Patients with high blood pressure, or hypertension, have an increased risk of dementia, a term referring to a range of aberrant brain changes associated with progressive cognitive impairment such as memory problems and eventual loss of independence in daily activities. However, reducing blood pressure with antihypertensive drugs has not been consistently associated with a reduced risk of dementia. Some antihypertensive drugs named dihydropyridines are of particular interest because, aside from lowering blood pressure, they may have a direct effect on the brain and may therefore have an additional direct protective effect against dementia. Specifically, some dihydropyridines easily penetrate into the brain while others do not, suggesting that the former may have a direct neuroprotective effect. Thus, we will assess whether individuals who are treated with dihydropyridines easily penetrating into the brain have a decreased risk of dementia compared with individuals treated with other dihydropyridines. To perform this study, we will use the Clinical Practice Research Datalink (CPRD). We will select all patients with hypertension treated with dihydropyridines and determine whether those treated with dihydropyridines penetrating easily into the brain are less frequently diagnosed with dementia compared with those treated with other dihydropyridines. The proposed research project will provide information on the potential benefit of these drugs to prevent dementia. If we show that these drugs are beneficial, they could be prescribed preferentially to patients at high risk of dementia and could improve the prognosis of these patients.
Arterial hypertension is a major contributor to cognitive impairment and dementia, given its high prevalence and strong association with both aging and dementia. Thus, controlling blood pressure (BP) with antihypertensive medications (AHMs) represents an opportunity for the prevention of dementia. There is emerging evidence that dihydropyridine (DHP) calcium channel blockers (CCBs), commonly used first-line AHMs, may have neuroprotective effects. Specifically, some DHPs easily cross the blood-brain-barrier (BBB), while others such as amlodipine do not, suggesting that the former may have a direct neuroprotective effect compared with the latter. Our primary objective is therefore to assess whether use of BBB-crossing DHPs is associated with a decreased risk of dementia compared with non-BBB-crossing DHPs among patients with hypertension. Secondary objectives include assessing whether the risk depends on duration of use, age, sex, history of various comorbidities, and individual drugs.
We will use the Clinical Practice Research Datalink to assemble a cohort of patients newly treated with BBB-crossing or non-BBB-crossing DHPs between 1995 and 2021. Marginal structural Cox models will be fit to estimate hazard ratio and 95% CI of dementia associated with use of BBB-crossing DHPs compared with non-BBB-crossing DHPs. We will conduct secondary analyses to assess effect measure modification and sensitivity analyses to assess the robustness of our results. Our population-based study will provide critical information on the potential decreased risk of dementia associated with BBB-crossing DHPs and whether risk is associated with patient or DHP use characteristics.
Dementia diagnosis. List of relevant diagnostic codes are provided in Appendix 1.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Samy Suissa - Corresponding Applicant - Sir Mortimer B Davis Jewish General Hospital
Christel Renoux - Collaborator - McGill University
James Brophy - Collaborator - McGill University
Janie Coulombe - Collaborator - University Of Montreal
Kyle Johnson - Collaborator - McGill University
Rhian Touyz - Collaborator - McGill University
Robert Platt - Collaborator - McGill University
Sarah Beradid - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Practice Level Index of Multiple Deprivation