Orthostatic hypotension, blood pressure variability, and neurovascular outcomes

Orthostatic hypotension (OH), and blood pressure variability (BPV), are major contributors to the burden of falls and cardiovascular risk in older adults. My thesis addresses areas of uncertainty in the epidemiology and management of patients with orthostatic hypotension (symptomatic and asymptomatic), including whether use of anti-hypertensive therapy increases the risk of adverse events such as falls in populations with OH, whether OH is associated with adverse neurovascular outcomes (dementia, cognitive decline) and cardiovascular events, whether sodium (salt) and potassium intake are modifiable risk factors for OH and its consequences, and explore an approach to identifying optimal levels of salt intake, in patients with symptomatic OH, associated with the lowest risk of falls. In Chapter 2, I conduct a meta-analysis of blood pressure lowering randomised controlled trials, to evaluate whether treatment estimates for effectiveness and safety (e.g. falls, syncope) differ between clinical trials that included populations with OH compared to clinical trials that specifically excluded populations with OH. In Chapter 3, I report on the prospective association of OH with neurocognitive (and cardiovascular) outcomes in a population at high vascular risk, and evaluate whether increases in anti-hypertensive treatment intensity modifies the magnitude of association. In Chapter 4, I report the association of BPV (measured during early hospitalisation) with functional outcomes at 1- month following hospital admission for acute stroke. In Chapter 5, I report the association of sodium and potassium excretion with risk of injurious fall events in a large international prospective cohort study. In Chapter 6, I detail a protocol for a feasibility-phase randomised controlled trial (SalT supplementation in Older adults with Orthostatic intolerance Disorders [STOOD] trial) evaluating salt supplementation for the management of symptomatic OH in older adults. The STOOD trial will determine whether increased sodium (salt) intake is associated with improvements in orthostatic measures, BPV, symptoms related to OH and falls. In Chapter 7, I report the progress of the STOOD feasibility trial (outlined in Chapter 6) and discuss future research directions. My thesis provides evidence to support an association of OH with dementia and cardiovascular events, but this association appears to be unmodified by incremental use of renin-angiotensin-aldosterone system blockers. It also provides observational evidence to support use of increased sodium intake for prevention of falls, involving the largest epidemiologic study to evaluate the association of sodium and falls events. While the study did not specifically measure postural blood pressure change, the association was strongest in older adults, thereby providing indirect observational evidence to support current guideline recommendations for increasing salt intake to prevent recurrent falls in patients with symptomatic OH. However, the recommendation for long-term increases in salt intake to high intake levels, in patients with symptomatic OH, may have adverse cardiovascular consequences, raising clinical uncertainty about the risk to benefit trade-off in older adults at increased cardiovascular risk. Accordingly, randomised control trials are required to evaluate whether there are clinical benefits and risks of long-term high salt intake in population with OH. To date, no long-term clinical trials have evaluated the effect of sustained high sodium intake in patients with symptomatic OH. The STOOD trial is specifically designed to address this evidence gap, and is currently evaluating the feasibility of a randomised controlled trial of salt supplementation (versus control) in a population with symptomatic OH and also provide preliminary evidence of efficacy and safety. Initial findings suggest a definitive Phase III clinical trial is feasible, and will be a focus of my future clinical research career.

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University of Galway

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CC BY-NC-ND

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University of Galway Theses (PhD Theses)