CDU Contributing Editor

LAS VEGAS, Nevada Vascular surgery has historically been characterized by a cautious attitude toward new procedures. But the trend toward a minimally invasive approach that has impacted many other areas of medicine is emerging as a force in changing the practice of vascular medicine. The merits of new interventional approaches to vascular medicine were the subject of several informative talks at the Vascular Interventional Advances (VIVA) conference, held here last month.

The treatment of carotid artery disease has been dominated for more than 50 years by carotid endarterectomy (CEA). This surgery, the most commonly performed major vascular procedure in the U.S., has shown rapid growth in the past decade, fueled by landmark clinical trials that demonstrated that CEA provides significantly better protection against embolic stroke than does medical management for both symptomatic and asymptomatic patients. The two most widely-recognized CEA trials are the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS).

About 175,000 carotid endarterectomies were performed in the U.S. in 2002, with another 100,000 in other countries. The number of CEAs has roughly doubled in the past 10 years, following publication of the NASCET and ACAS results.

The vascular surgery community remains steadfast in its belief that a CEA is the best form of intervention to prevent an embolic stroke. Richard Cambria, MD, a vascular surgeon at Massachusetts General Hospital (Boston, Massachusetts), said at the VIVA meeting: "No one argues that CEA is a better choice than medical management for high-grade carotid stenosis." However, the initiation of several well-designed carotid artery stenting (CAS) trials in recent years has presented a challenge to CEA.

Two important carotid artery stenting trials that have completed enrollment are Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) and AccuLink for Revascularization of Carotids in High-Risk Patients (ARCHeR). The former is sponsored by the Cordis Endovascular (Warren, New Jersey) division of Cordis (Miami Lakes, Florida), a unit of Johnson & Johnson (J&J; New Brunswick, New Jersey). The latter trial is sponsored by Guidant (Indianapolis, Indiana).

One-year results for SAPPHIRE, the first multi-center, randomized study comparing CEA to CAS in high-risk patients, were presented at the Transcatheter Cardiovascular Therapeutics (TCT) conference held in Washington in September. The study compared CAS using the Cordis Precise nitinol self-expanding stent in combination with the Angioguard embolic protection system, with carotid endarterectomy. A total of 310 patients were randomized, about half to each arm. Based upon numerous endpoints, CAS demonstrated excellent safety and efficacy. The 30-day major adverse event (MAE) rate for CAS was 5.8% compared to 12.6% for endarterectomy.

Similarly, the multi-center, prospective, non-randomized, single-arm ARCHeR trial, which enrolled 145 patients both in the U.S. and Europe, has demonstrated excellent safety and efficacy. This trial used Guidant's Acculink stent and Accunet embolic protection device. Its impressive preliminary 30-day results were presented earlier this year at the annual meetings of both the American College of Cardiology (Bethesda, Maryland) and the Society of Interventional Radiology (Fairfax, Virginia).

In a detailed comparison of CAS to CEA at the VIVA conference, Tom Shimshak, MD, an interventional cardiologist from the Ohio Heart Health Center (Cincinnati, Ohio), said that the safety and efficacy of CAS has "dramatically improved" over the past decade. He cited data from the Global Carotid Artery Stent Registry (GCASR) that showed a 5.3% MAE rate in the first 6,668 cases CAS, a rate that dropped to 2.3% in the last 4,005 cases. He said that was due to the use of embolic protection devices, which has "unequivocably improved the safety of carotid artery stenting." The results of the registry, which covered CAS procedures performed from 1997 through September 2002, were presented in the October issue of Catheterization and Cardiovascular Interventions.

Virtually all the significant carotid artery stenting trials now under way employ an embolic protection device. Another VIVA speaker, Timothy Sullivan, MD, a vascular surgeon from the Mayo Clinic (Rochester, Minnesota), said that there has been "massive improvements in embolic protection devices," which has fostered lowered MAE results in the CAS trials. Sullivan noted that the first-generation devices had a 7 Fr profile, while the newer models can be delivered at 3 Fr or less. He said that "over 90% of all patients" now can receive an embolic protector with their CAS procedure.

Numerous CAS trials are ongoing worldwide. Perhaps the most important one is the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), which is a prospective, randomized, multicenter study comparing CEA to CAS in the prevention of stroke in patients with symptomatic stenosis greater than or equal to 50%. CREST, which was launched in 2000, is sponsored by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health (both Bethesda, Maryland).

This landmark trial was designed to address the broader symptomatic patient who suffers from significant carotid artery stenosis, whereas the other CAS trials were designed only to treat the high risk, non-surgical candidate patients. CREST will ultimately enroll a total of 2,500 patients at 60 centers in the U.S. and Canada. Thus far, more than 600 training cases have entered the trial (which will not be included in the randomized phase of the trial) and about 100 patients who have been randomized. Given the size of the trial, it is unlikely to be completed for another two years or so. Guidant's Acculink stent, as well its Accunet embolic protection system, were selected as the exclusive devices for this trial.

At this year's TCT meeting, 30-day follow-up results of the Study to Evaluate the NeuroShield Barewire Cerebral Protection System and Xact Stent in Patients with High Risk for Carotid Endarterectomy (SECuRITY) sponsored by the Abbott Vascular Devices (Redwood City, California) division of Abbott Laboratories (Abbott Park, Illinois) were disclosed. This study was a prospective, multicenter registry on 350 patients who were considered at high risk for surgery. Nearly 30% of the patients were older than 80. The results showed a 7.2% MAE rate. The prospective, multi-center registry reported on 305 high-risk patients at 30 sites. Patients were treated with the EmboShield bare wire filter and Xact carotid stent, both developed by MedNova (Galway, Ireland). Abbott Vascular has an exclusive distribution arrangement with MedNova.

Medtronic (Minneapolis, Minnesota) has completed enrollment of the Evaluation of the Medtronic AVE Self-Expandable Carotid Stent System with Distal Protection In the Treatment of Carotid Stenosis (MAVErIC II) trial and is in a one-year follow-up period. That trial is assessing short- and long-term safety and efficacy using the company's Exponent stent system and the GuardWire protection device.

Two major barriers remain before carotid artery stenting can have a major impact. First, FDA approvals are still several months away, with J&J likely to be the first company to market. Second, the Centers for Medicare & Medicaid Services (Baltimore, Maryland) has issued a non-coverage reimbursement decision on CAS, due mainly to the lack of published safety and efficacy evidence.

In a debate concluding the VIVA conference sessions on treating carotid artery disease, Mark Bates, MD, an interventional cardiologist from the Charleston Area Medical Center (Charleston, West Virginia), argued that the solid CAS clinical data supports its role as first-line therapy. Not surprisingly, Cambria, the vascular surgeon, asserted that CEA remains the gold standard, citing recent data on 12,000 patients in Connecticut treated with CEA that indicated a low incidence of MAE and just a one-night hospital stay for more than 90% of those patients. This data has not been published as of yet in any peer-reviewed journal. Cambria did concede that carotid artery stenting "is a valued addition to the therapeutic options."

Another prominent vascular disease whose treatment choice has become quite contentious is abdominal aortic aneurysm (AAA). Although not generally recognized as a significant cause of death, in fact, ruptured aneurysms in both the abdomen and chest kill an estimated 18,000 Americans a year. AAA disease is the 13th-leading cause of death in America overall and the 10th-leading cause of death among men older than 55. Indeed, some industry pundits believe that the impact of AAA disease may be substantially understated, as people who die from unexplained causes and do not undergo an autopsy may have fallen victim to a ruptured aortic vessel due to an aneurysm.

More public attention was focused on the treatment of aortic aneurysms with the publication Nov. 4 of a front-page article in The Wall Street Journal on the treatment or lack thereof of such aneurysms. As the Journal said in its story, "A common misconception among physicians is that aortic disease is rate, when in fact it kills an estimated 25,000 Americans a year. That is a larger toll than that of AIDS and most kinds of cancer." Another misconception, the newspaper said, is that little can be done about aortic aneurysms. "The reality is that improvements in diagnostic-scanning methods ... and greater experience with aortic surgery have vastly enhanced the ability to detect and repair aneurysms."

Prior to Guidant and Medtronic approvals in the U.S. of the first-generation endovascular aneurysm repair (EVAR) devices in September 1999, the only treatment option for patients requiring AAA repair was open surgery. While regarded as a durable procedure, open surgery is highly invasive, has a long hospital stay, lengthy recovery period and often is very harsh on the patient's quality of life. A study in the May 2001 issue of the Journal of Vascular Surgery found that only two-thirds of post-operative AAA interviewed patients said that they had enjoyed a full recovery to their normal activities.

The availability of the far less invasive EVAR devices has provided patients and their physicians with an attractive alternative to open surgery. The relative merits of these two approaches was discussed in depth at the VIVA meeting, by two well-respected vascular surgeons Luis Sanchez, MD, of Washington University School of Medicine (St. Louis, Missouri) debating Michael Bacharach, MD, of the North Central Heart Institute (Sioux Falls, North Dakota).

Sanchez, who during the VIVA meeting gave an excellent presentation on the "Status of New Investigational Devices for Endo AAA Repair," said that EVARs offer numerous advantages to patients over the short, intermediate and long term. In addition to a significantly lower mortality rate from endovascular repair, which he estimated at less than 2% vs. 6% to 8% for open procedures, Sanchez said that the benefits of early recovery and a higher quality of life are "very important issues in the choice of open vs. endovascular repair."

Taking the more traditional view, Bacharach said that there are several shortcomings of EVARs that need to be recognized by the medical community. In particular, he cited an endoleak rate that is reported in the literature at 16% to 44%. According to him, this results in a re-intervention for more than one-third of patients receiving an EVAR. Bacharach also said there is a need for follow-up CT scans to verify that the stent graft is properly functioning, which are expensive and inconvenient for the patient. Bacharach presented data from the Cleveland Clinic Foundation (Cleveland, Ohio) from 2000, noting that 158 or 36% of the total number of patients treated had received an EVAR for their AAA. He concluded his comments by saying that he believed that 40% of patients were true candidates for an EVAR, while the rest were better served with an open repair.

A few days later, at the 89th annual clinical congress of the American College of Surgeons (Chicago, Illinois) held in Chicago, a similar debate took place, pitting two other vascular surgeons. Presenting the positive view on EVARs was Kenneth Ouriel, MD, chairman of the department of vascular surgery at the Cleveland Clinic, while John Hallett, MD, director of the East Maine Medical Center (Bangor, Maine), took the opposite point of view, saying that endovascular stent-grafts are "not yet ready for prime time and therefore open surgery is still the gold standard today."

Hallett said that most patients who have AAA surgery live another five years and therefore durability is a very large consideration in the choice of EVAR vs. open surgery. He further commented that "the standard of care in vascular surgery is five to 10 years" and that EVAR devices have not been used long enough to meet that lofty standard.

Ouriel said that the goals of AAA repair are to prevent mortality over the long term, minimize peri-operative morbidity and mortality and be economically attractive to the healthcare system. Based on a careful analysis of these key criteria, he asserted that EVAR is fulfilling its promise as a viable alternative to open surgery. However, he stressed that "we really need a well-run randomized trial" to determine which approach is best for most patients.

In this regard, Ouriel mentioned two major trials that are under way. The first is sponsored by the Department of Veterans Affairs (Washington), which has recently begun a multi-center, randomized clinical trial comparing EVAR to open surgery for safety and effectiveness. This eight-year trial, called Open Versus Endovascular Repair (OPEN) will enroll more than 1,200 patients. Another large study, sponsored by the Dutch Health Insurance Council, is called the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial and has enrolled more than 300 patients to date. DREAM is a randomized multicenter study of elective treatment of an abdominal aortic aneurysm. The primary endpoint is combined operative mortality and morbidity. Secondary endpoints and additional assessments include quality of life, length of hospital stay, and cost-effectiveness. A total of 400 patients will be randomized.

The results of these two trials will certainly go a long way toward resolving the lively debate that is currently raging in the vascular surgery community.

Interestingly, both physicians agreed that EVAR could be appropriately used in 40% to 50% of all AAA surgical candidates. With this in mind, a revised market model for endovascular aneurysm repair is presented in Table 1. The two key points in this market projection over the next five years is that ultrasound screening, which is demonstrating excellent efficacy and is highly cost-effective, will identify more AAA patients for earlier intervention, thereby increasing the number of total interventions. Second, the continued technological improvements in EVAR devices, including better attachment mechanisms, lower profiles and stronger and thinner materials, will enable more patients to be treated with an endo device instead of open surgery.

As a result, Cardiovascular Device Update estimates that the global market for EVAR products, as shown in Table 1, will more than double in the next five years, exceeding $500 million by the year 2007. The penetration of EVAR in the U.S. will be higher than the rest of the world, reflecting better reimbursement and the more rapid acceptance of new medical technology in this country.

Four U.S.-based companies Guidant, Medtronic, W. L. Gore (Flagstaff, Arizona) and Cook (Bloomington, Indiana) have now received final FDA approval. The first two companies received their approvals in September 1999. As was widely reported, Guidant exited the AAA market earlier this year. The W. L. Gore device, the Excluder, received FDA approval for its modular bifurcated system in November 2002, while Cook received premarket approval for its Zenith graft in May.

Increased competition is looming in the AAA market. It was anticipated that the next market entrant would be Medtronic's Talent device, which has been hugely successful outside the U.S., with FDA approval foreseen in the latter half of 2004. However, the company recently told the financial community that its launch would be delayed. Through industry sources, CDU has learned that the FDA has some reservations about the quality of the clinical data.

Thus, the next likely entrant may be Endologix (Irvine, California), which has completed its pivotal clinical trial and expects to submit its premarket approval application (PMA) before the end of 2003. Following Endologix, CDU expects that Edwards Lifesciences (also Irvine) will be the next competitor. It has completed enrollment of its patient cohort for its Lifepath device and is now in its one-year follow-up phase. A PMA will likely be filed around mid-2004.