The Evaluation of blood pressure treatment stratified according to Central Aortic Systolic Pressure (CASP) in Young Hypertensive Patients - The TREAT CASP study

Lead Research Organisation: University College London

Abstract

High blood pressure (BP) is a leading cause of heart disease and strokes and the commonest chronic condition treated in primary care. In the UK, ~25% of all adults and 50% aged over 65yrs have high BP. NICE guidance recommends treatment when BP exceeds 160/100mmHg (called stage II hypertension). NICE also recommends treatment of lower pressures (140-159/90-99mmHg, i.e. stage I hypertension) in those with evidence of damage due to BP, those with diabetes and/or cardiovascular disease (CVD) or those calculated to be at higher risk. However, there is uncertainty what to do about treatment of younger people (aged 40yrs and under) with stage I hypertension because; i) younger people have rarely been included in clinical trials, ii) are unlikely to have developed CVD and iii) risk calculators do not apply to this younger age group. NICE has identified this group of over 1 million younger people as a key priority for research to better identify who would benefit from treatment. BP is routinely measured with a cuff wrapped around the arm and the assumption is made that pressure measured in the arm accurately reflects the pressure in the artery (aorta) close to the heart and the vital organs. We have developed a simple, non-invasive method to measure pressure in the aorta, next to the heart. This pressure is termed "central aortic systolic pressure" or CASP. Importantly, we have shown that pressure in the arm may not be an accurate measure of CASP, especially in younger people. Moreover, CASP is a better predictor of stress on the heart and may better predict stroke and CVD compared to BP measured in the arm. Our study will take place at the UCL vascular physiology unit and will recruit young men (aged 18-40 years) with stage I hypertension. We hypothesise that men with a low CASP (despite a high BP in the arm) actually have a normal BP, with no evidence of strain on the heart and do not need treatment. In contrast, those with a high CASP value will have early evidence of strain on the heart and arteries and will benefit from treatment. We will use MRI to sensitively measure the structure of the heart and the arteries. We will compare in men with high CASP, the effects of treatment for 1 year to lower BP versus no treatment, to see whether lowering CASP improves early heart and artery damage. Our study has no ethical issues as people recruited into the study would not normally receive treatment. We are well placed to conduct this study because of our experience in developing novel ways of measuring CASP, our experience in large clinical trials and in sensitive MRI measurements. The cost of our study is curtailed because of access to our research technology, including our research MRI scanner. Resources requested are to fund staff, clinical tests and consumables. Findings from our study may provide compelling evidence for a better way to stratify younger people with early hypertension who would benefit most from treatment and also avoid long-term treatment of those who would get no benefit.

Technical Summary

Research design: This two-stage study incorporates a stage 1 screening study (n=500) to identify men with HIGH and LOW CASP values who will enter a Stage 2 randomized clinical trial (RCT) using a PROBE design (n=130), or an observational follow up study (n=65). Study population: Men aged 18-40 years with stage 1 hypertension (brachial blood pressure 140-159/90-99mmHg) not currently treated and without cardiovascular disease (CVD) or target organ damage. Exclusions include men with secondary hypertension, target organ damage, diabetes, significant arrhythmia. Planned Interventions: Stage 1 has no intervention. The Stage 2 RCT will compare no treatment (control intervention) versus BP lowering (active treatment) according to NICE treatment guidelines for people aged <55years, with titration to achieve a CASP value of <120mmHg and/or at least a 5mmHg reduction from baseline Proposed Outcome Measures:Primary outcome is the change in left ventricular mass index (LVMI) from baseline to study end (12 months), between treatments. Secondary outcomes are markers of cardiovascular damage measured by MRI including LV mass/volume ratio; CMR myocardial tissue tagging; interstitial fibrosis; aortic distensibility; carotid and aortic wall thickness. Albumin excretion rate and retinal photography comprise other outcomes. Assessment & Follow up: In Stage 1, brachial BP and CASP will be measured by CASPro (n=500) which combines a BP monitor with radial tonometry. At the end of Stage 1, 130 men with HIGH CASP and 65 men with LOW CASP values will undergo measurement of LVMI by MRI. In the RCT and observational follow-up (Stage 2), brachial BP and CASP will be monitored at scheduled, 3 monthly follow-up visits, with more frequent visits during titration for the active treatment group. LVMI and secondary outcomes will be measured by MRI after 12 months follow up for all Stage 2 groups. Proposed sample size: The Stage 2 RCT will compare treatment vs. no treatment in groups of 65 men from the HIGH CASP group. We anticipate a change in LVMI between treatments of 6.6 g/m2 based on published data from 4 treatment studies comprising 7 active treatment arms in 627 individuals, SD 10.9g/m2. Power calculations indicate a sample size of 58 people per treatment are required to show a difference in LVMI with 90% power at p=0.05. Statistical analysis: The primary analysis at the end of the Stage 2 will use a linear regression model to compare the change in LV mass from baseline to study end between treatments. A students” t-test will also be used at the end of Stage 1 to compare values for LV mass index between the HIGH and LOW CASP groups. Projected timetables: 500 men with stage 1 hypertension will be identified and screened in the first 18 months of the study (Stage 1). The expected recruitment rate is similar to that of our previous screening studies. A 1 year RCT and an observational follow-up study (Stage 2) will follow completion of Stage 1.

Publications

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Banegas JR (2018) Ambulatory Blood Pressure and Mortality. in The New England journal of medicine

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Banegas JR (2018) Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality. in The New England journal of medicine

 
Description NICE Hypertension Guidelines Chairman
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Guideline published paper in Lancet confirming that the changes in practice would lead to changes in efficiency and cost effectiveness of diagnosis of hypertension which affects 25% of the adult population Recent Lancet paper - May 2014 has demonstrated the impact of the NICRE hypertension guidance in improving BP control in the UK which should translate into improvements in cardiovascular health
URL http://www.nice.org.uk/guidance/cg127
 
Description British Heart Foundation Clinical Study Grant - Co-investigator
Amount £754,472 (GBP)
Funding ID BHF Clinical Study no. CS/17/3/32799 "Biomarkers in urine, anyihypertensive treatment and blood pressure control in hypertensive patients - outreach study" 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 05/2020
 
Description British Heart Foundation Special programme Grant
Amount £1,000,000 (GBP)
Funding ID TIME study - Treatment In the Morning versus Evening (TIME) BHF CS/14/1/30659 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2014 
End 06/2019
 
Description Health Data Research UK - pan-London site - Co-investigator (H. Hemingway - lead applicant)
Amount £5,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 03/2023
 
Description NIH University College London Hospitals Clinical Research Facility - Co-applicant
Amount £6,500,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description NIHR BRC competition 3 - Resdesignation and new funding award to NIHR University College Hospitals Biomedical Research Centre - Director
Amount £111,500,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description Wellcome Trust Strategic Award - Electronic Health Records
Amount £50,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Strategic Award
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
End 02/2017
 
Title Development of new methods to measure central aortic pressure 
Description developed a novel method to measure aortic pressure from the radial pulse wave. this meted has been commercialised and is now widely used in research. the method has been adopted as a US FDA standard for central aortic pressure measurement 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact research grant to my group from NIHR EME/MRC to evaluate its use in better stratification of treatment decisions for young people with hypertension. used by Novartis Pharma in evaluating new drug efficacy in clinical trials 
URL http://www.healthstats.com/index3.php
 
Title Developing methods to assess aortic function and flow using MRI 
Description Using MRI physics to model aortic haemodynamics in relation to the evaluation of patients recruited into our TREAT CASP study We anticipate that this model will be an advance on current methods that could ultimately be applied in clinical assessment of patients in the NHS once the validation is complete 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact Still in development 
 
Description Clinical Practice Research Data link (CPRD) 
Organisation Medicines and Healthcare Regulatory Agency
Department Clinical Practice Research Datalink (CPRD)
Country United Kingdom 
Sector Public 
PI Contribution Engaged with CPRD and obtained funding from NOCLOR to support CRPD assistance with recruitment
Collaborator Contribution Screening GP data bases to identify suitable patients to be invited to participate in this study and liaising with the GP practices to send out letter - 899 potential participants identified already
Impact 899 potential study participants being invited to participate in the study
Start Year 2013
 
Description Collaboration with the UCL Farr institute 
Organisation Farr Institute of Health Informatics Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Developing data science infrastructure strategy for the BRC renewal bid and to ensure closer collaboration with the NHS via UCLH This has also been instrumental in the success of our contribution to the NIHR Health Informatics Collaborative My contributions been leadership via the BRC and research and clinical expertise
Collaborator Contribution Major input on data science strategy and the development of our Health Informatics, Genomics, Omics and Data Science (HIGODS) cross cutting theme for our successful BRC application in 2016 which I led. Prof Harry Hemingway the UCL Farr Director is now the BRC HIGODS theme director which has led to even greater collaboration and working. For the TREAT CASP study we have used the UCL data safe haven embedded within the Farr institute The Farr institute has now become the lead site for the London centres for HDRUK - I am a co-applicant on the successful London Centres bid for HDRUK funding in 2018
Impact There have been a number of publications emanating from the collaboration. The most significant output has been the establishment of a multidisciplinary research team embedded within the NHS to help drive data science at UCLH and via the NIHR HIC project
Start Year 2013
 
Description NIHR UCL Hospitals Biomedical Research Centre 
Organisation University College London Hospital
Department NIHR Comprehensive Biomedical Research Centre
Country United Kingdom 
Sector Public 
PI Contribution working with infrastructure within the BRC and CRF
Collaborator Contribution support for a Clinician scientist who is working directly on the project but was only part funded from the original grant support - this additional support from the BRC has enabled him to focus full time on this project and related studies in experimental medicine
Impact none so far - study just completed set up and about to start recruiting
Start Year 2013
 
Description NIHR Wellcome UCL Hospitals CRF Director 
Organisation National Institute for Health Research
Department UCLH/UCL Biomedical Research Centre
Country United Kingdom 
Sector Public 
PI Contribution In June 2013 I assumed the role as Director of the NIHR Wellcome UCL Hospitals CRF. We have developed a collaboration with the Leonard Wolfson Experimental Neurology Centre (LWENS) to share expertise and develop joint SOPs and governance procedures for research I have led the development of a new CRF build for UCL Hospitals which was opened in 2016 and I then stepped down from the role as CRF Director to focus on my roles at NIHR UCLH/UCL BRC Director and Director of Research for UCLH I handed over the Directorship in 2017 to a newly appointed NIHR CRF Director I was co-applicant on successful bid for funding for the CRF from NIHR 2017-2022 £6.5m I continue to provide oversight of the BRC in my roles as BRC Director and UCLH Director of Research
Collaborator Contribution Developed the collaboration above to increase the depth and efficiency of our experimental medicine research. the BRC supports experimental medicine research in the NIHR UCLH CRF
Impact CRF redesignated a NIHR CRF in the 2016 national competition and was awarded £6.5m
Start Year 2013
 
Description NIHR Wellcome UCL Hospitals CRF Director 
Organisation University College London
Department Leonard Wolfson Experimental Neurology Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution In June 2013 I assumed the role as Director of the NIHR Wellcome UCL Hospitals CRF. We have developed a collaboration with the Leonard Wolfson Experimental Neurology Centre (LWENS) to share expertise and develop joint SOPs and governance procedures for research I have led the development of a new CRF build for UCL Hospitals which was opened in 2016 and I then stepped down from the role as CRF Director to focus on my roles at NIHR UCLH/UCL BRC Director and Director of Research for UCLH I handed over the Directorship in 2017 to a newly appointed NIHR CRF Director I was co-applicant on successful bid for funding for the CRF from NIHR 2017-2022 £6.5m I continue to provide oversight of the BRC in my roles as BRC Director and UCLH Director of Research
Collaborator Contribution Developed the collaboration above to increase the depth and efficiency of our experimental medicine research. the BRC supports experimental medicine research in the NIHR UCLH CRF
Impact CRF redesignated a NIHR CRF in the 2016 national competition and was awarded £6.5m
Start Year 2013
 
Description NIHR Wellcome UCL Hospitals CRF Director 
Organisation University College London Hospital
Department NIHR Comprehensive Biomedical Research Centre
Country United Kingdom 
Sector Public 
PI Contribution In June 2013 I assumed the role as Director of the NIHR Wellcome UCL Hospitals CRF. We have developed a collaboration with the Leonard Wolfson Experimental Neurology Centre (LWENS) to share expertise and develop joint SOPs and governance procedures for research I have led the development of a new CRF build for UCL Hospitals which was opened in 2016 and I then stepped down from the role as CRF Director to focus on my roles at NIHR UCLH/UCL BRC Director and Director of Research for UCLH I handed over the Directorship in 2017 to a newly appointed NIHR CRF Director I was co-applicant on successful bid for funding for the CRF from NIHR 2017-2022 £6.5m I continue to provide oversight of the BRC in my roles as BRC Director and UCLH Director of Research
Collaborator Contribution Developed the collaboration above to increase the depth and efficiency of our experimental medicine research. the BRC supports experimental medicine research in the NIHR UCLH CRF
Impact CRF redesignated a NIHR CRF in the 2016 national competition and was awarded £6.5m
Start Year 2013
 
Description Sterring Committee Chairman for the CALM studies in resistant hypertension 
Organisation Vascular Dynamics, Inc.
PI Contribution I have developed the protocol in collaboration with an industry sponsor (Vascular Dynamics, USA) for a pivotal global RCT evaluating a stent like device inserted into the carotid bulb for the treatment of drug resistant hypertension. The study is now open for recruitment at over 30 sites globally including a number of sites in the UK
Collaborator Contribution Chairman of steering committee (global)
Impact Spiering W, Williams B, et al. Lancet 2017 - Reporting the results of first in man studies with this device in Europe
Start Year 2017
 
Title methods to measure aortic pressure 
Description devices currently marketed. we have developed a partnership between UCL Business and Healthstats UK 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Market authorisation
Year Development Stage Completed 2011
Development Status Under active development/distribution
Clinical Trial? Yes
Impact I won the Times Higher Award for outstanding contribution to innovation and technology 2011 URL:http://www2.le.ac.uk/offices/press/press-releases/2011/november/university-of-leicester-wins-national-award-for-outstanding-contribution-to-innovation-and-technology-1 
URL https://clinicaltrials.gov/show/NCT00819767
 
Description Attended House of Lords Select Committee to answer questions on the life science strategy 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I was invited to give evidence to a house of lords select committee on the government side sciences strategy in my capacity as a BRC Director
Year(s) Of Engagement Activity 2018
URL http://goo.gl/edE5ik
 
Description BBC News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact major story on BBC news about our research - see link below
many enquiries from the public which i have replied to
the technology we have developed and cited in this report on BBC is now being used in patient assessment in the NHS and in our research

see above
also had enquiries from Apple and Samsung about business collaboration related to this technology
Year(s) Of Engagement Activity 2013
URL http://www.bbc.co.uk/news/health-22812477
 
Description Development of the UCL Hospitals Research Gateway 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact An online gateway highlighting the research opportunities for members of the general public linked to their disease of interest

Mutliple website hits and enquiries about participation in studies from the general public who had never previously engaged with research
Year(s) Of Engagement Activity 2014
URL http://www.uclhospitals.brc.nihr.ac.uk/news/uclh-research-gateway-launches
 
Description Meeting at Foreign office to discuss sector bid for life sciences for government economic strategy 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact contribution to discussions to frame the sector bid for life sciences led by Sir John Bell
Year(s) Of Engagement Activity 2017
 
Description NIHR UCL Hospitals BRC Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact As BRC Director I Developed a BRC newsletter for communication to the UCL and UCLH community about the work of the BRC

wider and better engagement with the BRC
Year(s) Of Engagement Activity 2012,2013
URL http://www.uclhospitals.brc.nihr.ac.uk
 
Description New Method to Measure Aortic Pressure - BBC TV 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact reported a new method to estimate aortic pressure - could revolutionise future BP measurement
received major BBC news coverage

major BBC new coverage
Year(s) Of Engagement Activity 2011
URL http://www.bbc.co.uk/news/health-12518633
 
Description Presentation on London BRCs and their contribution to economic growth at Med City event in London February 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact major show and tell event with industry (SMEs and major industry) highlighted collaborative opportunities in biomedical science with London and Oxford and Cambridge BRCs
Year(s) Of Engagement Activity 2017
 
Description Schools visit to review BRC strategy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact BRC Director and theme leads presented the BRC strategy and objectives to school science students for discussion and debate - excellent feedback from the students
Year(s) Of Engagement Activity 2016
 
Description UCL Hospitals Research Open day for the general public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Excellent feedback from the general public and schools who attended and major interest in participation in our research project - led to increased recruitment

A number of schools asking if they could attend next year
Year(s) Of Engagement Activity 2014
 
Description UCL Hospitals Research open day June 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Major research open day organised by our BRC and hosted by UCLH. Over 50 stalls displaying ongoing clinical and transitional research
Year(s) Of Engagement Activity 2016