Comparative Risk of Epilepsy Among Antihypertensive Medications: An Emulated Target Trial

Background: The use of angiotensin receptor blockers (ARBs) has been associated with a reduced incidence of epilepsy.

Objectives: This study aimed to specify the antiepileptogenic effects of ARBs in various subgroups of hypertensive patients in the United States (US).

Methods: Data were obtained from a national health administrative database on privately insured beneficiaries who were older than 18 years with a diagnosis of primary hypertension and dispensed at least one ARB, angiotensin-converting enzyme inhibitor (ACEI), β-blocker (BB), or calcium channel blocker (CCB) from 2010 to 2017. The study design adhered to the framework of target trial emulation. Cox regression analyses were conducted to compare the incidence of epilepsy between ARB users and individuals using other individual or combined antihypertensive classes dispensed within the defined exposure windows. Propensity score matching or stratification was employed to control for confounding. Subgroup analyses were performed to examine the association between ARB use and epilepsy incidence in various sub cohorts, including age, gender, baseline stroke, cardiovascular diseases (CVD) or mental disorders, and specific ARBs. Dose response was evaluated. A series of sensitivity analyses were conducted to address potential confounding and misclassification.

Results: In the 1:1 matched ARB-ACEI, ARB-BB, and ARB-CCB cohorts, a total of 619,858, 619,828, and 601,002 patients were included, respectively. Baseline characteristics were equally distributed between comparison groups after matching with propensity scores. The use of ARBs was associated with a decreased incidence of epilepsy compared to ACEIs (HR: 0.75; 95%CI: 0.58-0.96), BBs (HR: 0.70; 95%CI: 0.54-0.90), CCBs (HR: 0.80; 95%CI: 0.61-1.04), and a combination of other antihypertensive classes (HR: 0.72; 95%CI: 0.56-0.95). Subgroup analyses revealed protective antiepileptogenic effects of ARBs, primarily with the use of losartan, in patients with no preexisting history of stroke or CVDs. Sensitivity studies using alternative propensity score methods and different definitions of exposure windows, study cohorts or outcomes yielded similar results.

Conclusions: ARBs, mainly losartan, were associated with a lower incidence of epilepsy compared to other antihypertensive agents in hypertensive patients with no preexisting stroke or CVDs.