Stenting for Intracranial Aneurysms: How to Paint Oneself into the Proverbial Corner

Intracranial stents designed to assist coil embolization of intracranial aneurysms have been around for nearly a decade. Yet we know very little about them. The article by Hwang et al in this issue of the American Journal of Neuroradiology¹ is a valuable contribution to an ongoing controversy, but it raises more questions than it answers. The following important questions need to be addressed properly: When should stents be used, how effective are they, and what price must patients pay in terms of complications? This article has an air of déjà vu: How intracranial stents became a part of aneurysm treatment is a typical example of how we have gone about introducing new tools and techniques. We need to do this better to protect patients from our contradictions.

When the first stent was originally introduced as a Humanitarian Use Device, the application was “not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose.”² In other words, there is no need to show that the device works. “The application, however, must contain sufficient information for FDA [US Food and Drug Administration] to determine that the device does not pose an unreasonable or significant risk of illness or injury and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.”² These are very vague statements.

Let us look at how they can be interpreted. The initial FDA application for the first coil-assist stent included the results of research on 35 rabbits. As far as we can tell, this preclinical research has never been published.³ Thirty-one patients treated in Europe were presented, 16 with asymptomatic aneurysms. The mean aneurysm size was 7.4 ± 4.3 mm. There were 12 serious adverse events in 5 patients (17% of the 29 patients who got the stent; 95% confidence interval [CI], 3%–31%). There were 21 other adverse events. The Center for Devices and Radiologic Health (CDRH) determined that the device “will not expose patients to an unreasonable or significant risk of illness or injury, and the probable benefit to health . . . for the treatment of wide-neck, intracranial, saccular aneurysms that are not amenable to treatment with surgical clipping outweighs the risks of illness or injury,” and issued an approval order on September 11, 2002.³ Three questions immediately come to mind:

• 1) What would it take for the CDRH to judge that a device would need further studies to prevent “unreasonable or significant risks”?

• 2) How dismal must the prognosis be to justify the introduction of an experimental device, with no proof that it works and so little clinical experience? Half of the patients had asymptomatic unruptured aneurysms, a disease that may not justify such a blind leap of faith in new technology.

• 3) Finally, how could the CDRH judge that patients included in the application and future patients in whom the device would be implanted would not be amenable to surgical clipping, a more standard approach?

One of the very first reports in 2005 should have tempered the rate of adoption of stents by the endovascular community: Stent placement led to adverse events in 8 of 32 treated patients (25%), resulting in a permanent neurologic deficit or death in 4 patients (12.5%; 95% CI, 2%–25%).⁴

However, you cannot stop progress. By September 2009, at least 1 such stent had been used in more than 45,000 patients. The quarterly report of the company in 2010 mentions that “our . . . adjunctive stent in both Europe and the US continues to receive positive feedback from physicians. In the third quarter [of 2010]… sales in US and Europe were up 34% compared with the third quarter last year and 24% versus the second quarter of this year.”⁵

What has sparked such enthusiasm within our community? There must be evidence showing that patients have greatly benefited from the use of this device. Many case series have been published. Looking at the abstracts of these articles, one cannot miss the enthusiasm or doubt the reality of publication bias. Some even sound like advertisements: “The aim of this study was to re-enforce the use of this stent for EVT [endovascular treatment] of wide-necked cerebral aneurysms.” “The . . . is very useful for EVT of wide-necked intracranial aneurysms because it is easy to navigate and to deploy accurately.”⁶ “In treating complex intracranial aneurysms, the . . . stent-assisted coiling is a secure and effective technique.”⁷ “For complex unruptured middle cerebral artery aneurysms, EVT by using a self-expandable intracranial stent was feasible, safe, and durable and could be considered as the first-option treatment.”⁸

Multiple other devices have since taken the same path, with equally positivistic case series.⁹

Perhaps case series in our literature should be followed by the same kind of notice that can be found at the end of industry press releases: “This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934. Forward-looking statements may be identified by words like ‘anticipate,' ‘expect,' ‘project,' ‘believe,' ‘plan,' ‘estimate,' ‘intend,' and similar words. These forward-looking statements are based on our beliefs, assumptions, and estimates by using information available to us at the time and are not intended to be guarantees of future events or performance.”⁵

Not a single one of these series, no matter how enthusiastic, has been convincing. One large experience, published last year,¹⁰ clearly shows the dilemma as well as the drift. It seems that follow-up angiographic recurrences of aneurysms treated with stent-assisted coiling, as far as they can be compared with those treated with coiling alone, were improved from 33.5% to 15%, while procedure-related morbidity and mortality were much higher with stent placement (7.4% versus 3.8%; P = .0001). However, groups may not be comparable, with aneurysms chosen for stent placement more often being unruptured sidewall aneurysms, as opposed to bifurcation aneurysms. Stented aneurysms were not followed up as long (a mean of 14 months compared with 22 months in coil-only patients). All these are factors that would tend to decrease recurrence rates for stented aneurysms. Most interesting, in more than half of the patients, stents were implanted after coiling, rendering absurd the claim that stents are mainly used to treat patients untreatable by other means. Encouraged by countless “forward-looking” presentations by physicians and engineers, the reason for stent use has shifted away from being only for otherwise uncoilable lesions. The rationale for stent use in addition to coils is now (supposedly) because it decreases the risk of recurrences. This hypothesis has never been formally tested, much less proved, to our knowledge.

Following publication of this large series, a letter to the editor commented, “This is an alarmingly high rate of serious complications, especially in a population harboring mostly unruptured aneurysms (with benign natural history) located on sites that are easily accessible for surgery.”¹¹

Another article in favor of moderation appears in this issue. There are 3 strengths to the article by Hwang et al,¹ which directly addresses our hopes for decreasing recurrences: First, the authors, during the years, have mastered alternative techniques to manage wide-neck aneurysms (multiple-catheter technique, balloon-assistance) and are thus capable of offering a comparison between groups that are similarly challenging. Second, while many reports of new devices tend to compare recurrences occurring years after simple coiling with 6-month recurrence rates for the new device, the authors have fixed the time period for angiographic follow-up at 2 years for all patients to allow a fairer comparison of recurrence rates. Finally, the article emphasizes the common pitfall of finding that a new device can lead to an improved result at follow-up. As the authors have shown, most of time, this phenomenon simply reflects more frequent incomplete occlusions immediately, which have then a higher chance of showing improved results in a delayed fashion, especially relevant when we remember that the baseline images are usually obtained with the patient under procedural doses of heparin. When simple platinum coiling was assessed in a similar fashion, there was no difference in the number of patients who had “improved”.¹

Nevertheless, the methodology used in all reports, so far, is weak, and by all acceptable standards, the results cannot be used to guide clinical decisions. A decade has passed, and an amazing number (at least 45 000) of patients have been treated with stents. What happened to them? What can we learn from this? Nobody can tell.

• © 2011 by American Journal of Neuroradiology