The Source for Neurovascular News and Education

August 10, 2020

The most remarkable finding, two experts say, is the link between reduced rupture risk and hypercholesterolemia.


Multiple demographic, clinical, and imaging factors have been linked to risk of rupture of intracranial aneurysms in a large multicenter case-control analysis conducted in the United Kingdom and published online last month in Neurosurgery. The findings have spurred speculation among experts as to what each association might mean and how best to use these data to reduce rupture risk and inform the design of new trials.

Researchers led by Isabel C. Hostettler, MD (University College London, England), identified 2,334 patients—1,729 with aneurysmal subarachnoid hemorrhage and 605 with unruptured aneurysms—who were treated at 22 UK hospitals between 2011 and 2014.

After multivariate adjustment, factors independently associated with a greater risk of rupture were black ethnicity and various aneurysm locations. Factors independently associated with a lower risk of rupture were use of antihypertensive medication, hypercholesterolemia, aspirin use, location in the internal carotid artery, and larger aneurysm size.

Independent Predictors of Rupture



95% CI

Black Ethnicity vs. White



Location in Anterior Cerebral/Communicating Artery vs. Middle Cerebral Artery



Location in Posterior Communicating Artery vs. Middle Cerebral Artery



Location in Posterior Circulation vs. Middle Cerebral Artery



Use of Antihypertensives






Use of Aspirin



Location in Internal Carotid Artery



Aneurysm Size (per mm increase)



James E. Towner, MD, and G. Edward Vates, MD (University of Rochester Medical Center, Rochester, NY), who wrote a commentary accompanying the study, told Neurovascular Exchange that the most remarkable finding was the link between reduced rupture risk and hypercholesterolemia, which was independent of statin use. “Previous studies had suggested this may be a possibility, but the study populations were too small to show a definitive effect,” they noted. “While completely speculative, the results suggest atherosclerotic vessels may have a stabilizing effect on aneurysms, preventing growth or changes. Similarly, it has been previously hypothesized that hypercholesterolemia and atherosclerotic vessels may be protective against vasospasm in patients with aneurysmal subarachnoid hemorrhage.”

A finding of particular clinical relevance was the protective effect of using antihypertensives, according to Towner and Vates. “Treatment, rather than length of treatment, was associated with a lower odds ratio for rupture. This rapid benefit of antihypertensive therapy suggests that it is not the long-term remodeling of blood vessels which occurs with chronic hypertension, but rather acute spikes which contribute to aneurysm rupture,” they said. “It should serve as a reminder for those who treat aneurysms to vigilantly advise patients with unruptured aneurysms to treat their hypertension and remain compliant with treatments.”

They also called for “further investigation as to why having a black ethnicity is associated with aneurysm rupture. While unfortunate, it would not be surprising if the authors’ speculation that the differences were due to socioeconomic and medical systems biases, rather than true genetic differences, was the root cause. If this is the case, it is another sad reminder that we must do more as physicians to limit this bias.”

Role of Aspirin and Aneurysm Size Biggest Conundrums

The role of aspirin therapy as a protective factor against rupture has been a topic of longstanding interest, noted Towner and Vates. “This notion proposes that the anti-inflammatory properties of aspirin may decrease aneurysm wall inflammation, thereby decreasing aneurysm growth and risk of rupture,” they wrote, adding that this study “certainly strengthens the argument that unruptured aneurysms are not a contraindication to antiplatelet therapy and in fact antiplatelet drugs may be protective.”

But the safety and benefits of aspirin therapy remain uncertain because the patient population in this study is highly selected and thus the findings may not be widely generalizable, they continued. For this reason, they agreed with the authors that a randomized controlled trial is needed to provide a more definitive answer.

There are additional unanswered questions as well, according to David M. Hasan, MD, and James Torner, MD (University of Iowa, Iowa City) and Seppo Juvela, MD (University of Helsinki, Finland). They emphasized the need to investigate why larger aneurysms were associated with reduced rupture risk, given that previous research has typically linked larger size with a greater risk of rupture.

Hasan and Torner also pointed out that research into the effects of aspirin should take into account patient sex, as previous studies suggest it may be more protective in men.

Taken together, said Towner and Vates, the findings can be used to help counsel patients with unruptured aneurysms about their likely risk of rupture as well as the risks and benefits of intervention versus conservative management.

They point out, however, that a case-control study of this nature cannot infer causality and that there are important cohorts of patients who were not addressed. Those include patients who die prior to reaching the hospital or die while in a tertiary care hospital prior to transfer, as well as those with incidentally noted unruptured intracranial aneurysms who are not referred to a specialist for evaluation.



Hostettler IC, Alg VS, Shahi N, et al. Characteristics of unruptured compared to ruptured intracranial aneurysms: a multicenter case-control study. Neurosurgery. 2017;Epub ahead of print.


Hostettler and the commentators report no relevant conflicts of interest.