Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis.
NCT ID: NCT02132026
Last Updated: 2021-10-14
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
152 participants
Study Classification
INTERVENTIONAL
Study Start Date
2014-11-12
Study Completion Date
2019-11-28
Brief Summary
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Aortic stenosis is a condition whereby one of the heart valves (aortic valve) becomes narrowed, due to calcium deposition, over time. This can lead to chest pain, heart failure and sudden death. It is the commonest valve disease requiring surgery in the developed world and as the population becomes increasingly older, it is predicted that the prevalence of aortic stenosis will double in the next 20 years. Currently the only treatment is replacement of the aortic valve. Whilst this is excellent treatment, not everyone is suitable for it.
The primary objective of our study is to determine whether 2 drugs used in the treatment of osteoporosis (a condition of bone thinning) can halt/retard the progression of aortic stenosis. This is on the basis that studies have suggested that altered regulation of calcium metabolism may be an important mechanism perpetuating the disease. Both drugs work by reducing calcium release into the bloodstream from bones and therefore calcification of the aortic valve.
150 patients will therefore be randomly allocated to either of the trial drugs which are denosumab,the bisphosphonate (alendronic acid), or a placebo.
Positron Emission Tomography (PET) scanning is a technique where biochemically active molecules are injected and are taken up at sites of ongoing calcification activity where they emit radiation and can be detected by the PET scanner. We have previously shown that this technique can demonstrate areas of newly developing calcification on an aortic valve.
We therefore propose that patients receiving bisphosphonates or denosumab will have reduced evidence of active calcification and slower progression of their disease at two years as assessed by Echocardiography (ultrasound) and a change in their calcium score (quantity of calcium on the aortic valve measured using Computed Tomography \[CT\] ).
The data from this study will then be used to design a larger trial.
The primary objective of our study is to determine whether 2 drugs used in the treatment of osteoporosis (a condition of bone thinning) can halt/retard the progression of aortic stenosis. This is on the basis that studies have suggested that altered regulation of calcium metabolism may be an important mechanism perpetuating the disease. Both drugs work by reducing calcium release into the bloodstream from bones and therefore calcification of the aortic valve.
150 patients will therefore be randomly allocated to either of the trial drugs which are denosumab,the bisphosphonate (alendronic acid), or a placebo.
Positron Emission Tomography (PET) scanning is a technique where biochemically active molecules are injected and are taken up at sites of ongoing calcification activity where they emit radiation and can be detected by the PET scanner. We have previously shown that this technique can demonstrate areas of newly developing calcification on an aortic valve.
We therefore propose that patients receiving bisphosphonates or denosumab will have reduced evidence of active calcification and slower progression of their disease at two years as assessed by Echocardiography (ultrasound) and a change in their calcium score (quantity of calcium on the aortic valve measured using Computed Tomography \[CT\] ).
The data from this study will then be used to design a larger trial.
Detailed Description
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BACKGROUND Aortic Stenosis is a common cause of valvular heart disease in which the valve cusps become progressively calcified. The only available treatment is aortic valve replacement and previous attempts at providing medical therapies to modify the disease process have proved unsuccessful.
Pathophysiology of Aortic Stenosis. The initiating event is believed to be caused by mechanical damage to the cells lining the valve in a process similar to that which occurs in atherosclerosis. However the propagating mechanism is more likely to be that of active calcification. In support of this, a growing body of pre-clinical and clinical data indicates that treatments for osteoporosis, which work by preventing the breakdown of bone and therefore calcium release into the blood, can reduce calcium deposition (calcification) of the blood vessels. These agents therefore hold considerable promise as novel therapies for aortic stenosis.
Denosumab in Aortic Stenosis Denosumab is a drug which prevents bone cells called osteoclasts from breaking down bone and releasing calcium into the blood. For this reason it is used to treat osteoporosis. It works on a specific pathway which we believe to be important in regulating calcium release from bone. Mice engineered with defects within this pathway were found to have increased bone breakdown and blood vessel calcification. Furthermore there have been two studies to assess the role of this pathway in patients with aortic valve disease. Both studies have also demonstrated altered regulation within this pathway
Bisphosphonates in Aortic Stenosis Bisphosphonates are a group of drugs widely used for the treatment of osteoporosis and also prevent bone breakdown by osteoclasts. They have also been shown to have important cardiovascular effects with a consistent reduction in calcification of blood vessels and the aortic valve. This in part appears to be a consequence of their inhibition of bone breakdown but also by reducing the production of key inflammatory substances implicated in the early stages of aortic stenosis. We plan on using alendronic acid which is a bisphosphonate commonly used in the management of osteoporosis.
PET CT scanning in Aortic Stenosis. 18F-NaF (Sodium Fluoride) is biochemical compound which preferentially binds to regions of newly developing calcification and emits radiation. When used in combination with Computed Tomography (CT) it enables it to be localized. This way we are able to identify areas of newly developing calcification on an aortic valve.
In previous studies in our institution, we demonstrated we could quantify 18F-NaF uptake in the aortic valve and that there was a progressive rise in activity with increasing disease severity. We found that at At 1 year, the baseline 18F-NaF uptake emerged as a powerful predictor of the progression in aortic valve calcification. Following analysis of 2 year follow up data, 18F-NaF emerged as an independent predictor of aortic valve replacement and cardiovascular mortality
Therefore these findings have led us to propose that
1. Calcification is the key driver to Aortic Stenosis Progression
2. We want to reduce calcification activity using Denosumab and Biphosphonates
3. We predict that this will reduce the 18F-NaF signal and disease progression on Echocardiography and CT.
STUDY DESIGN This will be a double-blind, randomized, placebo-control trial of denosumab and alendronic acid in patients with aortic stenosis.
Study population and randomization
We aim to recruit 170 patients in total with non-rheumatic calcific aortic stenosis.
20 patients will only participate in scan-rescan reproducibility studies. They will not proceed to the randomization stage.
Of the remaining 150 patients, 75 subjects will be randomized (2:1) to either subcutaneous denosumab 60 mg (n=50) or matched placebo (n=25) every 6 months; and a further 75 will be randomized (2:1) to oral alendronate 70 mg (n=50) or matched placebo (n=25) once weekly
Assessment and follow up
All subjects will undergo a standardized clinical assessment at baseline and every six months. Data will be collected with respect to symptomatic status, the trial safety endpoints, routine biochemical profiling, biomarkers, quality of life questionnaires and electrocardiography.
Aortic stenosis severity will be assessed at baseline and every 6 months by echocardiography performed by a single, dedicated sonographer to maximize reproducibility. Severity will be assessed using the peak and mean aortic valve pressure gradients (this technique is used to monitor aortic stenosis severity; the higher the pressure gradient across the aortic valve the more severe the narrowing). We will also calculate the aortic valve area and calcification score.
PET CT and CT calcium scoring.
Both will be performed using a combined PET and 128-multidetector CT scanner (Biograph 128, Siemens).
CT calcium scoring measures the amount of calcium in the valve and will be assessed at baseline, 6 months and 2 years. It will act as an additional marker of disease severity and progression alongside Echocardiography. Those with a heart rate of \>65 /min will be given heart-slowing medication (beta blockers) if deemed safe. The region of the aortic valve will be then be scanned during a breath hold.
18F-NaF PET uptake will be measured at baseline, and 6 months to assess the early impact of the intervention on valvular calcification activity. PET images on their own are difficult to interpret as they do not tell you where the radiation is coming from. For this reason the PET needs to be performed alongside CT which gives us images of the aortic valve. By superimposing the two images we are able to identify where the 'PET signal' is originating from.
To ensure optimal image quality patients will be required to adhere to a high fat, low carbohydrate diet for 48 hours prior to the scan. The subject will then be cannulated to enable injection of the 18F-NaF tracer. They will then rest in a quiet environment for 60 minutes to enable the tracer to reach the valve before transfer to the imaging suite. Those with a heart rate of \>65 /min will be given beta-blockade if it is deemed suitable and safe. This is routine practice in cardiac CT. A scout CT will be performed to allow optimal alignment of the PET and CT scanners (so we can be sure the radiation we are detecting is coming from the aortic valve). The patient will then be asked to lie still for 30 minutes so that the PET data can be acquired.
Finally a 'CT angiogram' will be performed of the aortic valve. This involves image acquisition following injection of a radio opaque dye into the aorta. This again allows more accurate localization of our PET signal.
The additional twenty patients will only undergo repeat PET/CT imaging within 2 weeks of their baseline scan to investigate scan-rescan reproducibility of the 18F-NaF PET signal. They will not proceed with the trial beyond this stage to avoid facing increased radiation exposure.
Pathophysiology of Aortic Stenosis. The initiating event is believed to be caused by mechanical damage to the cells lining the valve in a process similar to that which occurs in atherosclerosis. However the propagating mechanism is more likely to be that of active calcification. In support of this, a growing body of pre-clinical and clinical data indicates that treatments for osteoporosis, which work by preventing the breakdown of bone and therefore calcium release into the blood, can reduce calcium deposition (calcification) of the blood vessels. These agents therefore hold considerable promise as novel therapies for aortic stenosis.
Denosumab in Aortic Stenosis Denosumab is a drug which prevents bone cells called osteoclasts from breaking down bone and releasing calcium into the blood. For this reason it is used to treat osteoporosis. It works on a specific pathway which we believe to be important in regulating calcium release from bone. Mice engineered with defects within this pathway were found to have increased bone breakdown and blood vessel calcification. Furthermore there have been two studies to assess the role of this pathway in patients with aortic valve disease. Both studies have also demonstrated altered regulation within this pathway
Bisphosphonates in Aortic Stenosis Bisphosphonates are a group of drugs widely used for the treatment of osteoporosis and also prevent bone breakdown by osteoclasts. They have also been shown to have important cardiovascular effects with a consistent reduction in calcification of blood vessels and the aortic valve. This in part appears to be a consequence of their inhibition of bone breakdown but also by reducing the production of key inflammatory substances implicated in the early stages of aortic stenosis. We plan on using alendronic acid which is a bisphosphonate commonly used in the management of osteoporosis.
PET CT scanning in Aortic Stenosis. 18F-NaF (Sodium Fluoride) is biochemical compound which preferentially binds to regions of newly developing calcification and emits radiation. When used in combination with Computed Tomography (CT) it enables it to be localized. This way we are able to identify areas of newly developing calcification on an aortic valve.
In previous studies in our institution, we demonstrated we could quantify 18F-NaF uptake in the aortic valve and that there was a progressive rise in activity with increasing disease severity. We found that at At 1 year, the baseline 18F-NaF uptake emerged as a powerful predictor of the progression in aortic valve calcification. Following analysis of 2 year follow up data, 18F-NaF emerged as an independent predictor of aortic valve replacement and cardiovascular mortality
Therefore these findings have led us to propose that
1. Calcification is the key driver to Aortic Stenosis Progression
2. We want to reduce calcification activity using Denosumab and Biphosphonates
3. We predict that this will reduce the 18F-NaF signal and disease progression on Echocardiography and CT.
STUDY DESIGN This will be a double-blind, randomized, placebo-control trial of denosumab and alendronic acid in patients with aortic stenosis.
Study population and randomization
We aim to recruit 170 patients in total with non-rheumatic calcific aortic stenosis.
20 patients will only participate in scan-rescan reproducibility studies. They will not proceed to the randomization stage.
Of the remaining 150 patients, 75 subjects will be randomized (2:1) to either subcutaneous denosumab 60 mg (n=50) or matched placebo (n=25) every 6 months; and a further 75 will be randomized (2:1) to oral alendronate 70 mg (n=50) or matched placebo (n=25) once weekly
Assessment and follow up
All subjects will undergo a standardized clinical assessment at baseline and every six months. Data will be collected with respect to symptomatic status, the trial safety endpoints, routine biochemical profiling, biomarkers, quality of life questionnaires and electrocardiography.
Aortic stenosis severity will be assessed at baseline and every 6 months by echocardiography performed by a single, dedicated sonographer to maximize reproducibility. Severity will be assessed using the peak and mean aortic valve pressure gradients (this technique is used to monitor aortic stenosis severity; the higher the pressure gradient across the aortic valve the more severe the narrowing). We will also calculate the aortic valve area and calcification score.
PET CT and CT calcium scoring.
Both will be performed using a combined PET and 128-multidetector CT scanner (Biograph 128, Siemens).
CT calcium scoring measures the amount of calcium in the valve and will be assessed at baseline, 6 months and 2 years. It will act as an additional marker of disease severity and progression alongside Echocardiography. Those with a heart rate of \>65 /min will be given heart-slowing medication (beta blockers) if deemed safe. The region of the aortic valve will be then be scanned during a breath hold.
18F-NaF PET uptake will be measured at baseline, and 6 months to assess the early impact of the intervention on valvular calcification activity. PET images on their own are difficult to interpret as they do not tell you where the radiation is coming from. For this reason the PET needs to be performed alongside CT which gives us images of the aortic valve. By superimposing the two images we are able to identify where the 'PET signal' is originating from.
To ensure optimal image quality patients will be required to adhere to a high fat, low carbohydrate diet for 48 hours prior to the scan. The subject will then be cannulated to enable injection of the 18F-NaF tracer. They will then rest in a quiet environment for 60 minutes to enable the tracer to reach the valve before transfer to the imaging suite. Those with a heart rate of \>65 /min will be given beta-blockade if it is deemed suitable and safe. This is routine practice in cardiac CT. A scout CT will be performed to allow optimal alignment of the PET and CT scanners (so we can be sure the radiation we are detecting is coming from the aortic valve). The patient will then be asked to lie still for 30 minutes so that the PET data can be acquired.
Finally a 'CT angiogram' will be performed of the aortic valve. This involves image acquisition following injection of a radio opaque dye into the aorta. This again allows more accurate localization of our PET signal.
The additional twenty patients will only undergo repeat PET/CT imaging within 2 weeks of their baseline scan to investigate scan-rescan reproducibility of the 18F-NaF PET signal. They will not proceed with the trial beyond this stage to avoid facing increased radiation exposure.
Conditions
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Calcific Aortic Stenosis
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Alendronic Acid
50 patients will receive once weekly Alendronic Acid tablets (70mg).
Group Type
ACTIVE_COMPARATOR
Alendronic Acid
Intervention Type
DRUG
Alendronic Acid placebo
25 patients will receive alendronic acid placebo tablets.
Group Type
PLACEBO_COMPARATOR
Alendronic Acid Placebo
Intervention Type
DRUG
Inert Capsule containing lactose monohydrate manufactured and labelled by Investigational Supplies Group (ISG) University of Edinburgh.
Denosumab
50 patients will receive 6 monthly denosumab injections
Group Type
ACTIVE_COMPARATOR
Denosumab
Intervention Type
DRUG
Denosumab Placebo
25 patients will receive a 6 monthly placebo injection.
Group Type
PLACEBO_COMPARATOR
Denosumab Placebo
Intervention Type
DRUG
subcutaneous injection of 0.9%Saline at baseline, 6 months, 12 months and 18 months
Interventions
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Denosumab
Intervention Type
DRUG
Alendronic Acid
Intervention Type
DRUG
Denosumab Placebo
subcutaneous injection of 0.9%Saline at baseline, 6 months, 12 months and 18 months
Intervention Type
DRUG
Alendronic Acid Placebo
Inert Capsule containing lactose monohydrate manufactured and labelled by Investigational Supplies Group (ISG) University of Edinburgh.
Intervention Type
DRUG
Other Intervention Names
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Prolia
Marketing Authorisation Number : EU/1/11/703/003
ATC number M05BX04
Marketing Authorisation Number PL 30306/0032
ATC codes M05B A04
Eligibility Criteria
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Inclusion Criteria
1. age \>50 years
2. peak aortic jet velocity of \>2.5 m/s on Doppler echocardiography
3. grade 2-4 calcification of the aortic valve on echocardiography
2. peak aortic jet velocity of \>2.5 m/s on Doppler echocardiography
3. grade 2-4 calcification of the aortic valve on echocardiography
Exclusion Criteria
1. Anticipated or planned aortic valve surgery in the next 6 months,
2. Life expectancy \<2 years,
3. Inability to undergo scanning
4. Treatment for osteoporosis with bisphosphonates or denosumab.
5. Long-term corticosteroid use.
6. Abnormalities of the oesophagus or conditions which delay oesophageal/gastric emptying,
8\) Inability to sit or stand for at least 30 minutes, 9) Known allergy or intolerance to alendronate or denosumab, or any of their excipients, 10) Hypocalcaemia, 11) Maintenance calcium supplementation, 12) Dental extraction within 6 months, 13) History of osteonecrosis of the jaw, 14) Major or untreated cancers, 15) Poor dental hygiene, 16) Women of child-bearing potential who have experienced menarche, are pre-menopausal, have not been sterilised or who are currently pregnant, 17) Women who are breastfeeding, 18) Renal failure (estimated glomerular filtration rate of \<30 mL/min), 19) Allergy or contraindication to iodinated contrast, 20) Inability or unwilling to give informed consent, 21) Likelihood of non-compliance to treatment allocation or study protocol
2. Life expectancy \<2 years,
3. Inability to undergo scanning
4. Treatment for osteoporosis with bisphosphonates or denosumab.
5. Long-term corticosteroid use.
6. Abnormalities of the oesophagus or conditions which delay oesophageal/gastric emptying,
8\) Inability to sit or stand for at least 30 minutes, 9) Known allergy or intolerance to alendronate or denosumab, or any of their excipients, 10) Hypocalcaemia, 11) Maintenance calcium supplementation, 12) Dental extraction within 6 months, 13) History of osteonecrosis of the jaw, 14) Major or untreated cancers, 15) Poor dental hygiene, 16) Women of child-bearing potential who have experienced menarche, are pre-menopausal, have not been sterilised or who are currently pregnant, 17) Women who are breastfeeding, 18) Renal failure (estimated glomerular filtration rate of \<30 mL/min), 19) Allergy or contraindication to iodinated contrast, 20) Inability or unwilling to give informed consent, 21) Likelihood of non-compliance to treatment allocation or study protocol
Minimum Eligible Age
50 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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British Heart Foundation
OTHER
Sponsor Role
collaborator
NHS Lothian
OTHER_GOV
Sponsor Role
collaborator
University of Edinburgh
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Rong Bing, MbChB
Role: PRINCIPAL_INVESTIGATOR
University of Edinburgh
David E Newby, BA BSc PhD BM DM FRCP DSc FRSE
Role: STUDY_CHAIR
University of Edinburgh
Locations
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Clinical Research Facility University of Edinburgh
Edinburgh, , United Kingdom
Site Status
Countries
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United Kingdom
References
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Dweck MR, Jenkins WS, Vesey AT, Pringle MA, Chin CW, Malley TS, Cowie WJ, Tsampasian V, Richardson H, Fletcher A, Wallace WA, Pessotto R, van Beek EJ, Boon NA, Rudd JH, Newby DE. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ Cardiovasc Imaging. 2014 Mar;7(2):371-8. doi: 10.1161/CIRCIMAGING.113.001508. Epub 2014 Feb 7.
Reference Type
BACKGROUND
Dweck MR, Khaw HJ, Sng GK, Luo EL, Baird A, Williams MC, Makiello P, Mirsadraee S, Joshi NV, van Beek EJ, Boon NA, Rudd JH, Newby DE. Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation? Eur Heart J. 2013 Jun;34(21):1567-74. doi: 10.1093/eurheartj/eht034. Epub 2013 Feb 7.
Reference Type
BACKGROUND
Dweck MR, Joshi FR, Newby DE, Rudd JH. Noninvasive imaging in cardiovascular therapy: the promise of coronary arterial (1)(8)F-sodium fluoride uptake as a marker of plaque biology. Expert Rev Cardiovasc Ther. 2012 Sep;10(9):1075-7. doi: 10.1586/erc.12.104. No abstract available.
Reference Type
BACKGROUND
Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, Marsden M, Pessotto R, Clark JC, Wallace WA, Salter DM, McKillop G, van Beek EJ, Boon NA, Rudd JH, Newby DE. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012 Jan 3;125(1):76-86. doi: 10.1161/CIRCULATIONAHA.111.051052. Epub 2011 Nov 16.
Reference Type
BACKGROUND
Geers J, Manral N, Razipour A, Park C, Tomasino GF, Xing E, Grodecki K, Kwiecinski J, Pawade T, Doris MK, Bing R, White AC, Droogmans S, Cosyns B, Slomka PJ, Newby DE, Dweck MR, Dey D. Epicardial adipose tissue, myocardial remodelling and adverse outcomes in asymptomatic aortic stenosis: a post hoc analysis of a randomised controlled trial. Heart. 2025 Jun 26;111(14):686-694. doi: 10.1136/heartjnl-2024-324925.
Reference Type
DERIVED
Geers J, Bing R, Pawade TA, Doris MK, Daghem M, Fletcher AJ, White AC, Forsyth L, Evans E, Kwiecinski J, Williams MC, van Beek EJR, Kwak S, Peeters FECM, Tzolos E, Slomka PJ, Lucatelli C, Ralston SH, Prendergast B, Newby DE, Dweck MR. Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial. J Am Heart Assoc. 2024 Sep 17;13(18):e032571. doi: 10.1161/JAHA.123.032571. Epub 2024 Sep 9.
Reference Type
DERIVED
Pawade TA, Doris MK, Bing R, White AC, Forsyth L, Evans E, Graham C, Williams MC, van Beek EJR, Fletcher A, Adamson PD, Andrews JPM, Cartlidge TRG, Jenkins WSA, Syed M, Fujisawa T, Lucatelli C, Fraser W, Ralston SH, Boon N, Prendergast B, Newby DE, Dweck MR. Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial. Circulation. 2021 Jun 22;143(25):2418-2427. doi: 10.1161/CIRCULATIONAHA.121.053708. Epub 2021 Apr 29.
Reference Type
DERIVED
Pawade T, Clavel MA, Tribouilloy C, Dreyfus J, Mathieu T, Tastet L, Renard C, Gun M, Jenkins WSA, Macron L, Sechrist JW, Lacomis JM, Nguyen V, Galian Gay L, Cuellar Calabria H, Ntalas I, Cartlidge TRG, Prendergast B, Rajani R, Evangelista A, Cavalcante JL, Newby DE, Pibarot P, Messika Zeitoun D, Dweck MR. Computed Tomography Aortic Valve Calcium Scoring in Patients With Aortic Stenosis. Circ Cardiovasc Imaging. 2018 Mar;11(3):e007146. doi: 10.1161/CIRCIMAGING.117.007146.
Reference Type
DERIVED
Pawade TA, Cartlidge TR, Jenkins WS, Adamson PD, Robson P, Lucatelli C, Van Beek EJ, Prendergast B, Denison AR, Forsyth L, Rudd JH, Fayad ZA, Fletcher A, Tuck S, Newby DE, Dweck MR. Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis. Circ Cardiovasc Imaging. 2016 Oct;9(10):e005131. doi: 10.1161/CIRCIMAGING.116.005131.
Reference Type
DERIVED
Pawade TA, Newby DE, Dweck MR. Calcification in Aortic Stenosis: The Skeleton Key. J Am Coll Cardiol. 2015 Aug 4;66(5):561-77. doi: 10.1016/j.jacc.2015.05.066.
Reference Type
DERIVED
Pawade TA, Newby DE. Treating aortic stenosis: arresting the snowball effect. Expert Rev Cardiovasc Ther. 2015 May;13(5):461-3. doi: 10.1586/14779072.2015.1037284. Epub 2015 Apr 16.
Reference Type
DERIVED
Other Identifiers
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SALTIRE2-2014
Identifier Type: -
Identifier Source: org_study_id