BB&T Contributing Writer

LOS ANGELES — The purpose of a clinical trial, particularly a huge, multi-center, prospective and randomized one, is to provide sufficient data to guide physicians to deliver the best care for their patients. The vast majority of trials, whether device or drug-based, generally achieve this goal.

However, based on the heated debate about how to treat carotid artery stenosis that occurred at this year's International Stroke Conference, which is sponsored by the American Heart Association (AHA; Dallas), that clearly does not appear to be the case.

Recall that the 2010 conference featured the release of data from the landmark and keenly anticipated Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Sponsored by the National Institutes of Health (Bethesda, Maryland), CREST enrolled more than 2,500 patients at 117 centers in the U.S. and Canada and took a remarkable nine years to complete.

Patients were randomized 1:1 to either carotid stenting (CAS) or carotid endarterectomy (CEA), with just over half the patients with symptomatic disease. The primary endpoint was a composite of any stroke, myocardial infarction (MI) or death within 30 days. The secondary endpoints contrast CEA and CAS by symptomatic events, sex, restenosis and health-related quality of life (QOL) and cost.

The conclusion from last year's conference was essentially that either procedure is a good way to treat carotid artery occlusions and thus to limit the risks of having a stroke. The choice between the two procedures could be more a matter of patient preference than scientific certainty.

Stated differently, Wayne Clark, MD, a vascular neurologist from Oregon Health Sciences University Medical Group (Portland) said, “I am excited to say that we now have two very good options to prevent stroke.“

Further, the lead CREST investigator Thomas Brott, MD of the Mayo Clinic (Jacksonville, Florida) indicated last year that while the stroke and heart attack rates were different “unfortunately, there is not a lot of scientifically valid information that tells us which is more important to the patient.“

A recent guideline document, titled “Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease“ was published in the January 2011 issue of Circulation. Developed with experts from the AHA and the American College of Cardiology (Washington) and several other medical societies, it essentially echoes these viewpoints.

The October 2010 issue of Endovascular Today was heavily devoted to this topic, with an editorial from the chief medical editor's page titled “The CAS Data Puzzle.“ The issue contained numerous articles on the topic from some of the world's most renown experts from vascular and cardiovascular surgery to interventional neurologists, cardiologists and neuroradiologists.

Clearly, CREST is a highly important study and the massive interest in this subject was exemplified here at a session with a standing room only crowd to attend talks on “Carotid Angioplasty and Stenting versus Endarterectomy.“ From the size of the audience to the passionate views from speakers and the audience in a lively Q&A, it was clear that the controversy is still very much alive and indeed, far from being resolved.

The session's moderator Seemani Chaturvedi, MD, professor of neurology at the Wayne State School of Medicine (Detroit), kicked off the proceedings, saying that it is especially timely, a year after CREST was unveiled, to re-visit the data and update the medical community. He further noted that recent regulatory developments made it even more important to review treatment options.

Chaturvedi's reference to new regulatory events concerned an FDA Circulatory Systems Devices Panel advisory committee meeting that took place on January 26. The committee considered the application from Abbott Vascular (Abbott Park, Illinois) to broaden the indication for its RX Acculink carotid artery stent and companion embolic protection device, the RX Accunet, from patients who are at high risk for a carotid artery endarterectomy procedure to those who are at standard risk.

With a 7-3 affirmative, the panel basically supported the CREST data and voted to expand the label for this patient population. Final FDA approval is presumably going to follow in the next few months, although the FDA is certainly not obligated to follow the committee's recommendations.

The session here began with Jorg, Ederle, MD, from the Stroke Research Group, Institute of Neurology (London), who provided a detailed review of the various trials that have been conducted around the world in the past several years. His two main conclusions were that CAS is riskier than CEA (due to a higher stroke rate) especially in asymptomatic patients and that the efficacy of the two approaches is quite similar, particularly a few years after the procedure has been performed.

Robert Harbaugh, MD, chairman of the department of neurology at Penn State Hershey Medical Center (Hershey, Pennsylvania), provided an extensive analysis of the CREST data, noting that the results were quite similar. He was adamant in his opinion that “symptomatic patients are the most important to treat“ and later in his remarks, slammed CAS, saying “it is criminal to treat these asymptomatic patients with stenting and angioplasty.“

Adnan Siddiqui, MD, assistant professor of neurosurgery and radiology at State University of New York (Buffalo, New York), was the final speaker of the session. He took a more balanced approach in his prepared remarks, commenting that “equipoise has been reached“ and that “both approaches are very complementary.“ He noted that the rate of adverse events in carotid stenting has significantly declined with the addition of distal protection devices. This benefit was first demonstrated in the SAPPHIRE trial in 2005 and has continued to be a boon to CAS procedures, according to Siddiqui.

A lively question and answer period brought emotions to a head with Harbaugh and Siddiqui strongly disagreeing on the role of CAS vs. CEA. Harbaugh again reiterated the “criminal“ word in regard to Medicare patients being “over-stented,“ adding that “if we perform stenting procedures on asymptomatic patients, we will cause more strokes than we will prevent.“

All physicians in the session agreed that another study, measuring CEA and CAS against medical management was sorely needed. Chaturvedi noted that medical management has improved significantly in recent years and that many neurologists contend that most patients can be successfully managed medically.

“We desperately need the stroke neurologists to help us decide which therapy is best for each patient,“ he said.

A final indication of the smoldering nature of this disease, which accounts for an estimated 125,000 to 150,000 procedures per year in the U.S. is that a few days before this meeting, the cerebrovascular section of the American Association of Neurological Surgeons (AANS; Rolling Meadows, Illinois) met in Los Angeles. According to a research report written by analyst Josh Jennings of the investment banking firm Jefferies & Co. (New York) a lively CREST debate at AANS occurred because “neurosurgeons are at risk of losing carotid endarterectomy procedure volumes.“

Jennings went on to opine that “we now believe that carotid artery stenting procedures can increase five-fold on the heels of a positive panel (meeting) for Abbott's Acculink and pending a positive reimbursement decision by CMS and commercial payers over the next four to five years . . .“

ISC spotlight is focused on acute ischemic stroke

One of the key topics at the ISC meeting was the treatment of an acute ischemic stroke (AIS).

According to the AHA's “Heart & Stroke Statistics 2011 Update“ AIS accounts for 691,000 (87%) of the estimated 795,000 new or recurrent annual strokes in the U.S. By comparison, hemorrhagic strokes account for only 13% of the total. BB&Testimates the global hemorrhagic market at about $1 billion worldwide, growing about 12% per year. Meanwhile, the AIS market, despite accounting for nearly seven times as many strokes, is currently generating revenue that BB&T estimates at about $125-150 million worldwide.

The AIS market has grown rapidly in recent years. Two key market drivers are vastly improved devices and better imaging modalities, especiallly diffuson weighted MR imaging.

At a presentation here, Gregory Albers, MD, director of the Stanford Stroke Center (Stanford, California) discussed how better imaging technology is changing how acute ischemic stroke is managed.

“We now have the (imaging) technology . . . that will change the paradigm of stroke treatment . . . based on salvageable tissue, not time windows,“ said Albers.

The concept that the time window is secondary to brain tissue salvageability is significant, because the vast majority of patients cannot get treated within the narrow three-to four hour time “window of opportunity“ of thrombolytic therapy. Moreover, many do not arrive in a timely fashion for the six-to-eight hour mechanical recanalization window. Many US stroke centers are now relying on images of brain pathophysiology, rather than arbitrary time frames to aid in the selection of appropriate therapies for patients who present outside the accepted stroke treatment window.

Two private, California-based companies, Concentric Medical (Mountain View) and Penumbra (Alameda) are leading the charge with evolving devices and global sales and marketing efforts. In 2004, Concentric became the first to receive FDA clearance for a mechanical thrombectomy or clot removal device, which was trade named the Merci Retrieval System. The company has made numerous modifications to its system since it first debuted, resulting in improved recanalization rates.

The results of a 1,000 patient, open label, prospective, multicenter Merci registry were presented here by Marilyn Rymer, MD, from the Mid-America Brain and Stroke Institute (Kansas City, Missouri). The goal of the registry, according to Rymer was: “what does the real-world, unconstrained treatment of acute ischemic stroke look like . . .“

The data were impressive, with an 80% recanalization rate vs. 64% in earlier Concentric trials, while the 90-day mortality rate declined from 38% to 33%. Two key conclusions from this study were: (1) They validate the results from earlier pivotal trials, MERCI and Multi MERCI; (2) Successful recanalization is associated with higher rates of favorable outcomes.

Concentric's latest innovation is the Trevo stent-retriever system. Designed for quick access, rapid clot integration and retrieval, it combines a stent and a thrombus-removing catheter. The concept of this device, which has been dubbed a “stentriever,“ is that the stent can restore blood flow and the retriever can grab the clot and remove it.

Commercial sales began in Europe in late-2010 and early reports indicate that it is off to a strong start. The company commenced the TREVO (Thrombectomy Revascularization of large Vessel Occlusions) study in Europe in late-2010 and very recently, it began enrolling patients in TREVO-2, a randomized IDE clinical trial designed to gain domestic approval. The Trevo is being sold in Canada and a few other countries.

At a talk titled “Endovascular Therapy for Acute Ischemic Stroke Using Retrievable Stents,“ Aitziber Aleu, MD, from the Germans Trias i Pujols (Barcelona) discussed the results attained with these devices. 141 patients were treated with either the Trevo or Solitaire device – sold by the ev3 neuro division of Covidien (Dublin, Ireland – and the data revealed a high level of recanalization, shorter procedure times and better patient outcomes.

Covidien is the market leader in this category, the Solitaire dominates the European stentriever market. In the U.S., enrollment in the Solitaire with the Intention for Thrombectomy (SWIFT) IDE trial, with 200 patients randomized to 1:1 Merci, is nearly complete.

After this presentation, a renown stroke specialist who did not want to be quoted by name by BB&T said “based on the data presented today, this concept looks like the real deal.“

Penumbra entered the AIS market in January 2008, with its first product trade named the Penumbra System. Like the Merci Retrieval System, this product is designed for use in intracranial large-vessel occlusions, however, the Penumbra System differs because it removes the clot proximal to the thrombus using continuous aspiration.

In 2009, Penumbra introduced a new, larger internal diameter size catheter that has four times the flow rate of the company's previous largest catheter. According to a poster presented here by Donald Frei, MD, Swedish Medical Center (Englewood, Colorado) the 0.054-inch Penumbra System “can enhance aspiration efficiency and speed, leading to a shorter aspiration time and a more complete revascularization . . .“

Commenting on the study of the Penumbra Early Evacuation Device (SPEED) trial, Frei told BB&T that not only did the TIMI scores increase nicely, but that the time required for aspiration dropped 60%, from 45 minutes to only 18 minutes with the larger catheter.

Reduced aspiration or procedural time is critical, as demonstrated in a talk titled “Microcatheter to Recanalization (Procedural Time) Predicts Outcomes in Endovascular Treatment in Acute Ischemic Stroke Patients,“ delivered by Ameer Hassan, DO, of the Zeenat Qureshi Stroke Research Center (Minneapolis). This study of 242 AIS patients found that the procedural time “. . . appears to be a critical element for achieving favorable outcomes.“

Just prior to the ISC, Penumbra announced FDA marketing clearance for its new embolic coils for treating intracranial aneurysms. According to company officials, these coils are softer and more flexible, therefore should be safer to deploy. Their flexibility allows for more dense packing, which implies that the aneurysm space should be filled more fully, potentially reducing post-procedural bleeding and the need for re-treatments. The delivery catheter is larger, thus larger coils can be delivered, which in turns means that fewer coils will be needed per case. A reduction in the number of coils should reduce the time of the procedure and thus will lower the overall cost of the procedure.

Penumbra attained CE mark for its coils in September 2010 and had already begun commercial sales. It will now begin domestic marketing with its highly regarded sales force.

In late-2010, Penumbra enrolled the first patients in its European PULSE clinical trial to evaluate a self-expanding, fully retrievable, dense mesh temporary stent designed to be deployed into a clot blocking blood flow to the brain immediate flow. The Pulse flow restoration device is designed to offer immediate flow restoration while simultaneously allowing the continued aspiration of clot using the Penumbra system.

Two other private California companies that are targeting the AIS market are venture capital-backed Reverse Medical (Irvine) and privately-funded Insera Therapeutics (Sacramento). The former has developed a suite of products, including its ReStore thrombectomy microcatheter, which received the CE Mark in July 2010. In December, Reverse achieved FDA approval to begin an IDE study in 200 patients, randomized 1:1 to the Merci device.

CEO Jeff Valko told BB&T that ReStore, which he believes incorporates the only non-self expanding nitinol stent available, has several advantages. “It is extremely safe and versatile and enables super selective contrast and therapeutic infusion, flow restoration and thrombectomy.“ The company's other products include the RePort radial expanding guide catheter (which has CE mark, awaiting FDA clearance), and the kink resistant ReFlex aspiration guide catheter (CE mark and FDA approval expected soon).

Reverse plans to go direct in the U.S. and is using Getz Bros. (Hong Kong) for distribution in numerous Asian markets. They are also engaging key distributors for European markets.

Insera Therapeutics is a relatively new player in the AIS market, with its SHELTER (Stroke Help using an Endo-Luminal Transcatheter Embolus Retrieval) device. It features a nickel-titanium mesh basket which grabs the clot, which is then contained in an outer sheath. The inner part of the device has a soft, spongy tip to prevent the accidental puncturing of blood vessels.

The engineering and development of this product was partially funded by the National Science Foundation's (NSF; Arlington, Virginia) Small Business Innovation Research program. According to an NSF press release, SHELTER is the first platform to filter and remove clots, the first to entrap the clot from both its near and far ends and the first capable of accessing small vessels in the brain. Critically, the technology can be custom-fit for the specific length and diameter of a patient's clot, a personalized approach that may improve treatment success.

The device has been used in several human cases in India and the company very recently began working to attain CE mark approval. Insera hopes to initiate a domestic clinical trial in late-2012.