In prior research, findings have shown that losartan reduced the risk of epilepsy in patients by blocking astrocyte activation and reducing blood brain barrier damage.
Published in JAMA Neurology, a new retrospective cohort study showed that use of angiotensin receptor blockers (ARBs), particularly losartan (Cozaar; Merck), was linked to a reduction in incidence of new-onset epilepsy compared with other antihypertensive agents among patients with hypertension who had no preexisting stroke or cardiovascular disease. Further research in regard to these findings, such as randomized clinical trials, may confirm the comparative antiepileptogenic properties of antihypertensive medications.1,2
Among 2,261,964 patients (mean age, 61.7 years [SD, 13.9]; women, n = [49.5%]) included in the study analysis, 309,978 received ARBs, 807,510 received ACEIs, 695,887 received β-blockers, and 448,589 received calcium channel blocker (CCB). Conducted from April 2022 to April 2024, investigators observed that usage ARBs in patients with hypertension was associated with a decreased incidence of epilepsy in comparison with angiotensin-converting enzyme inhibitors (ACEIs; adjusted hazard ratio [aHR], 0.75; 95% CI, 0.58-0.96), β-blockers (aHR, 0.70; 95% CI, 0.54-0.90), and a combination of other antihypertensive classes (aHR, 0.72; 95% CI, 0.56-0.95).
“We read the interesting finding of the observational study by Doege C, et al.3 and reviewed the related animal studies on ARB’s apparent antiepileptic effects,” lead author Xuerong Wen, PhD, an associate professor of pharmacy practice at University of Rhode Island, told NeurologyLive®. “So, we decided to see if we could reproduce the findings of Doege C, et al. in a different cohort with a larger sample.”
Led by senior author Kimford J. Meador, MD, professor of neurology and neurosciences at Stanford University, and colleagues, the study utilized data with propensity score (PS) matching between January 2010 and December 2017 from a national health administrative database. The analyzed cohort included privately insured adult patients with primary hypertension and who dispensed at least 1 ARB, ACEI, β-blocker, or CCB between 2010 and 2017. Researchers excluded in the analysis patients diagnosed with epilepsy at or prior to the index date or dispensed an antiseizure medication 12 months before or 90 days after starting the study medications.
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For the analysis, authors had propensity scores generated according to baseline covariates and noted that they were used to match patients who received ARBs with those who received either ACEIs, β-blockers, CCBs, or a combination of the antihypertensive medications. Investigators also used cox regression analyses to assess epilepsy incidence during follow-up to make a comparison of the ARB cohort with other antihypertensive classes. To evaluate the association between ARB use and epilepsy incidence in various subgroups, researchers performed subgroup and sensitivity analyses.
Across the 4 comparison groups, investigators reported that demographic and clinical characteristics differed before PS matching. In comparison with ARB users, patients who received ACEIs were predominantly men and had diabetes, CCB users were generally older, and β-blocker users had more comorbidities as well as concurrent medications.
The 1:1 PS-matched subgroups included 619,858 patients for ARB versus ACEI, 619,828 patients for ARB versus β-blocker, and 601,002 patients for ARB versus CCB. Authors observed that baseline characteristics were equally distributed between comparison groups after matching with propensity scores. Notably, researchers reported a significant association between ARB use, primarily losartan, and epilepsy incidence in patients with no preexisting history of stroke or cardiovascular disease when performing a subgroup analyses.
“In epidemiological studies, subgroup analysis usually is used to address confounding and biases, as well as to identify effect modifiers. Our subgroup analyses revealed a significant association between ARB use (primarily losartan) and epilepsy incidence in patients with no preexisting history of stroke or cardiovascular disease,” Wen added. “This may be due to the small sample size of patients with stroke and cardiovascular diseases. However, the results showed that the estimates of epilepsy risk in this group are closer to null.”
Investigators recognize that the current study has several limitations because of unmeasured confounding factors, potential misclassifications, and a small sample size in subgroup analyses. In addition, authors noted that the exclusion of unmatched ARB users may have reduced the statistical power, and that the reliance on data from private health plans might have limited the generalizability of these findings to a broader population, particularly patients who have a lower socioeconomic status or more comorbidities.
“A randomized double-blind trial in humans on different hypertensives is needed to confirm the ARB associations in our human observational studies are a real effect,” Wen said.
