PARIS A majority of the estimated 10,000 attendees crammed into the Palais de Congr s for the EuroPCR 2005 meeting in late May gathered together to attend a late-breaking clinical trial session that had a decided focus toward the hot topic du jour, that of drug-eluting stents (DES). In two presentations, follow-up studies for Boston Scientific's (Natick, Massachusetts) Taxus Express2 paclitaxel-eluting stent were released for the first time.
Neil Weissman, MD, director of cardiac ultrasound and ultrasound core laboratories at the Cardiovascular Research Institute at Washington Hospital Center (Washington), said that follow-up results from the TAXUS V study, using ultrasound within the vessels, showed improvement in patients with small vessels, large vessels and severe blockages requiring multiple, overlapping stents, compared with a control group.
The TAXUS V study, which involved 1,172 patients at 66 sites in the U.S., represents the most complex patient and lesion cohort yet subjected to a blinded, randomized, controlled trial: total length 28.4 mm, 2.25 mm stents in 17.6%, 4.0 mm stents in 17.5%, multiple stents in 32.8% and 30.8% of diabetic patients
In this complex patient population, the slow-release, polymer-based Taxus stent was safe, with low rates of death, MI and stent thrombosis at 30 days and nine months compared to control, and was very effective with marked reduction in clinical and angiographic restenosis.
"The lesions studied in TAXUS V are some of the most difficult we confront in interventional cardiology," said Weissman. "The TAXUS V IVUS data provides an especially rich source of information on the excellent performance of the Taxus system. The uniform neointimal suppression across both single stents and multiple overlapping stents attests to the efficacy of Taxus across a wide range of lesion lengths."
The company previously disclosed in March that the trial met its primary endpoint of nine-month target vessel revascularization (TVR), as well as all secondary endpoints.
In a second Boston Scientific study called TAXUS VI, which evaluated the moderate-release version of the Taxus stent, a continued reduction in the rate of repeat procedures was demonstrated after two years in 428 patients. The rate of patients living free of serious complications was 90.3%, vs. 79% for the bare-metal stent control group.
In the randomized, double-blind trial, lesion size ranged from 18 mm to 40 mm in length and 2.5 mm to 3.75 mm in diameter. Safety and efficacy benefits were maintained at two years, and even with a dosing rate eight to 10 times higher than the slow-release stent, there was no compromise in safety.
The results were presented by Eberhard Grube, MD, of the Heart Center (Siegburg, Germany). According to Grube, TAXUS VI is the first clinical trial to support durability of drug-eluting stents in complex lesions at two years. Clinical follow-up included more than 95% of the patients enrolled at two years (428 out of 446).
"The two-year data from TAXUS VI clearly demonstrate the sustained safety and efficacy of the moderate-release Taxus paclitaxel-eluting stent system in the treatment of patients with long lesions treated with multiple, overlapping stents," he said. "These data indicate that Taxus stents offer sustained TLR [target lesion revascularization] benefits over time."
Boston Sci launched the slow-release Taxus Express2 stent in the U.S. in March 2004. The moderate-release version of the stent hasn't yet been approved for commercial distribution.
Rival stent maker Johnson & Johnson (J&J; New Brunswick, New Jersey), via its Cordis (Miami Lakes, Florida) subsidiary, also released positive data from two studies measuring the performance of its Cypher sirolimus-eluting stent in diabetic patients, who can be more difficult to treat because of smaller blood vessels. In a study of 607 diabetic patients, called ARTS II, those receiving a Cypher stent had lower rates of major complications such as death, stroke and heart attack than diabetic patients who underwent bypass surgery in a predecessor trial called ARTS I. Marie-Claude Morice, MD, head of cardiology at Institut Jacques Cartier (Massey, France), reported results from that trial
J&J also released longer-term results from its RAVEL RAndomized Study with the Sirolimus-eluting VELocity Balloon Expandable Stent study that showed patients who received the Cypher drug-coated stent required fewer repeat procedures after four years than those receiving bare-metal stents.
Eduardo Sousa, MD, PhD, professor of interventional cardiology at Dante Pazzanese Institute (Sao Paulo, Brazil), presented results showing that 91.8% of patients with a Cypher stent were free of major complications including heart attack and death after four years, compared with 73.4% in the control group. Additionally, stent-related side effect rates including stent thrombosis and late stent thrombosis continued to remain at zero for Cypher stent patients.
"Since the first data from the RAVEL trial were released, the impressive initial clinical and angiographic outcomes from the study further supported with four years of clinical follow up, confirm the impressive safety and efficacy profile of the Cypher stent year after year," said Sousa. "The four-year data provides physicians with further time-tested clinical evidence for using sirolimus-eluting stents to treat patients."
A randomized study involving 238 patients in 19 centers across Europe and Latin America, RAVEL was the first double-blinded trial to demonstrate that a sirolimus-eluting stent virtually suppress post-stenting angiographic late loss at six months. In the study there was no restenosis or target lesion revascularization at the six month follow-up.
Positive 12-month results for CoStar
Conor Medsystems (Menlo Park, California), a developer of what it terms "controlled vascular drug delivery technologies," reported at the EuroPCR meeting positive 12-month follow-up clinical data from a pivotal trial of its CoStar stent.
The clinical results were presented by Keith Dawkins, MD, director of cardiac interventions at Southampton University Hospital (Southampton, UK), who said the findings for the 12-month period, "include low incidence of target lesion revascularization and major adverse cardiac events. With its low profile and high radiopacity, the CoStar stent is highly deliverable and permits direct stenting even in narrow and tortuous vasculature." He noted also that use of bioresorbable polymers in the stent "ensures that no permanent polymer residue or drug remains at the target site."
Dawkins and Antonio Colombo, MD, director of the cardiac catheterization laboratory at Emo Centro Cuore Columbus (Milan, Italy), are principal investigators for the trial.
A total of 176 lesions were treated in 145 patients using the CoStar stent, formulated to release a therapeutic dose of 10 mcg of paclitaxel per 17 mm stent over about 30 days. Complex characteristics of the patient group include an average vessel diameter of 2.62 mm and multi-vessel disease in more than 50% of patients. About 52% of the lesions were treated by direct stenting. At 12-month follow-up, the TLR rate was 2.9%, and the rate of cumulative major adverse cardiac events (MACE) was 7.6%. There were no reported cases of stent thrombosis between the cessation of anti-platelet therapy at six months and 12-month follow-up.
"We are very pleased with the consistent clinical results for the CoStar stent, which after 12 months continues to demonstrate a positive safety and efficacy profile," said Frank Litvack, MD, chairman and CEO of Conor. "A low-dose, long-release formulation of paclitaxel proved to be efficacious over the long-term, reinforcing our earlier positive clinical findings."
EUROpean cobalt chromium STent with Antiproliferative for Restenosis (EuroSTAR) is a prospective, multi-center, sequentially enrolled, non-randomized, two-arm dose-ranging pivotal study evaluating the safety and performance of the CoStar stent for the treatment of restenosis. The study sequentially enrolled patients from 18 European centers into one of two registry arms with two different dose formulations of paclitaxel. The 12-month follow-up data reflect the first arm of the study, which evaluated the clinical performance of a 10 mcg dose formulation per 17 mm stent released over about 30 days among 145 patients. The second arm of the study, employing a 30 mcg dose released over about 30 days, completed enrollment in March.
In contrast to surface-coated stents, Conor's stents are designed for vascular drug delivery. Its CoStar cobalt chromium paclitaxel-eluting stent incorporates hundreds of small holes, each one a reservoir into which drug/polymer compositions can be loaded. The CoStar also uses bioresorbable polymers that are absorbed by the body after the drug is released, leaving no permanent residual polymers at the target site.
Data from Conor's EuroSTAR trial were used to support the company's CE mark application filed earlier this year. The company said it anticipates receiving CE-marking of the CoStar stent in late 2005. Pending regulatory approval, the CoStar stent will be marketed in Europe, Latin America and parts of Asia by one of the company's distributors. In March, a limited market release of the CoStar stent began in India through Conor's South Asia distribution partner.
MIST findings give boost to PFO repair
The idea that fixing a congenital defect of the heart can help to alleviate migraine headaches received another boost with preliminary release of data at EuroPCR from the Migraine Intervention with STARflex Technology (MIST) trial. The condition, known as a patent foramen ovale (PFO), is an incomplete closure of the atrial membrane of the heart and has been implicated, although not conclusively proven, to cause various neurological disorders such as stroke or migraine headaches. Awareness of its potential role in these disorders has dramatically increased in recent years.
The trial uses NMT Medical's (Boston) STARflex septal repair technology to close the PFO in a minimally invasive procedure. The PFO closure procedure using STARflex takes about 30 minutes to perform in a cardiac catheterization lab. Patients can return to normal activity soon after the procedure. The company initiated enrollment in the study in January.
MIST is the first prospective, randomized, controlled study to evaluate the potential relationship between PFO, a common structural heart defect, and certain migraine headaches. It is believed that a PFO allows venous blood, unfiltered by the lungs, to shunt, or flow, into the arterial circulation of the brain. This unfiltered venous blood may contain elements that possibly trigger migraine headaches or other brain attacks in some patients.
Data on the incidence of PFO observed in the multi-center MIST study were presented by Peter Wilmshurst, MD, consultant cardiologist at the Royal Shrewsbury Hospital (Shrewsbury, UK), at a late-breaking trials session. In a press conference after his presentation, Wilmshurst, who also is co-primary investigator for the trial, said, "In our evaluation of 370 migraine patients, we found that 50% of them had a PFO, which allows a right to left shunt, or flow, of venous blood into the arterial circulation. This important finding is consistent with earlier observational data and is twice what one would expect to find in the general population."
In addition to PFOs, he said researchers found other shunts, predominately pulmonary, "in another 10% of the migraine patients studied, which again is greater than what one would expect." What is remarkable, he said, is that more than 40% of the migraine patients studied had a large shunt; "this is six times greater than what would be expected in the general population. By far, the PFO was the most prevalent large shunt we saw in the migraine patients, accounting for over 85% of all large shunts detected."
Interestingly, he said, this unusually high incidence was found in a group of people who have frequent migraine attacks with aura, but are otherwise healthy and have no symptoms to indicate a heart defect. Previous studies have reported finding PFOs in 27% of the general patient population with only 7% of them being large
Wilmshurst, an avid diver, first became familiar with PFOs when he studied their association with decompression illness, also known as "the bends," back in 1986. His work on PFO in divers led to observing a high rate of migraine in those with PFO and the observation that when PFOs were closed, migraine was improved or cured.
Andrew Dowson, MD, director of the King's Headache Service, Kings College Hospital (London), the other co-lead investigator, said during the press conference that he found the initial data from MIST to be intriguing.
"We are not certain what causes migraine headaches," he said. "If, however, shunts like the PFO allow venous blood to enter the cerebral circulation, unfiltered and unmanaged by the lungs, perhaps that venous blood contains materials that trigger migraines in some patients."
The next question the MIST study is designed to answer is whether closing the PFO with the STARflex implant technology reduces or eliminates migraine headaches. "We should be able to provide an answer to that question by the end of this year or early next year," Dowson said.
To date, NMT Medical said, more than 15,000 PFOs have been closed globally with its implant technology, but migraine is a potentially lucrative new application for the technology originally designed for the treatment of recurrent stroke and transient ischemic attack.
In a conference call that coincided with the initiation of enrollment in January, NMT said that the new indication could have a more immediate impact on the company's growth than that of its initial stroke focus. "The initiation of our MIST trial is a landmark event for NMT as we expand our PFO closure focus beyond stroke to other brain attacks," said President and CEO John Ahern. "We believe that PFO closure for migraine represents a substantial and more immediate revenue growth opportunity for NMT as compared to stroke."
He also said that he believes the initial target patient population for PFO closure with the company's technology would be 5% of all migraine sufferers, a number that he based on statistics from the World Health Organization (Geneva, Switzerland) and the American Council for Headache Evaluation (Mt. Royal, New Jersey), which indicates the prevalence of migraines in the U.S., Europe and Japan is about 10% of the general population.
Ahern also noted that published medical research indicates that about 20% of migraine sufferers have migraine with aura, often referred to as the classic migraine, and that up to 50% of those suffering from migraine with aura are unresponsive to current medications, another requirement for enrollment in the study.
The target market for the devices, which cost about $5,000, is about 1.5 million patients in the U.S., with another 2.5 million via the international market The MIST study's patient recruitment process was supported by the Migraine Action Association (MAA), a migraine headache advocacy group representing more than 14,000 members in the UK.