By AARON LORENZO
CDU Washington Writer
and LARRY HAIMOVITCH
CDU Contributing Editor

WASHINGTON – Long-term findings released at the Transcatheter Cardiovascular Therapeutics (TCT) in October demonstrated the durability of carotid artery stenting to prevent stokes compared to endarterectomy. Specifically, preliminary three-year data from the SAPPHIRE (Stentings and Angioplasty with Protection in Patients at High Risk for Endarterectomy) study revealed similar stroke rates among patients treated with both techniques: 7.1% in those who received stents and 6.7% in endarterectomy patients (945 patients in all), representing the stents’ non-inferiority. Notably, all patients in the study were classified as high-risk. The SAPPHIRE study involved use of the Precise nitinol self-expanding stent from Cordis, coupled with the Angioguard XP emboli capture guidewire system.

“It’s quite clear that this is a durable procedure,” said Jay Yadav, MD, of the Cleveland Clinic, after noting prior questions as to the permanence of carotid artery stenting. “That’s been taken off the table as a concern.”

Also relative to stroke, from 30 days to three years, the data revealed an incremental risk increase of 1% per year in stented patients, a rate compatible to endarterectomy patients. In addition, similar incidence of long-term stroke was seen in symptomatic and asymptomatic patients. As a result, Yadav concluded that carotid stenting leads to an “identical long-term risk of stroke” as endarterectomy.

Other notable findings from the study showed a significantly lower need for repeat procedures in stented patients. In particular, among the 334 patients in SAPPHIRE’s randomized arm, only 3% of those who received a stent required target lesion revascularization after three years, compared to 7.1% of endarterectomy patients. Yadav made note of the novelty of such data, labeling these findings “the first time we have proven this.”

And he said that regulatory agencies should heed the scope of the evidence unveiled after three years, showing the ability of carotid stenting to lower both stroke risk and repeat procedures.

“Hopefully this will have some impact,” he said in reference to the Centers for Medicare & Medicaid Services (CMS; Baltimore), which covers only what he called a “sliver” of the FDA-approved labeling for stent use in this setting.

The feelings vis-a-vis CMS were echoed by Cordis representatives. The company just delivered these new data to the FDA, and according to Brian Firth, MD, PhD, its vice president of medical affairs and health economics worldwide, the findings should satisfy CMS’ concerns.

“The bottom line is that it clearly answers the question about the durability and whether the procedure does what it’s supposed to do, which is to prevent strokes longer-term,” he told CDU. “That’s significant after three years of follow-up.”

Such data also could convince a constituency of different physicians, such as neurologists, who have advocated a slow adoption of CMS reimbursement of the procedure. Firth said further data would satisfy their concerns.

He added that CMS would continue to await data that would show whether these findings can be generalized, which SAPPHIRE does not address. But post-market approval data eventually will provide such answers. After CMS decides to update coverage, a nine-month review process begins before any final decisions are issued.

In January of this year, CMS issued a greatly expanded coverage decision for implantable cardioverter defibrillators based on the publication of findings in the landmark SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) study, which showed that ICDs cut the risk of death in heart failure patients by 23%.

The SAPPHIRE findings were corroborated by final three-year data from the U.S. Carotid Feasibility Study (USFS), which also were reported at the conference.

Also, additional data from the SAPPHIRE and USFS trials, as well as the CASCADE study, further highlighted carotid artery stenting involving Angioguard by collectively suggesting that emboli protection is effective in preventing major strokes during carotid stenting: 30-day stroke rates were 8.6% for the 266 patients who received only a stent and 2.6% in the 116 patients treated with the stent/Angioguard combination.

Also, no Angioguard-treated patients in CASCADE, USFS or in the treated randomized portion of SAPPHIRE had a major stroke, and about two-thirds of the minor ipsilateral strokes that occurred in these trials resolved with time.

Another carotid stenting study, the CREATE (Coratid Revascularization with eV3 Arterial Technology Evolution) trial, corroborated the SAPPHIRE findings. The study tested the use of the Prot g stent with the Spider distal protection system from eV3 (Plymouth, Minnesota).

In addition to showing 30-day rates of major adverse cardiac events comparable to other studies, CREATE showed that because neurological events typically occurred in the first month after the procedure, most late adverse events were not due to stroke and instead rather reflect the risk profile of patients with severe co-morbidities.

Migraine focus central to PFO sector

The topic of patent foramen ovale (PFO) closure achieved substantial prominence during TCT, with several live cases and a broad array of sessions specifically devoted to this rapidly emerging topic.

Indeed, in a talk presented at the beginning of the conference, Gregg Stone, MD, of the conference-sponsoring Cardiovascular Research Foundation (New York), commented that structural heart disease, which includes PFO, would “become the hottest area in transvascular therapeutics.” Stone further predicted that “PFO closure for stroke prevention and migraine treatment will become one of the most common non-coronary interventional procedures.”

PFO closure has been gaining momentum in the world of interventional cardiology over the past several years. Initially, the interest was focused on the use of closure devices to prevent a recurrence of a “cryptogenic stroke” (stroke of unknown origin) caused by the release of “paradoxical emboli“ or embolic material from an unknown source in the body. Unfortunately, the clinical trials for cryptogenic stroke have suffered from very sluggish enrollment, and interest has dwindled.

In sharp contrast to the stroke opportunity, interest in PFO closure for the treatment of severe migraine headaches has surged in the past year, fueled by the first randomized, multi-center trial that is investigating PFO closure for the treatment of severe migraine headaches with aura.

Known as MIST-1 (Migraine Intervention with Starflex Therapy) and sponsored by NMT Medical (Boston), this UK-based trial enrolled at an incredibly fast pace in the first half of 2005. The last patient was enrolled in early July.

According to informed industry sources, the final results for the landmark trial are expected to be released at the annual meeting of the American Academy of Neurology (St. Paul, Minnesota), which takes place in San Diego next April 1-8

Live cases from two relatively new competitors in the PFO sector were featured at TCT. The PFX Closure System, which uses radio frequency (RF) to seal tissue, was developed by privately owned, venture-capital-backed Cierra (Redwood City, California). The procedure was performed by interventional cardiologist Horst Sievert, MD, of the Cardio-Vascular Center, Sankt Katharinen (Frankfurt, Germany), and the case was completed quickly and successfully.

According to Sievert, “Tissue welding using RF energy as a means of repairing soft tissue and surgical lesions has been the subject of medical research for decades. Our initial experience with this unique application for PFO closure has been very exciting and we look forward to additional research that will lead to broader uses for this promising device. As reported at TCT, 29 patients were treated with this approach, with 26 of 29 procedures successfully performed. Immediate closure was attained in 17 of the 26 patients. No complications or device related adverse events were observed during or after any of these procedures.

Cierra is targeting a European market launch in mid-2006, following CE-mark approval. In addition, it hopes to commence a U.S.-based pivotal PFO closure trial for migraine relief sometime in the first half of next year.

Another live case was performed using the Velocimed (Minneapolis) Premere PFO device. This device was obtained by St. Jude Medical (St. Paul, Minnesota) this past spring when it acquired Velocimed for $74 million in cash and possible future milestone payments. Clinical results released during TCT showed that the Premere device safely and effectively closed PFOs in 87% of cases after six months with no adverse events. The trial included 67 patients at five research sites in Europe. “The Premere design conforms well to PFO anatomy, using materials that minimize complications, limit the body’s exposure to foreign material and enable physicians to precisely place the device,” said Paul Buckman, president of St. Jude’s Cardiology Division. “The absence of complications during the trial confirms the device was successful in meeting these important clinical objectives.”

In December 2004, Premere received European CE mark approval for sale in Europe and select international markets. An estimated 250 Premere ihave occurred to date. St. Jude has said that it hopes to begin a domestic migraine trial called Effect of Septal Closure of Atrial PFO on Events of Migraine with Premere (ESCAPE) before year-end.

NMT Medical, which has the longest presence in the PFO market, was prominent at TCT. At a breakfast meeting, speakers discussed the company’s MIST-I trial, the upcoming MIST-II migraine trial in the U.S. and the ongoing BioStar Evaluation Study (BEST). Mark Reisman, MD, director of the cardiac cath lab at Swedish Heart Institute (Seattle) and the cardiology principal investigator of the MIST-II trial, indicated that based on his experiences with several hundred patients and numerous non-randomized, single-arm closure trials, “the association with PFO and migraine is indisputable.” Nevertheless, he said that because of the well-known effect of placebo in drug-related migraine clinical trials, the “challenge in proving this association is large.”

Stewart Tepper, MD, a neurologist and director of the New England Center for Headache (Stamford, Connecticut) and co-principal investigator of MIST-II, noted that there is a tremendous amount of anecdotal evidence with closure PFO and migraines and rhetorically asked the audience “with so much smoke, is there fire?” He noted that the FDA standard for migraine drug trials is a 50% reduction in migraine headaches, and that the very best medicines achieve that target. CDU believes that it is likely that one of the key endpoints for MIST-II will include at least a 50% decrease in migraine occurrence.

Taking the cautious stance that has typified the neurology community’s position on this topic, Tepper said that “neurologists are skeptical about the PFO/migraine link. Cardiologists will need to convince them.” He later told CDU that because migraines are not a life-threatening condition, the safety of PFO closure devices would be a crucial element in their acceptance by neurologists. In this regard, he said that as an investigator for NMT’s trial, “it is reassuring to me that their device has been implanted in over 15,000 patients.” NMT recently reported that more than 18,000 devices have been implanted worldwide.

One of the emerging concepts of PFO is that the medical community and their patients would look favorably on a device that would close the PFO but not remain in the body after the PFO is closed. Both the Cierra device and one being developed by another private company, CoAptus Medical (Redmond, Washington), involve the coaptation, or joining together of tissue, followed by RF heating. Thus, no device is left in the body after the PFO closes.

NMT also is developing that type of device. The BioSTAR features a bio-absorbable collagen matrix on a self-centering framework, which causes the collagen matrix to be replaced with native tissue and promotes more rapid and complete PFO closure. The BioSTAR also incorporates an elutable heparin substrate to reduce protein deposition and potential thrombus formation, which has been one of the criticisms of earlier-generation devices.

The initial clinical results of the multi-center BEST trial using BioSTAR were presented by Michael Mullen, MD, interventional cardiologist at Royal Brompton Hospital (London) and chief investigator for BEST. At the NMT breakfast gathering, he said, “This device is intuitively very attractive, because it is so highly bio-compatible and quickly melts away after implantation.” Mullen reported solid data on the first 30 BioSTAR patients that have reached 30 days of post-procedure follow-up, with no major adverse events reported. He said: “I have no doubt that in the next five years, all current devices will be obsolete. The future of PFO closure will be in bio-absorbable materials and devices.”

At another PFO session, Werner Budts, MD, an interventional cardiologist at University Hospitals (Leuven, Belgium), discussed the Intrasept PFO occluder, developed by another private company, Cardia (Burnsville, Minnesota). He described it as a “fourth-generation” device that features a low profile, with an articulated configuration for optimal adaptation to the septum. About 2,000 Intrasept devices have been implanted, almost all in Europe.

A total of 7,000 Cardia PFO closure devices have been implanted worldwide. The company is conducting a small, randomized trial for PFO and cryptogenic stroke in the U.S. and hopes to commence its migraine trial in 2006. That trial, dubbed FORMAT (Patent Foramen Ovale Closure to Reduce Migraine Attacks), will enroll patients with migraine with aura that are refractory to conventional medical management. Its protocol and endpoints will likely to parallel that of the other migraine/PFO trials.

Another competitor in the PFO field, AGA Medical (Golden Valley, Minnesota), whose lead product is the Amplatzer PFO Occluder device, does not yet have approval for a trial for the migraine indication. AGA has had a long and successful role in PFO closure and undoubtedly will be a significant player in the PFO market.

Data from two studies presented at TCT demonstrated the efficacy of PFO closure in reducing migraine symptoms. The first study, which was conducted at Tufts-New England Medical Center (Boston) and led by Carey Kimmelstiel, MD, director of the adult cardiac catheterization laboratory, examined data of all transesophageal echocardiograms over a one-year period. Enrolleees were divided into one of three groups, the first group who had their documented PFO closed, the second group with a documented PFO that was not closed and the third age and gender matched who did not have a PFO. As shown in Table 1, both the patients in the closed and open PFO groups were significantly more likely to have migraine symptoms than patients in the control group. Also, as shown in the table, the frequency and severity of migraine symptoms were substantially reduced in patients who underwent a PFO closure procedure.

“Our data suggest that patients with PFO experience migraine symptoms significantly more frequently than patients in whom PFO is not present. Additionally, we found that PFO closure is highly associated with a reduction in migraine symptomatology,” said Dr. Kimmelstiel.

Results from another study, led by Sherm Sorenson, MD, director of the cardiac catheterization laboratory at the LDS Hospital (Salt Lake City) indicate that micro-embolisms in patients with a large right-to-left shunt due to a PFO may travel to the brain, causing migraine symptoms. Transcranial Doppler (TCD) was used to evaluate these patients. “Our data show that migraine and associated neurological symptoms are related to the severity of the shunt,” said Sorenson. “These may occur in patients who have never had a migraine in daily life but are four times more likely in patients with previous migraine.”

These comments were based on a study of 490 patients with recurrent stroke who underwent a PFO closure procedure. Prior to PFO closure, 176 patients (36% of the total) reported having severe migraine, whereas after the PFO closure, the number of migraineurs was reduced to 23 patients (5%). Based upon these results, Sorenson and his colleagues will soon embark on a randomized, multicenter trial of prospective TCD patients pre-and post-PFO closure.

Although there is a plethora of evidence that PFO closure may aid migraine sufferers and prevent recurrent embolic stroke, there still is tremendous controversy on whether it should be widely adopted. In a well-attended debate titled “Interventional PFO Closure is Overused and Abused and Extending Treatment to Migraine Sufferers is Ludicrous,” Lawrence Wechsler, MD, a professor of neurology and neurosurgery at the University of Pittsburgh, took the protagonist view while Paul Kramer, MD, an interventional cardiologist from Kramer and Crouse Cardiology (Shawnee Mission, Kansas), took the antagonist position. Kramer has been one of the most active cardiologists in the PFO closure field and is an investigator in NMT’s CLOSURE-1 stroke trial.

“Just because everybody is doing it doesn’t mean it works,” said Wechsler who a drew parallel with the strategy of extracranial to intracranial (EC-IC) bypass, first pioneered in 1967 and then enthusiastically adopted as a cure for ischemic stroke. Its widespread use was only supported by a small number of nonrandomized studies and later, well-designed prospective, randomized trials debunked its efficacy.

Wechsler noted that “just like the EC-IC-bypass example, multiple studies have been published suggesting an association between PFO and stroke and that you can prevent recurrent events through PFO closure. The problem is, the data are all inadequate. These are retrospective, nonrandomized series, and meta-analyses of these series are just compounding the problem. Reports of improved results with PFO closure are all self-reported, unblinded, uncontrolled series, not data that we can really hang our hat on.”

Kramer countered: “This is the third year I’ve stood up here and preached the importance of enrolling patients in randomized controlled trials. Nevertheless and despite vigorous efforts, there are problems with enrollment. The three trials currently enrolling patients in the US began three years ago, with well over 120 centers enrolling, At the current rate of enrollment, it will probably be another decade before the most aggressively enrolling trial comes to completion. There are unintended consequences of insisting on this kind of evidence to move the field forward.”

Although they clearly disagree about the solution, both physicians concur that the problem lies in too many people already undergoing PFO closure for stroke prevention. In the past year a disappointing 250 patients have received a PFO device in the randomized IDE trial comparing closure to medical management. In addition to NMT’s CLOSURE-1 trial, AGA is in the midst of its RESPECT trial.

A second group of patients is receiving devices under a humanitarian device exception (HDE) specification. PFO-closure devices are permitted under an HDE for people with recurrent cryptogenic stroke on oral anticoagulants within a therapeutic INR.

“In that small group, it’s also appropriate to place one of these devices,” Wechsler argued. “The number of patients receiving an HDE-based device, however, is somewhat surprising, roughly 1,000 per year.” CDU estimates that about 3,000 to 4,000 patients received a PFO device in the last 12 months in the U.S., but it is difficult to estimate how many were enrolled through the HDE route.

The real problem, Wechsler indicated, is the off-label use of the devices. “We have no way of knowing how many of these devices are used off label, although we do know that the number is probably a large multiple of the patients entered into the IDE and HDE categories,” he said.

Kramer countered that the HDE criteria falls short of recognizing all the people who could benefit from PFO closure. For example, a patient who has a first stroke but who is already on anticoagulants; someone who has a TIA while on therapeutic anticoagulation following a first presumed paradoxical embolic stoke; someone in whom anticoagulation is strictly contraindicated; or someone who has a non-cerebral paradoxical embolism, such as a retinal embolus, either recurrently or after a previous stroke, while therapeutically anti-coagulated.

All of these patients would not meet the current HDE criteria but clearly are still at risk, he noted. Moreover, while these patients are not officially candidates for PFO closure, there are no regulatory barriers for them being sent for open-heart surgical closure. CDU is aware of at least one prominent cardiac surgeon that is closing PFOs through an incision in the sternum, not through endovascular techniques.

As a result, Kramer said, a large majority of patients undergoing device closure today are not enrolled in a trial, but the covert, off-label use thus undermining any efforts to understand the true safety and efficacy of the devices. An alternative, he argued, would be the creation of a registry. “The opportunity to learn about the safety and efficacy of PFO closure is being squandered. A well-designed registry can at least assess the absolute if not the relative outcomes of percutaneous PFO closure.”

But while use of PFO-closure devices for stroke prevention ramps up – despite a lack of proof of efficacy – excitement also is mounting for PFO closure as a treatment for migraine headaches, again despite only scant evidence supporting such a strategy. Summing up the evidence, Kramer pointed out that PFOs are more common in migraine sufferers than in the general population. He also noted that a history of migraine is twice as prevalent in people who undergo PFO closure.

While intrigued with the concept, Wechsler said, “so far I haven’t heard of any biologically plausible mechanism.” In addition, he argued that “we’re dealing with unblinded, retrospective, self-reported data, not to mention a possible placebo effect and the effect of post-closure aspirin and clopidogrel, which in and of itself can have an effect on migraines.”

The solution here, too, is a randomized controlled trial, Kramer said. And indeed, the MIST trial is ongoing, with results expected in early 2006. In this case, he added, he is much less cynical about the ability of the trials to enroll patients, given the “desperation of chronic migraine-sufferers willing to try anything to get rid of their pain.”

Kramer concluded that “extending PFO closure to migraine sufferers isn’t ludicrous but it is premature. Experience suggests that randomized controlled trials currently starting in the U.S. will enroll rapidly due to the large population of motivated refractory migraineurs and great interest and awareness among neurologists.” That said, he cautioned, “If closure devices gain regulatory approval for migraine sufferers, the opportunity to determine their safety and efficacy in cryptogenic stroke will be lost.”