Pharmacoepidemiology
Antihypertensive target trial emulation for dementia prevention: combining US electronic health records with weighting strategies to inform drug repurposing alternatives Marie-Laure Charpignon* Marie-Laure Charpignon Bella Vakulenko-Lagun Colin Magdamo Bowen Su Sudeshna Das Anthony Philippakis Munther Dahleh Deborah Blacker Mark Albers
Alzheimer’s disease, the most common type of dementia, affects 6.7 million Americans and costs $345B annually. Since disease-modifying therapies are limited, repurposing FDA-approved drugs may offer an alternative, expedited path to preventing dementia. Hypertension is a major risk factor for dementia onset. However, prior observational studies contrasting antihypertensive drug classes (Angiotensin Converting Enzyme inhibitors: ACEI, Angiotensin Receptor Blockers: ARB, and Calcium Channel Blockers: CCB), provided mixed results. We hypothesize that ACEI have an off-target pathogenic mechanism. To test this assumption, we emulate a target trial comparing patients initiating ACEI vs ARB using electronic health records from the US Research Patient Data Registry. We perform intention-to-treat analyses among patients aged 50+, applying Inverse Propensity score of Treatment Weighting to balance the two treatment arms and accounting for competing risk of death. In a cause-specific Cox Proportional Hazards (PH) model, the hazard of dementia onset was lower in ARB vs ACEI initiators (HR=0.72 [95% CI: 0.68-0.77]). Findings were robust to outcome model structures (i.e., Cox PH vs nonparametric) and generalized to patients with no hypertension diagnosis at initiation. Our trial emulation suggests that ARB initiation may reduce the risk of dementia onset. Future work will evaluate differential effects by brain penetrance and the mediating role of blood pressure control in dementia prevention.
