Background:
A large number of observational studies show links between hypertension or higher blood pressure (BP) in mid-life and an increased risk of later dementia. In late life, the evidence is more mixed with some studies indicating higher BP is associated with higher dementia risk and some finding U-shaped associations between BP and incident dementia in older age. The clinical trials of antihypertensives to lower BP have shown largely negative results when examining the relationship between antihypertensive use and incident dementia. However, the trials were designed to examine cardiovascular endpoints and several stopped early for cardiovascular benefit thus limiting their statistical power and ability to accrue dementia outcomes. To overcome some of these limitations a pooled individual patient data meta-analysis of five seminal double-blind placebo-controlled randomised trials was undertaken to better define the effects of BP lowering treatment for the prevention of dementia.
Methods:
The double-blind placebo-controlled randomised antihypertensive trials; 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), and SYSTolic Hypertension in EURope Trial (SYST-EUR) were merged into a single database. 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, baseline Mini-Mental State Exam (MMSE) score and presence of prior stroke.
Results:
All trials were balanced across randomised groups. The combined sample was n = 28,008 recruited from 20 countries. Mean baseline age was 69.1 (Standard Deviation 9.3). Median follow-up 4.3 years. Incident dementia occurred in 2.9% and 3.3% of those in active and placebo groups, respectively. 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 10/4mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age, sex, baseline systolic BP, baseline MMSE or prior stroke.
Discussion:
This is the first single-stage individual patient data meta-analysis from double-blind placebo-controlled clinical trials. It provides high-quality evidence to support the benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential benefit from antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia.
