18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome

Study Overview
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Brief Summary
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This study will evaluate the two main types of replacement tissue heart valve used in current practice, comparing outcomes from surgical aortic valve replacement (AVR) with that of the more recently introduced key-hole procedure called transcatheter aortic valve implantation (TAVI). Participants will be recruited at various time points ranging from 1 month to 10 years following valve replacement with either AVR or TAVI. It is thought that progressive calcium (chalk) formation is responsible for the failure of the majority of these valves. All participants will therefore have a PET-CT scan with a special type of tracer called 18F-fluoride in order to measure active calcium formation in the valve. They will then have annual clinical follow-up for 5 years and be invited back for a repeat CT scan at 2 years to measure change in calcium burden. This study aims to investigate, firstly, the effects of valve age and type on calcium formation as measured by PET-CT and, secondly, whether this measure of calcium formation can help to predict how long different types of valve will last. If successful, 18F-fluoride PET-CT could become a valuable tool for testing new treatments to improve valve longevity and new valve designs.

Detailed Description
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Aortic stenosis is the commonest form of valve disease in the western world and the leading indication for valve surgery. Bioprosthetic valves are known to degenerate via a process that is predominantly driven by calcification. Transcatheter aortic valve implantation (TAVI) has recently emerged as a less invasive alternative to conventional aortic valve replacement (AVR) surgery. Whilst this technique holds great promise, long-term follow up data are lacking and the longevity of these valves remains to be established. In this longitudinal, cross-sectional study of 180 subjects with either surgical or transcatheter implanted bioprostheses, this study proposes to look for the earliest signs of active calcification using 18F-fluoride positron emission tomography (PET). During a 5 year follow-up period, this study hopes to demonstrate that 18F-fluoride PET will predict subsequent bioprosthetic valve degeneration and identify patients at risk of premature valve failure. The study also hopes that it will inform about the comparative durability of novel percutaneous valves. If successful, 18F-Fluoride could provide a useful method of assessing novel therapeutic strategies targeted at improving the longevity of bioprostheses and help to guide future valve design.

Official Title
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18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome

Conditions
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Heart; Complications, Valve, Prosthesis

Intervention / Treatment
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* Radiation: 18F-Fluoride PET-CT
* Radiation: CT calcium score of aortic valve


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort 1 able to provide informed consent aged over 40 years patients with a bioprosthetic aortic valve who are due to undergo a redo-surgical aortic valve replacement Cohort 2 able to provide informed consent aged over 40 years patients at 1 month (n=10), 2 years (n=20), 5 years (n=20) and 10 years (n=20) following surgical bioprosthetic aortic valve replacement Cohort 3 able to provide informed consent aged over 40 years patients at 1 month (n=10), 2 years (n=20) and 5 years (n=20) following transcatheter aortic valve implantation (TAVI) with the Edward's SAPIEN and the COREVALVE. Exclusion Criteria: Inability to give informed consent Pregnancy Breastfeeding Claustrophobia Allergy to iodinated contrast Liver failure Chronic kidney disease (with estimated glomerular filtration rate <30 mL/min) Metastatic malignancy Paget's disease

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 (Explanted valves)<br>10 subjects who are due to undergo repeat aortic valve replacement surgery Investigations: Baseline 18F-Fluoride PET-CT scan Retrieval of explanted bioprosthetic aortic valve at time of surgery for analysis | Radiation: 18F-Fluoride PET-CT<br>* Injection of 18F-Fluoride with target activity 125MBq giving an anticipated radiation exposure of 3mSv CT scanning protocol giving an anticipated radiation exposure of 13mSv<br>|
| Experimental: 2 (AVR)<br>70 subjects with surgical bioprosthetic AVR, to include 10 subjects who have had a valve replacement < 1 month; 20 at 2 years; 20 at 5 years and 20 at >10 years. Investigations: Baseline 18F-Fluoride PET-CT scan Repeat CT calcium score of aortic valve at 2 years Annual clinical follow-up for 5 years (history, examination, blood tests, ECG and echocardiogram) | Radiation: 18F-Fluoride PET-CT<br>* Injection of 18F-Fluoride with target activity 125MBq giving an anticipated radiation exposure of 3mSv CT scanning protocol giving an anticipated radiation exposure of 13mSv<br>Radiation: CT calcium score of aortic valve<br>* CT associated with an anticipated radiation exposure of 3mSv (Cohorts 2 and 3 only)<br>|
| Experimental: 3 (TAVI)<br>50 subjects who have undergone TAVI with the COREVALVE and 50 subjects with the SAPIEN valve. In each group this will include 10 subjects who have had TAVI < 1 month; 20 at 2 years and 20 at 5 years. Investigations: Baseline 18F-Fluoride PET-CT scan Repeat CT calcium score of aortic valve at 2 years Annual clinical follow-up for 5 years (history, examination, blood tests, ECG and echocardiogram) | Radiation: 18F-Fluoride PET-CT<br>* Injection of 18F-Fluoride with target activity 125MBq giving an anticipated radiation exposure of 3mSv CT scanning protocol giving an anticipated radiation exposure of 13mSv<br>Radiation: CT calcium score of aortic valve<br>* CT associated with an anticipated radiation exposure of 3mSv (Cohorts 2 and 3 only)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 18F-Fluoride uptake in aortic bioprostheses | 18F-Fluoride uptake expressed as tissue to background ratio (TBR) in aortic valve bioprostheses of different age and type as measured by PET/CT | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CT calcium score of aortic valve | Change in aortic valve calcium score (Agatston units) from baseline to 2 years as determined by CT | Baseline and 2 years | 
| Echocardiographic evaluation of aortic valve function | Change in echocardiographic parameters of aortic valve function (both stenosis and regurgitation) from baseline to 1 year and 2 years as determined by Doppler echocardiography | Baseline, 1 year and 2 years | 
| Frequency of major adverse cardiovascular events | Frequency of major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, admission with heart failure, repeat valve surgery) as determined by annual clinical follow-up of study population over 5 years | 5 years | 
| Immunohistochemical staining of explanted aortic bioprostheses for marker of calcification | Immunohistochemical staining for markers of mineralisation (alkaline phosphatase, Runx-2, osteocalcin) in explanted aortic valve bioprostheses expressed as a percentage of total valve surface area. | intraoperative |