Comparison of antihypertensive drug classes for dementia prevention

ABSTRACT Introduction There is evidence that hypertension in midlife can increase the risk of Alzheimer’s disease and vascular dementia in late life. In addition, some treatments for hypertension have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose treatments for hypertension for dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using data on over 849,000 patients from the Clinical Practice Research Datalink. Methods Treatments for hypertension were assessed in an instrumental variable (IV) analysis to address potential confounding and reverse causation. Physicians’ prescribing preference was used as a categorical instrument, defined by the physicians’ last seven prescriptions. Participants were new antihypertensive users between 1996-2016, aged 40 and over. Findings We analysed 849,378 patients with total follow up of 5,497,266 patient-years. Beta-adrenoceptor blockers and vasodilator antihypertensives were found to confer small protective effects – for example, vasodilator antihypertensives resulted in 27 (95% CI: 17 to 38; p=4.4e-7) fewer cases of any dementia per 1000 treated compared with diuretics. Interpretation We found small differences in antihypertensive drug class effects on risk of dementia outcomes. However, we show the magnitude of the differences between drug classes is smaller than previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research with the ultimate aim of triangulating the evidence concerning this hypothesis. Funding This work was supported by the Perros Trust and the Integrative Epidemiology Unit. The Integrative Epidemiology Unit is supported by the Medical Research Council and the University of Bristol [grant number MC_UU_00011/1, MC_UU_00011/3]. RESEARCH IN CONTEXT Evidence before this study A recent systematic review and meta-analysis has collated the evidence for treating hypertension to prevent dementia. Seven comparable observational studies were identified that used either case-control designs with logistic regression or cohort designs with survival analysis. These studies suggested that some classes, such as angiotensin-II receptor blockers, may prevent dementia. However, conventional observational analyses, such as these, can be subject to confounding and reverse causation. Added value of this study We have provided new evidence about the potential effects of antihypertensives on risk of dementia through the novel application of instrumental variable analysis to this research question and have shown that the magnitude of the differences between drug classes is smaller than many observational studies have previously reported. Implications of all the available evidence Further research is needed to triangulate this evidence with other sources and to understand the inconsistencies between the studies conducted to date. Ultimately, this will inform the prioritization of antihypertensive drug classes for dementia prevention.