A Proposed Randomized Clinical Trial for Small Unruptured Intracranial Aneurysms

As brain imaging improves, small, asymptomatic, unruptured intracranial aneurysms (UIAs) are discovered with increasing frequency, often as incidental findings. Treatment for small UIAs may include surgical intervention (craniotomy and clipping of the aneurysm), endovascular coiling, or observation, with lifestyle changes such as lowering blood pressure and smoking cessation.

Interventional Treatment Options

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"The question today is no longer whether we can treat small UIAs, but should we? We have the technology to fix the vast majority, but distinguishing between those that will and those that will not rupture is difficult," explains Brian W. Chong, M.D., chair of the Division of Vascular and Interventional Radiology at Mayo Clinic in Phoenix/Scottsdale, Arizona. His neurosurgical colleague, Ricardo A. Hanel, M.D., at Mayo Clinic in Jacksonville, Florida, agrees, listing the many considerations that go into the decision about whether to intervene: the site, size, and shape of the UIA; the patient's age and medical and family history; and the relative risks and benefits of intervention versus management through observation. They both acknowledge that in many patients the discovery of an aneurysm causes considerable anxiety, and some patients fear any type of intervention. The question of which course of management is best has been a subject of controversy.

Findings to Date

Led by Mayo Clinic in Rochester, Minnesota, the International Study of Unruptured Intracranial Aneurysms (ISUIA) set out to shed light on the issue in 1991. By far the largest study of its kind, the first phases assessed the natural history and management outcomes of UIAs in more than 5,500 patients. Management included surgical clipping, endovascular coiling, or observation. Among the many findings was that size and location mattered relative to risk for rupture: the smaller the aneurysm, the lower the risk of rupture. In asymptomatic patients without a previous subarachnoid hemorrhage, aneurysms measuring less than 7 mm in diameter had a low rupture rate, regardless of family history. Small UIAs in the posterior circulation had a slightly higher risk of rupture than in the anterior circulation. The study also found that intervention and observation were similar in outcome and risk for small aneurysms.

"What we did not know," explains Robert D. Brown, M.D., chair of neurology at Mayo Clinic in Rochester and principal investigator of the study, "was what the outcome would be if we extended the follow-up. Would the rupture risk continue at a constant level, increase with age, or be reduced?"  The latest phase of ISUIA, completed in 2008, indicates that the annual risk of rupture remains the same over an average of nearly 10 years of follow-up. For small UIAs, risk neither increased nor decreased significantly with increased age of the patient or time after discovery.

Long-term Follow-up of Unruptured Intracranial Aneurysms.

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ISUIA Phase 4: A Proposed Clinical Trial

"ISUIA brought the best evidence to date to guide us in treating these small UIAs," says Dr. Hanel. However, as Dr. Brown points out, in patients for whom clinical equipoise exists, the question remains, "Which management strategy is best?" Clinical equipoise is the situation in which there is uncertainty about optimal management of a medical condition because the risks and benefits of various treatment options appear similar. Such is the case for many small UIAs, which, Dr. Brown says, "suggests that a clinical trial is needed to clarify the optimal treatment."

To find out if 1 treatment serves patients better, participating institutions are poised to enter phase 4, a prospective look at best management through a randomized clinical trial. Patients with small UIAs will be randomly assigned to 1 of 2 different approaches: observation with lifestyle changes or interventional management with either aneurysmal coiling or clipping.

David F. Kallmes, M.D., a neuroradiologist at Mayo Clinic in Rochester, is involved in designing the new study. As he explains, study patients must be screened for equipoise with great care to meet the highest ethical standards. He adds that techniques and materials used in interventional radiology and neurosurgical procedures to manage aneurysms are evolving. Thus, the specific procedures and the type of interventional management will not be prescribed by the study, but will be determined by each participating institution and may change over time.

The study aims to determine differences between treatment groups, not only in mortality and medical and overall functional outcome, but in cognitive and behavioral outcomes, quality of life, and utilization of health care resources. In patients randomly assigned to observation, an additional aim will be to define the frequency of and risk factors for aneurysm enlargement.

At Mayo's 3 sites, patients with UIAs are seen in a neurovascular clinic in which neurologists, radiologists, and neurosurgeons together arrive at the best treatment option. "The decision is highly individualized, but every bit of objective data helps. ISUIA has already helped the health care community understand that the decision to intervene when patients present with small UIAs must be made very selectively," states Giuseppe Lanzino, M.D., a neurosurgeon at Mayo Clinic in Rochester. "It is hoped that the ISUIA phase 4 trial will help clarify these difficult treatment decisions."