Title: Understanding the causes and clinical implications of blood pressure decline in older age
Funder: Department of Health and Social Care

Abstract: Background Blood pressure(BP) tends to increase through middle into older age, and treating hypertension reduces cardiovascular outcomes and mortality. However, BP in late life is influenced by co-morbidities and changes in physiological functioning, affecting maintenance of homeostasis. BP declines for over 10 years prior to death in approximately two thirds aged over 60 and in older patients with multimorbidity and frailty, lower systolic BPs (eg. Currently we do not understand the causes and mechanisms of longitudinal BP declines, or associations with cardiac function or co-morbidity. Early recognition of BP declines could aid early detection of serious conditions, such as specific cancers or heart failure. I hypothesise that longitudinal BP declines towards hypotensive BPs in previously hypertensive older individuals represent a 'post-hypertension syndrome', which may indicate higher risk of adverse events with continued antihypertensives. Overall Aim To identify the causes, mechanisms and outcomes of longitudinal BP declines in older age and test whether longitudinal BP data could aid early detection of conditions such as heart failure, cancer or dementia or identify those at increased risk of adverse outcomes. Timeline 80% FTE; 75 months Methods DataBuilding on extensive experience, analysis will be performed using world-leading data from UK Biobank (UKB) and Clinical Practice Research Datalink (CPRD), with secondary analysis of the OPTiMISE deprescribing trial. This fellowship is equivalent to 5 years full time, supported by expert mentors and collaborators, with a tailored training plan. UKB includes over 500,000 participants combining detailed baseline measures, genotypes and linked primary and secondary care electronic records, over 12 years of follow-up and MRI in 100,000 of the cohort. CPRD provides up to 20 years of large-scale population representative primary and secondary care data on over 2 million aged over 60. WP1 Model longitudinal BP trajectories in UK Biobank and CPRD and test associations with diagnoses, physiological and imaging measures, analysing conventional and genetic modifiers of risks for dementia, cancer, cardiovascular disease and frailty, as separate studies. Genetics can establish which risk factors and pathways are causally implicated in falling BP. WP2 Test associations between longitudinal BP trajectory and cardiovascular and adverse outcomes, specifically in older people with systolic BP WP3 Test whether longitudinal BP trajectory prior to study baseline modifies the association between antihypertensive prescribing and adverse outcomes, including falls in 1)the OPTiMISE RCT 2) the STRATIFY: antihypertensives study WP4 Test the association between longitudinal BP trajectory and PH, and PH and conventional and genetic cardiovascular modifiers to understand potential risk factors and overlap in phenotype. Collaborative studies (grant bids submitted to NIHR) to test the feasibility and validity of postural BP measurement. This research will provide the first estimates of the mechanisms, causes and outcomes of longitudinal BP decline in older adults. Results will be widely disseminated, including 8 detailed papers. This work could impact on patient safety and inform future targeted trials towards personalised antihypertensive prescribing.

Lay abstract: High blood pressure (BP), or hypertension, is very common and treatment reduces stroke, heart attack and mortality. BP increases with age, so people aged 70 or 80 have often had hypertension for decades. We now know that BP tends to fall in later life for over 10 years before death. BP is well studied in middle age and older people with new or difficult to control hypertension, but less is known about outcomes in older people with well-controlled or falling BP. We don't understand what causes falling BP trends, but BP falls more steeply with dementia, heart failure, cancer or frailty, and are not just due to BP treatments (antihypertensives). NICE guidelines recommended research into the optimum BP in older people and understanding BP trends may be key to this. In this fellowship I will analyse world class data from the UK Biobank (UKB; over 500,000 participants) and the Clinical Practice Research Datalink (CPRD; over 2 million) aiming to understand the causes of falling BP in older adults and working towards tailoring treatment to the individual needs. I work clinically as a geriatrician and for each treatment in every patient we weigh up the benefit versus risk. We don't know enough about the benefits versus risks of treatment of BP in certain groups - such as with chronic controlled hypertension but falling BP trend and potentially vulnerable groups often excluded from research, with multiple health conditions, frailty or dementia. My pilot work indicates that understanding longer term trends in BP could help to identify older people who are at excess risks from continuing antihypertensives and those who benefit most, which could guide treatment choices. Input from patients and clinicians has highlighted the importance of understanding individual risk. We also aim to test whether BP declines could help with early identification of serious conditions such as heart failure and cancer, leading to earlier treatment. I plan 4 research work packages, with input from expert mentors, collaborators, co-investigators and patient and public involvement advisors who will co-develop research plans and support interpretation and dissemination. Work package 1 will study BP trends in UKB and CPRD and test what factors (routine healthcare data, brain and heart scans and genetic risks) are associated with falling BP. We will test whether declining BP could give early warning of cardiovascular disease, dementia, frailty or cancer. Work package 2 focuses on people with BP below 140mmHg. We will test whether falling BP helps to predict outcomes, including cardiovascular, mortality and adverse outcome such as falls. This will include cardiovascular risk prediction, as my previous work indicates that existing risk prediction models may not adequately estimate risk for older people with falling BPs and low measured BP. Work package 3 will test whether falling BP helps to predict those at risk of adverse outcomes such as falls in existing studies on deprescribing of BP medication (OPTiMISE) and antihypertensive risk prediction (STRATIFY). Work package 4 will test whether falling BP is linked to a fall in BP on standing (postural hypotension) and test what other factors are associated, to see whether falling BP and postural hypotension could be part of a systemic loss of ability to adequately maintain BP. In collaborative work forming separate NIHR bids I will input into studies on how best to test for postural hypotension, the clinical barriers and feasibility of measuring postural BP. Overall, the research planned will provide the most detailed analysis of causes and mechanisms influencing BP in late life to date in 8 planned publications, plus presentations. It will inform clinical trials to improve safe, personalised antihypertensive prescribing in older age.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE