and JOHN BROSKY
Independence Day wasn't the only thing Abbott (Abbott Park, Illinois) celebrated over the holiday weekend last month. FDA approval of the company's Xience stent was reason enough to shoot off fireworks. Abbott received approval of Xience V everolimus-eluting coronary stent for the treatment of coronary artery disease on July 2, making it the second of the 2.0 family of drug-eluting stents to win marketing approval in the U.S.
Medtronic's (Minneapolis) Endeavor DES, which won approval in February, was the first second-generation DES to hit the U.S. market. Both products are expected to elbow aside to a considerable extent the first-generation DES devices, the Cypher from Johnson & Johnson's (J&J; New Brunswick, New Jersey) Cordis (Miami Lakes, Florida) unit, and the Taxus from Boston Scientific (Natick, Massachusetts).
Abbott says its Xience stent, which went on commercial sale immediately following receipt of the approval, is the only DES to have demonstrated superiority over Boston Scientific's Taxus paclitaxel-eluting coronary stent system.
Kelly Morrison, an Abbott spokeswoman, told Cardiovascular Devices & Drugs that the first implant was performed the morning of July 3 at New York Presbyterian Hospital/Columbia University Medical Center (New York).
"The strength of the data supporting Xience V is really unprecedented," Morrison said. "It's the first to show superiority over the market leading drug-eluting stent in clinical trials, it demonstrated a 45% reduction in major heart related events compared to Taxus at two years."
Because the device is based on Abbott's market-leading Multi-Link Vision bare-metal stent platform, Morrison said the company expects a healthy physician adoption of Xience.
"I think physicians have been waiting for a next-generation technology that really delivers on the promise of drug-eluting stents," Morrison said. "We've been hearing from physicians that they're very excited [about Xience] based on the clinical data."
Abbott is expecting a 25% to 30% market share in the U.S. within the first year of launch, Morrison said.
"Xience V represents an important treatment advance for the estimated 13 million people in the U.S. suffering from coronary artery disease, and we believe Xience V will quickly become the new standard for drug eluting stents given its outstanding clinical results," said John Capek, PhD, executive VP of medical devices at Abbott.
Xience won a panel recommendation for approval in early December 2007. The stent is used to treat heart disease by propping open a narrowed or blocked artery and releasing the drug, everolimus, in a controlled manner to prevent the artery from becoming blocked again following a stent procedure, Abbott said. The stent will be available on both over-the-wire and rapid exchange (RX) delivery systems.
Xience was launched in Europe and other international markets in October 2006. It is an investigational device in Japan and is currently under review for approval by Japan's Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency.
Everolimus, developed by Novartis Pharma (Basel, Switzerland), is a proliferation signal inhibitor, or mTOR inhibitor, licensed to Abbott for use on its drug-eluting stents. Everolimus has been shown to inhibit in-stent neointimal growth in the coronary vessels following stent implantation, due to its antiproliferative properties, the company noted.
Approval of Xience also was good news for Boston Scientific, which will share profits from the device. Guidant had been developing the stent and when Boston Scientific acquired that company in 2006, it had to divest the stent to Abbott, but it retained the right to sell the same device as the Promus under a private-label arrangement.
"The Promus stent has shown outstanding deliverability, low late loss and the potential to reduce the need for re-interventions," said Ted Feldman, MD, director of the cardiac catheterization lab at Evanston Northwestern Healthcare (Evanston, Illinois). "These benefits will make the Promus stent an attractive new treatment option for U.S. physicians and their patients."
Jim Tobin, president/CEO of Boston Scientific, said the approval fulfills the company's promise of an "unprecedented two-drug strategy — two distinct drugs on two highly deliverable stent platforms."
In a research note, Wachovia Capital Markets device analyst Larry Biegelsen said he expects Xience to capture share more quickly in the U.S. than in Europe. The company now indicates that Xience, including Promus, has surpassed Taxus' market share in Europe after about 19 months post-launch, Biegelsen said. "We expect Xience alone to reach this level in the U.S. after only 12 months," he said, due to widespread reimbursement, more compelling clinical data at the time of launch, the absence of Taxus Liberte and Cypher Elite, the lack of RX delivery for Endeavor in the U.S. and the absence of small European competitors.
The key barriers for Xience are likely to be the competitive pricing and contract arrangements between cath labs and Boston Scientific and J&J, Biegelsen noted.
"Xience V was designed to improve safety and efficacy compared to earlier generation stents. The long-term clinical data from two studies performed in both the U.S. and Europe have now confirmed that Xience V is a true next-generation drug-eluting stent with clinically important benefits for patients," said Gregg Stone, MD, of Columbia University Medical Center (New York), chairman of the Cardiovascular Research Foundation (also New York) and the principal investigator of the SPIRIT III U.S. pivotal clinical trial for Xience.
The robust clinical program for Xience includes long-term data from a total of 1,362 patients enrolled in the SPIRIT FIRST, SPIRIT II and SPIRIT III trials, as well as continued access and post-approval programs that will enroll more than 14,000 Xience patients, Abbott noted.
The FDA approved Xience based, in large part, on superior results from the 1,002 patient SPIRIT III U.S. pivotal clinical trial, in which the device demonstrated statistical superiority to Taxus on the study's primary endpoint of in-segment late loss (vessel renarrowing) at eight months, with a statistically significant 50% reduction.
The company said Xience also demonstrated statistical non-inferiority to Taxus in the co-primary endpoint of target vessel failure (TVF) at nine months, with an observed 20% reduction. TVF is a composite clinical measure of safety and efficacy outcomes defined as cardiac death, heart attack or target vessel revascularization.
With launch, post-approval study begins
Abbott is not wasting any time finding out how the second-generation DES performs in the real world. The company said just days after the approval that six hospital centers already were enrolling patients in the XIENCE V USA post-approval study just one week after FDA approved the device.
The XIENCE V USA study will evaluate the safety and effectiveness of the Xience V stent in a real-world clinical setting out to five years, Abbott said. Jack Jones, MD, an interventional cardiologist and medical director of the Stormont-Vail Catheterization Lab (Topeka, Kansas), was one of the first doctors to enroll a patient into the study.
"Xience V is an important innovation that gives patients in the U.S. access to a next-generation drug eluting stent that has been shown in clinical trials to improve patient outcomes," Jones said. "During the stent procedure, we found it easy to deliver Xience V to the diseased portion of the vessel. With its combination of clinical efficacy and deliverability, I believe that Xience V will become a key advancement in the treatment of coronary artery disease."
Unlike the SPIRIT trials evaluating Xience V in a very controlled patient population, James Hermiller, MD, an interventional cardiologist at St. Vincent Heart Center of Indiana (Indianapolis) and the principal investigator of the XIENCE V USA study, told CD&D that the post-approval study will be open to any patient who receives the device, so long as they give their consent to be in the trial.
Because there will be no patient exclusions, XIENCE V USA will provide a better idea of how the stent performs in a real-world setting than the company's SPIRIT trials, Hermiller said.
Jonathon Hamilton, an Abbott spokesman, told CD&D that the trial would enroll at least 5,000 coronary artery disease patients in about 250 hospital centers across the U.S. The primary endpoint of the study is a measure of stent thrombosis (formation of blood clots) every year out to five years, as defined by the Dublin/Academic Research Consortium (ARC). The ARC definition of late stent thrombosis was developed to eliminate variability in the definitions across various drug eluting stent trials.
The co-primary endpoint of the study is the composite rate of cardiac death and any heart attack (Q-wave or non-Q-wave myocardial infarction) in patients at one year, Abbott said. Secondary endpoints of the study include patient compliance with prescribed anti-platelet medication, measures of re-treatment by stenting or surgery, and device and procedural success.
"Post-approval studies allow physicians to follow the safety and efficacy of new treatments in a more complex patient population than is typically studied in pre-approval clinical trials. XIENCE V USA will provide significant insight about the performance of Abbott's new drug-eluting stent in a variety of patients," said Charles Simonton, MD, divisional VP of medical affairs and chief medical officer at Abbott Vascular (Santa Clara, California), the company's vascular care business. "Our ability to work with our physician partners to begin this post-approval study within days of FDA approval is further evidence of Abbott's commitment to help the interventional cardiology community gain additional insights about the clinical benefits of XIENCE V."
Medtronic (Minneapolis) has launched an international study comparing the Endeavor with the Xience V. The first implants in the RESOLUTE III All-Comers trial took place in Europe in May.
The teams of Stephan Windecker, MD, of University Hospital Bern (Bern, Switzerland), one of three principal investigators in the trial, and William Wijns, MD, of the Cardiovascular Centre Aalst in Belgium, enrolled the first patients in RESOLUTE III. Sigmund Silber, MD, of the Heart Catheterization Center (Munich, Germany), and Patrick Serruys, of the Heartcenter (Rotterdam, the Netherlands), are the trial's other principal investigators.
RESOLUTE III is the pivotal trial for the Endeavor Resolute drug-eluting stent and one part of the overall RESOLUTE clinical program. RESOLUTE III will randomize roughly 2,300 patients, in a one-to-one manner, to the Endeavor Resolute or Xience stent at 15 to 20 international medical centers in countries where both stents are commercially available. The primary endpoint for RESOLUTE III is target lesion failure, a composite of cardiac death, myocardial infarction and target lesion revascularization, at one year.
Raft of results in 'marathon'
Data on both the Xience V and Endeavor were presented during a marathon late-breaking trials session at the mid-May EuroPCR meeting in Barcelona, Spain.
The session was kicked off by Jean Fajadet, MD, of the Clinique Pasteur Unit de Cardiologie Interventionnelle (Tolouse, France), who delivered four-year data from the ENDEAVOR II clinical trial, a prospective, randomized, multi-center study comparing Medtronic's Endeavor drug-eluting stent (DES) to the company's own Driver bare-metal stent.
With 1,197 patients enrolled and a 97% follow-up rate, the trial showed sustained efficacy out to four years with a lower rate of target vessel failure (TVF), a combination of myocardial infarction and cardiac death rates, such as for patients treated with the Endeavor stent.
Fajadet also reported there were no new events requiring target lesion revascularization (TLR) between years three and four.
The Xience V was compared head-on to Taxus in the SPIRIT III trial. Stone reported that at two years Xience V demonstrates a 32% reduction in TVF and a 45% reduction in the risk of major adverse cardiac events (MACE), both results being superior to Taxus.