Prescribed drug use and aneurysmal subarachnoid haemorrhage incidence: A drug-wide association study

Background: Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid haemorrhage (aSAH) rarely outweigh treatment risks, and thus most intracranial aneurysms remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing.

Objectives: We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence.

Methods: This was a case-control study, where all aSAH cases were included between 2000 and 2020 using International Classification of Diseases (ICD) codes from the Secure Anonymised Information Linkage (SAIL) databank of Wales, the UK. Each case was matched to nine controls based on age, sex, and year of database entry. We defined three exposure windows for commonly prescribed drugs (>2% in study population) based on most recent prescription before index date (i.e. occurrence of aSAH), as current (within 3 months), recent (3-12 months), and past use (>12 months). A logistic regression model was fitted to compare drug use in these exposure windows versus never use, controlling for age, sex, known aSAH risk factors, and healthcare utilisation.

Results: We identified 4,879 aSAH cases (mean age 61.4 years, 61.2% women) with 43,911 matched controls. After Bonferroni correction, nine of the 205 commonly prescribed drugs studied showed a statistically significant association with aSAH (p < 0.05). We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril OR 0.63 95% CI 0.44-0.90, amlodipine OR 0.82 95% CI 0.65-1.04), and an increased aSAH risk for recent use (lisinopril OR 1.30 95% CI 0.61-2.78, amlodipine OR 1.61 95% CI 1.04 -2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). In contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56).

Conclusions: We identified several drugs associated with aSAH, of which five drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence.