Abstract and Introduction
Abstract
Aims: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia.
Methods and Results: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk.
Conclusion: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia.
Classification of Evidence: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.
Structured Graphical Abstract
• Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE).
• Hypertension in the Very Elderly Trial (HYVET).
• Perindopril Protection Against Recurrent Stroke Study (PROGRESS).
• Systolic Hypertension in the Elderly Program (SHEP).
• SYSTolic Hypertension in EURope Trial (SYST-EUR).
Introduction
Observational studies have shown strong associations between elevated blood pressure (BP), particularly in midlife (age 40–65 years), and increased risks of dementia and cognitive decline that support plausible mechanisms of interaction between the cardiovascular tree and cerebral function.[1] However, this evidence is not universal. A recent comprehensive meta-analysis of seven population-based cohorts involving 17 286 older adults (mean age 75 years) showed that the lowest risk of dementia occurred in those with a mean systolic BP of 185 mmHg [95% confidence interval (CI): 161–230 mmHg] over a mean of 8 years of follow-up but a U-shaped relationship between BP and dementia in the oldest old (age >80 years).[2] This echoed earlier work raising concerns over BP lowering in older age groups.[1,3–5] Although randomized controlled trials can overcome the issues of residual confounding and reverse causality inherent to such observational analysis, they are in themselves challenging and have produced mixed reports on the effects of BP lowering for the prevention of dementia.[6]
Clarity over the effects of BP lowering on the risk of dementia remains a high priority in guiding public health strategies as well as clinical guidelines, where there may be a requirement to tailor thresholds and intensity of BP lowering in older age. Only a handful of BP-lowering trials have included a dementia endpoint, still fewer have been placebo-controlled and, because cardiovascular events occur earlier than incident dementia, most have been stopped early upon achieving the estimated primary cardiovascular endpoint. The impact of BP lowering on cardiovascular events meant that each one of these trials changed cardiovascular guidelines in favour of treatment. Consequently, it is no longer ethical to recruit to a trial comparing antihypertensive treatment to a placebo group who are receiving no other BP-lowering treatment. This also means that although a new placebo-controlled trial specifically designed for the prevention of dementia is desirable, it will require a very large sample size of participants who are also able to have their risk of cardiovascular disease managed within guidelines.[7] Numerous meta-analyses have sought to fill the void,[8–21] but their conclusions are hampered by their inability to standardize analysis and data handling and, in some cases by the combining of observational and clinical trial data. The gold standard for providing precision in synthesizing data from clinical trials is individual participant data (IPD) meta-analysis, where the data from sufficiently similar studies are combined and analysed as a single dataset. Herein, we present the results of a single-stage IPD meta-analysis of the five double-blind placebo-controlled randomized trials of BP lowering that collected dementia endpoints and were designed solely to compare a BP lowering to a no treatment, placebo only arm and that remained double-blind and placebo-controlled throughout. This approach allows a better analysis of causal inferences, and potential interactions and modifications of the effects of treatment on the prevention of dementia. Ethically these trials cannot be replicated and combining their data into a single database provides the strongest opportunity to establish the impact of BP lowering on incident dementia.
Eur Heart J. 2022;43(48):4980-4990. © 2022 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.
