RAAS Inhibitors May Help Protect Against Brain Aneurysm Rupt… : Neurology Today

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Article In Brief

New research showed that those who took RAAS inhibitors for blood pressure control were less likely to experience aneurysm rupture compared with those who took non-RAAS inhibitors. RAAS inhibitors include commonly prescribed angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

The use of a renin-angiotensin-aldosterone system (RAAS) inhibitor, a blood pressure medication, may significantly reduce the risk of brain aneurysm rupture in persons with hypertension and an intracranial aneurysm, according to a retrospective study of patients in China.

The study, which included more than 3,000 adults with high blood pressure and intracranial aneurysm, found that those who took RAAS inhibitors for blood pressure control were less likely to experience aneurysm rupture compared with those who took non-RAAS inhibitors. RAAS inhibitors include commonly prescribed angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

“For hypertensive patients with intracranial aneurysms, RAAS inhibitors may be preferable to other antihypertensive medications in reducing the rupture risk,” concluded the study, published ahead of print on June 3 in Hypertension. The researchers estimated that the relative risk of ruptured aneurysms could be cut by about a third if patients with high blood pressure and a brain aneurysm were prescribed RAAS inhibitors.

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“Our results could help clinicians to optimize the antihypertensive medication choices for hypertensive patients with unruptured intracranial aneurysms.”—DR. QINGHAI HUANG

“Our results could help clinicians to optimize the antihypertensive medication choices for hypertensive patients with unruptured intracranial aneurysms,” said the study’s senior author Qinghai Huang, MD, PhD, professor of neurosurgery at Changhai Hospital of the Second Military Medical University in Shanghai, in an email interview.

The study authors noted that intracranial aneurysm rupture is the cause of about 85 percent of cases of subarachnoid hemorrhage, resulting in considerable morbidity and mortality. “Approximately one-third of the patients die, and another third remain dependent for daily life activities,” the study authors wrote.

Given the potential for devasting consequences, researchers have begun to focus more on primary prevention of intracranial aneurysm rupture, trying to identify and target modifiable risk factors. About half of patients with unruptured intracranial aneurysms have hypertension, a well-established risk factor for rupture, but no clinical study to date has investigated the effect of antihypertensive medication choice on rupture risk, the study authors noted.

Investigating the potential benefits of RAAS inhibitors made sense from a scientific perspective, the researchers said, because previous research in laboratory and animal models has shown that dysregulation of the body’s RAAS can lead to high blood pressure. Also, two components of RAAS—angiotensin-(1-7) and mineralocorticoid—are involved in the pathogenesis of intracranial aneurysms, the researchers wrote.

“Accordingly, we hypothesized that RAAS inhibitors, which block the effects of the RAAS, could decrease the rupture risk of intracranial aneurysms independent of blood pressure control,” the researchers said.

Real-World Database

To test that theory, the research team used the database of the National Research and Development Project of Intracranial Aneurysms. The project, started in 2016 and including 20 tertiary academic medical centers in China, was established as a real-world research database of intracranial aneurysms. It contains information registered prospectively on patient demographics, clinical characteristics, and aneurysmal indices.

The study population consisted of hypertensive patients with intracranial aneurysms who were registered in the database between 2016 and 2021. The participants were 18 years old or older with a diagnosis of aneurysm confirmed by digital subtraction angiography. Patients had also been diagnosed with hypertension and were treated with antihypertensive medication at least three months prior to registration in the database. The study excluded cases involving traumatic aneurysms, feeding artery aneurysms to arteriovenous malformations, or fusiform aneurysms.

Of the 3,044 hypertensive patients with aneurysms included in the analysis, 1,113 were men and 1,931 were women and the average age was just under 61. Of the total, 1,806 patients had unruptured aneurysms, and 1,238 had ruptured aneurysms by the end of the study. The patients were treated for their aneurysms by clipping, coiling, and conservative treatment as deemed appropriate.

The analysis found that multiple factors, including female sex, age, passive smoking, uncontrolled or unmonitored hypertension, RAAS medication use, use of more than two blood pressure medications, use of antihyperglycemic agents, hyperlipidemia, ischemic stroke and aneurysm location, were independently associated with risk of rupture. When it came specifically to blood pressure medication, “the use of RAAS inhibitors was significantly associated with a reduced rupture risk compared with the use of non-RAAS inhibitors (odds ratio, 0.49),” the study found.

The lower risk of aneurysm rupture associated with RAAS inhibitors use was independent of blood pressure control, the researchers reported, meaning persons taking non-RAAS inhibitors were still at higher risk for rupture even if their blood pressure was considered controlled.

In a secondary analysis the researchers matched 541 RAAS inhibitor users with 541 non-RAAS users. It found that about 32 percent of those who took RAAS inhibitors had a rupture, compared with 67 percent of those who were on a non-RAAS inhibitor.

The researchers estimated that “17.7 percent of ruptured aneurysms would be prevented if all patients were prescribed with RAAS inhibitors, reducing a relative rupture risk by 35.8 percent.”

Dr. Huang said that based on the study findings, RAAS inhibitors should be considered “first-line” therapy for patients with hypertension and unruptured intracranial aneurysm. The study found that both ACE inhibitors and ARBs were associated with a reduction in rupture risk, with ARBs showing a slight advantage.

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“Already in practice we do think of the profile of our patients, their comorbidities (such as diabetes or stroke history), and the nature of their blood pressure monitoring, when selecting blood pressure medications, but the new findings related to patients with unruptured aneurysms and hypertension add an interesting angle to consider.”—DR. ARAVIND GANESH

“Given our result that ARB users had a slightly lower rupture risk than ACE users and the equal antihypertensive efficacy but fewer adverse events with ARBs, it seems that ARBs are the preferred antihypertensive medications for hypertensive patients with intracranial aneurysms,” he said.

The researchers noted that their study had limitations, including the fact that it was retrospective. “We intend to perform a prospective study that follows up hypertensive patients with unruptured intracranial aneurysms to identify the distinct rupture risks according to antihypertensive medication choice,” Dr. Huang said. He said the study might also provide “mechanistic insight” into why RAAS inhibitors may help keep brain aneurysms from bursting.

Another limitation of the current study is that it used an outdated definition of hypertension (140/90 mm/Hg or higher), not the more recent one of 130/80. Also, the exact value of blood pressure was not recorded in the database and neither were the duration and dose of blood pressure medication used, information that could be useful for doctors making prescribing decisions.

Clinical Implications

Aravind Ganesh, MD, a neurologist and assistant professor in the department of clinical neurosciences at University of Calgary, said that clinicians have known for a long time that blood pressure control is important for reducing the risk of intracranial hemorrhage, but he said this new study goes a step further by suggesting that the type of antihypertensive agent used may be key to doing that.

While he agreed that the study had limitations, including the lack of specific blood pressure readings for the patients, “this is compelling data because of the size of the database and the sheer degree of follow up.”

“Already in practice we do think of the profile of our patients, their comorbidities (such as diabetes or stroke history), and the nature of their blood pressure monitoring, when selecting blood pressure medications, but the new findings related to patients with unruptured aneurysms and hypertension add an interesting angle to consider.”

“It has not been one of the factors featured in how I go about selecting blood pressure management,” he said, though “this will be an interesting space to watch.”

Stephan A. Mayer, MD, director of neurocritical care and emergency neurology services at Westchester Medical Center Health System, said the new study is statistically impressive and clinically relevant.

“I think it is very novel, and it may well have immediate implications for clinical practice,” Dr. Mayer said.

He said that while there has a “robust reduction” in recent years in the rate of brain aneurysm rupture, in part due to new treatment techniques, many smaller aneurysms are treated medically and followed with serial imaging.

Dr. Mayer said he already uses ACE/ARB inhibitors as his first-line option for secondary stroke prevention after ischemic or hemorrhagic stroke and will now use them in the setting of hypertension and unruptured brain aneurysms as well.

“My feeling in reading this study is that I don’t need a randomized clinical trial to start doing this,” he said, noting that he would likely choose ACE inhibitors over ARBs because they are so commonly used and are generally “very, very safe.”

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“I think it is very novel and it may well have immediate implications for clinical practice.”—DR. STEPHAN A. MAYER

Disclosures

Dr. Huang had no disclosures. Dr. Ganesh reports receiving honoraria and consulting fees from Alexion, Biogen, Atheneum, MD Analytics, MyMedicalPanel, Figure1, Creative Research Designs, and CTC Communications Corp. He has received research support from Microvention, and stock options from SnapDx and the Rounds. Dr. Mayer serves on the data safety and monitoring board for Biogen, and has received consulting fees from BrainCool, CSL Behring, and MaxQ. He has served on the steering committee and received consulting fees from Phaganesis, served on the steering committee and received consulting fees from Idorsia, and has received speaking fees from Ceribell.

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