Anti-Epileptogenesis: Some Roads Lead to Losartan

Abstract

Association Between Angiotensin Receptor Blocker Therapy and Incidence of Epilepsy in Patients With Hypertension

Doege C, Luedde M, Kostev K. JAMA Neurol. 2022;79(12):1296-1302. doi:10.1001/JAMANEUROL.2022.3413

Importance:

Arterial hypertension is associated with an increased incidence of epilepsy. Results from animal studies suggest that angiotensin receptor blocker (ARB) therapy could inhibit epileptic seizures. However, there is a lack of clinical data to support the use of ARB therapy in humans.

Objective:

To assess whether ARB therapy is associated with a decreased incidence of epilepsy in patients with hypertension.

Design, setting, and participants:

This cohort study obtained data from the Disease Analyzer database (IQVIA) on patients aged 18 years or older who had hypertension and at least 1 antihypertensive drug prescription. Patients were treated at 1274 general practices between January 2010 and December 2020 in Germany. Data were available for 1 553 875 patients who had been prescribed at least 1 antihypertensive drug. Patients diagnosed with epilepsy before or up to 3 months after the index date were excluded. A total of 168 612 patients were included in propensity score matching. Patients treated with 1 of 4 antihypertensive drug classes (β-blockers, ARBs, angiotensin-converting enzyme inhibitors, and calcium channel blockers [CCBs]) were matched to each other using propensity scores.

Main outcomes and measures:

The main outcome of the study was the incidence of epilepsy associated with ARB therapy compared with other antihypertensive drug classes. Cox regression models were used to study the association between the incidence of epilepsy and ARBs compared with all other antihypertensive drug classes as a group.

Results:

The study included a total of 168 612 patients, with 42 153 in each antihypertensive drug class. The mean [SD] age of patients was 62.3 [13.5] years, and 21 667 (51.4%) were women. The incidence of epilepsy within 5 years was lowest among patients treated with ARBs (0.27% at 1 year, 0.63% at 3 years, 0.99% at 5 years) and highest among patients receiving β-blockers and CCBs (0.38% for both β-blockers and CCBs at 1 year; 0.91% for β-blockers and 0.93% for CCBs at 3 years; β-blockers, 1.47%; and CCBs, 1.48% at 5 years). Angiotensin receptor blocker therapy was associated with a significantly decreased incidence of epilepsy (hazard ratio, 0.77; 95% CI, 0.65-0.90) compared with the other drug classes as a group.

Conclusions and relevance:

In this cohort study of patients with hypertension, ARB therapy was associated with a significantly decreased incidence of epilepsy. The findings suggest antihypertensive drugs could be used as a novel approach for preventing epilepsy in patients with arterial hypertension.

Commentary

Vascular risk factors have been established as risk factors for epilepsy, specifically late-onset epilepsy. ¹ Hypertension, in particular, carries a 2-fold increased risk of epilepsy. ² The exact mechanism for this is unclear, but possibilities include its strong association with cerebrovascular lesions (ischemic and hemorrhagic), dysregulation of the renin-angiotensin system, and its impact on blood–brain barrier integrity. ³

Hypertension affects 30% of adults worldwide, half of the US population, and up to 75% of adults older than 75 in the United States. ⁴ Guidelines to treat hypertension are constantly being updated, and there has been an increased push to diagnose and treat hypertension early to prevent long-term complications such as cardiovascular and cerebrovascular disease, and we can also add epilepsy to this list. The public health implications of correctly treating hypertension are immense. Now that large database analyses and prospective studies have shown this clear link between hypertension and epilepsy, the question becomes: (1) Does treating hypertension lower the risk of epilepsy in adults? (2) Is there a particular antihypertensive drug/drug class that shows the greatest benefit?

In this study, ⁵ the authors tried to answer the questions by analyzing a large German insurance claims database covering 3% of all outpatient practices in Germany. The study was based on ICD-10 codes, and included adults with an International Classification of Diseases (ICD-10) code for hypertension and prescription of an antihypertensive agent; beta-blockers (BB), calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARB). Subjects were then matched in a 1:1:1:1 fashion using propensity scores according to demographics and comorbid conditions; diabetes, Parkinson’s disease, cerebrovascular disease, dementia and cognitive impairment, and head injuries. A propensity score approach allows the authors to minimize significant differences in baseline characteristics and mimic a randomized control trial. The primary outcome of interest was an ICD code consistent with epilepsy. Follow-up was up to 5 years or until the antihypertensive agent was switched or discontinued. Subjects with blood pressure data were categorized into mild (140-159/90-99), moderate (160-179/100-109), and severe hypertension to determine whether those with different hypertension severity were more likely to be prescribed a specific drug class. The authors looked at the effect of ARBs versus other drugs, the effect of 6 individual ARBs, and the effect of the antihypertensive drugs on epilepsy subtypes (focal, generalized, rare, unspecified). There were 42 153 subjects per group with mean age 62.3 years. The authors found that ARBs were associated with a lower incidence of epilepsy compared to the other drug classes hazard ratio 0.77 (95% CI, 0.65-0.90). Out of 6 ARBs analyzed, only losartan was found to be significantly associated with this reduced risk. Findings were similar in subjects at high risk of epilepsy due to a diagnosis of cerebrovascular disease or dementia, they represented 4.5% of the cohort. With regard to hypertension severity, subjects were more likely to be prescribed an ARB as opposed to a BB if they had moderate hypertension.

Before discussing the relevance of the findings, a few limitations need to be highlighted some of which were discussed by the authors. One of the major limitations which applies to most ICD code studies is that misclassification or nonspecific classification is always an issue. For example, an adult population with a mean age in the 60s would be unlikely to have new onset generalized epilepsy at a rate of 5.6%. While a larger proportion, 73.6%, of the cases had “unspecified epilepsy.” There is also the issue of using propensity score matching using broad ICD codes. For example, someone with a pontine stroke could be matched with someone with a large cortical stroke because they both have a cerebrovascular disease ICD code, but the subject with the cortical stroke is at much higher risk of epilepsy. Neoplastic disease was not explored as a confounder despite its expected high prevalence in such a population and its strong association with epilepsy, in addition to other potential confounders such as psychiatric comorbidities and alcohol dependence. Data regarding medication adherence and the adequacy of blood pressure control were also lacking, and the analysis had to be limited to subjects on a single antihypertensive agent. Finally, the antihypertensive classes of interest in the study are not viewed equally by German practitioners because BB and ACEi were favored over ARBs; prior to matching, the number of subjects exposed to BB or ACEi were double that of those exposed to ARBs. Given this, there might be baseline, unappreciated differences in subjects prescribed ARBs versus other agents. As a result, these findings need to be replicated in a different geographic location and treatment approach to hypertension.

The analysis of large databases allows us to identify risk factors for epilepsy, potential disease-modifying agents, and long-term risks of anti-seizure medications. It is always important when a relationship is found to then seek to understand its biological plausibility. Why would ARBs and specifically losartan be protective? Animal models have revealed 2 potential mechanisms: (1) Blocking TGF-β signaling which has been linked with a host of downstream effects linked to epilepsy such as astrocytic transformation, downregulation of gamma-amino-butyric acid-related genes, and accumulation of extracellular glutamate. In models of vascular injury, losartan was found to prevent spontaneous seizures with an effect lasting weeks after drug withdrawal. ⁶ (2) Modulating microglia-induced neuroinflammatory responses and neuronal loss. ⁷ This lends more credibility to the findings with several lines of evidence from animal data showing neuroprotective effects for losartan. ⁸ Interestingly a positive effect for ARBs as a class was found on dementia incidence as well. ⁹ We must keep in mind that the effect in humans occurred in a short time frame since the study restricted follow-up to a maximum of 5 years, and it is unclear whether this effect would persist beyond this point.

Future hypertension treatment guidelines should start including epilepsy as another complication. However, it would be difficult to advocate the use of ARBs broadly in the population to prevent epilepsy based on the data we have. Instead, we should start planning randomized control trials in high-risk adult populations such as those with stroke and comorbid hypertension to prove this effect. The animal models and database studies are showing us that we might already have an easily accessible anti-epileptogenic agent, losartan, so let’s put it to the test.

Rani A. Sarkis, MD, MSc
Brigham and Women’s Hospital