned to test NSE levels at baseline by checking blood at the start of the TAVI procedure, and then taking a second blood sample 18-22 hours following the procedure to see if NSE levels had increased. Following ethical approval from the Health Research Authority, participants were invited to be recruited into the study if they were having a TAVI procedure at the Royal Sussex County Hospital between April 2022 and July 2023. During this time, patients who consented were already participating in the BHF PROTECT-TAVI trial. This meant that we were able to perform our NSE testing on a group of patients (100) who were randomly assigned to the use of Sentinel, or a standard TAVI. These patients were similar across a range of important factors such as age, renal function, previous stroke and procedural duration.Patients were not made aware of the results of their test because, patients were informed in their patient information sheet, that NSE is still under investigation as a marker of brain stress. It is not known how levels normally change after TAVI, or if an increase in NSE outside the setting of stroke has any impact on the patient’s health. Therefore, their treatment would not be changed in any way because of their NSE levels. Indeed, informing them of the result could potentially cause unjustified stress.
Results
Our results showed an increase in NSE in blood was common after TAVI. An increase of 20% above baseline was found in approximately 80% of patients. There were no patient or procedural factors that were found to influence NSE increase. No difference was seen in the degree of elevation between the control group, or patients who had a Sentinel device used.Some important factors should be noted when interpreting these results. Despite the increase in NSE after TAVI, no clinical strokes occurred in this group of patients. The clinical significance of a raised NSE without stroke symptoms is unclear. The Sentinel device does not offer complete coverage of the brain, and this may be the reason for a raised NSE in this group. However, the number of samples with evidence of damaged red blood cells was higher than predicted. It is likely that some of the NSE elevation seen was due to release from red blood cells, rather than neuronal damage. Given this, we recommend that any future biomarkers used to measure brain injury be more specific to brain tissue, so that more accurate results are available.
Poster presentations of the results are being planned.Summary
In summary, there was no difference in NSE elevation after TAVI in either control or Sentinel groups. This would suggest that, despite the use of cerebral protection, some damage to the brain could still be occurring. We note that these results should be interpreted with caution due to the potential inaccuracy of the test secondary to NSE release from red blood cells. Alternative biomarkers should be tested in this field. Further research is ongoing to further examine the clinical benefits of cerebral protection. The chief investigator, study team and sponsor would all like to thank the trial participants for making this study possible.This lay results summary has been reviewed by the UHSussex Research Champions, including members of the public, patients and patient representatives.
REC name
London - Surrey Research Ethics Committee
REC reference
22/PR/0441
Date of REC Opinion
20 Apr 2022
REC opinion
Favourable Opinion