Aneurysmal subarachnoid haemorrhage (aSAH) is a rare type of stroke that has a high death rate and burden on patients. There is currently no drug treatment to prevent aSAH, and the only available treatment option is surgery. A recent study that investigated the SAIL databank in Wales found that using the blood pressure medicines lisinopril and amlodipine may reduce the chance of developing aSAH. However, it is unclear whether these drugs manage high blood pressure (a known aSAH risk factor) or have direct effects on blood vessels and the prevention of aSAH.
In this study, we intend to further investigate this association by directly comparing the effects of lisinopril and amlodipine to other similar blood pressure medicines (from the same drug class) to see whether they genuinely lower the occurrence of aSAH. We will use established methods to investigate the timing and effects of different daily doses and duration of use.
By answering our research question, we will have a better knowledge of how lisinopril and amlodipine affect the risk of aSAH. This information could help clinicians (including neurologists) make better decisions about which blood pressure medicine to prescribe to lower the risk of aSAH in their patients. This information will also help patients who are at risk of aSAH to use a blood pressure medicine that can potentially lower the risk of an imminent aSAH.
Aneurysmal subarachnoid haemorrhage (aSAH) is a rare type of stroke with high morbidity and mortality, but no pharmacological treatment option. A recent drug-wide association study found signals of a lower aSAH incidence among current users of lisinopril and amlodipine. We aim to investigate whether using lisinopril or amlodipine lowers the risk of aSAH compared to other angiotensin converting enzyme (ACE) inhibitors and dihydropyridine calcium channel blockers (CCBs), respectively.
We will use an active comparator new-user design with data from CPRD GOLD and HES APC. The study population will comprise all adult individuals in CPRD with a hypertension diagnosis between 01.08.2004-31.12.2022. Two cohorts will be formed: initiators of lisinopril versus any other ACE inhibitor, and initiators of amlodipine versus any other dihydropyridine CCBs.
The primary analysis will be conducted using an intention-to-treat design and target trial emulation framework, with patients being followed up from the first prescription date of an exposure or active comparator until aSAH diagnosis, death, transfer out of database, last data collection by CPRD practice, or end of study. In secondary analysis, we will use an on-treatment design to analyse recency of use as well as duration- and dose-response relationships by considering time-varying exposure status and confounders.
Patients with aSAH diagnosis before the index date will be excluded. To account for confounding, propensity scores will be estimated with a 1:1 match of the exposure drug to the active comparator using the nearest neighbour matching algorithm.
Descriptive analyses at baseline will be reported. Incidence rates will be calculated, and a Cox proportional hazards model (multivariable time-dependent in on-treatment design) will be used to estimate the hazard ratios of aSAH associated with the use of lisinopril or amlodipine versus the use of other ACE inhibitors or dihydropyridine CCBs. In addition, a Kaplan-Meier analysis and time-to-event curves will be depicted.
A new occurrence of aneurysmal subarachnoid haemorrhage (aSAH) during the study period (2004-2022) among patients with a recent hypertension diagnosis.
Shahab Abtahi - Chief Investigator - Utrecht University
Shahab Abtahi - Corresponding Applicant - Utrecht University
Jos Kanning - Collaborator - Utrecht University
Olaf Klungel - Collaborator - Utrecht University
Patrick Souverein - Collaborator - Utrecht University
Ynte Ruigrok - Collaborator - University Medical Centre Utrecht
HES Admitted Patient Care;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation