CD&D

Metal stents for coronary artery disease could become passe technology within the next few years with a new generation of fully bioabsorbable stents on the way.

A larger trial has just been initiated to continue testing Abbott's (Abbott Park, Illinois) fully bioabsorbable stent after a smaller trial, just reported, has revealed that the everolimus-eluting stent made of polylactic acid not only does the job and then completely degrades, but it also leaves behind vessels that appear healthier, as if they were never treated.

Abbott's progress in developing the degradable stent marks the beginning of what will likely be a major shift for the $4 billion stent market and the company is boldly projecting to dominate more than half of that market within the next few years . . . assuming it launches the new-wave stent before others.

"We're certainly aiming for 50% potential market penetration," Richard Rapoza, general manager for Bioabsorbable Vascular Solutions at Abbott's Abbott Vascular (Redwood City, California) unit, told Cardiovascular Devices & Drugs. "There have been two other trials for degradable stents that I know of in Europe and Brazil from small start-ups. They started and have reached endpoints, but I don't think the data was so positive. They are now re-engineering."

Those two other trials were initiated by Reva Medical (San Diego) and Bioabsorbable Therapeutics (Menlo Park, California). Although they aren't the only companies developing bioabsorbable stents, Rapoza said they are the closest behind Abbott in the race to market.

Less than two weeks after a two-year analysis of Abbott's ABSORB trial was published in The Lancet demonstrating that the stent successfully treated coronary artery disease in 30 patients and then was absorbed into the walls of arteries within two years, the company initiated the second phase of ABSORB. The first patient was just enrolled in an 80-patient study at Onze Lieve Vrouw Ziekenhuis Hospital (Aalst, Belgium). A total of 10 centers in Europe, Australia and New Zealand will be included in the study.

Assuming this ABSORB trial goes well, Rapoza estimates the new stent could be on the market in Europe as early as 2012. He said conversations have been initiated with the FDA, but the company is focused on completing the ABSORB trial first so that it has more data to fuel U.S. regulatory application.

This isn't the first time Abbott has attempted to develop a bioabsorbable stent. Rapoza said the company abandoned its first attempt in the late 1980s after researchers found that the prototype didn't work. A different technological approach, use of polylactic acid (a material commonly used in medical implants such as dissolvable sutures) and the advent of new laser technology came together permitting the development of the new stent.

"The new stent is a polymer that's fairly strong and the same thickness as the Cypher [made by Cordis (Miami Lakes, Florida)]," Rapoza said. "It holds the vessel open and eludes for three months. Then there is a gradual decrease in the structure continuity as it absorbs water and degrades. The vessel is free to move after four to six months. There is a continual decrease in molecular weight. Somewhere between two and 2.5 years, there is full absorption."

Because about 70% of angioplasty patients come back for additional treatment due to negative remodeling (shrinkage of the vessel), Abbott wanted to make sure that the stent held the radial strength for at least three to four months, because that's when remodeling usually happens. "So we targeted that window," he said. "Then we wanted to make the absorption process gradual. There's no need for the stent to absorb quickly."

The most important findings from the ABSORB study, Rapoza said, were that, "It acts like and looks like a drug eluting stent. It deploys and holds its radial strength and works. But later we found out that the drug was doing its job because tissue build-up was low. At two years when we looked at patients, the vessels were not only responsive, but we saw a 10% to 12% plaque reduction. That was a surprise because that's not shown for any other stents."

He explained that the plaque reduction is likely a result of the body's natural healing mechanisms because the vessels are allowed to move freely after the stent degrades.

"We did not expect a reduction in plaque volume," he said. "We were quite surprised to see that. We think these devices are healing vessels differently than metallic stents."

Between the first phase of the ABSORB study and the new 80-patient trial just launched, Abbott made some changes to the stent.

"We looked at patient by patient to understand what we did the first time and what we could improve. We've came up with a new structure, but it's the same polymer and concept. This second trial should shed some light as to what the device is doing and to confirm the changes we made will hit the target to keep vessels open longer."

Apparently the previous structure had areas that were unsupported. The newer version allows for more even support of the vessel.

"The other change was that we retarded the degradation rate further so we wouldn't lose any lumen due to structural changes of the stent," he said.

One of the reasons this new stent seems to be working, compared to the failed prototype from the 1980s, is a new generation of short-pulsed lasers that can cut the tube made of polylactic acid to form the stent with far greater precision.

"That laser wasn't available in the early 1980s or 1990s," said Rapoza. He declined to name the laser's brand other than to say that it's currently available in the commercial space. "It's a matter of choosing the right laser and that's our trade secret. I can't tell."

The lead author of The Lancet study, Patrick Serruys, MD, professor of interventional cardiology at Thoraxcentre, Erasmus University Hospital (Rotterdam, the Netherlands) and co-principal investigator of the first phase of the ABSORB trial, said, "This bioabsorbable device has the potential to provide optimal vessel scaffolding and drug delivery capability over the crucial first several months after a stenting procedure while avoiding the long-term restrictions of metallic stents."

The first phase of the ABSORB trial demonstrated a 0% rate of stent thrombosis for all patients out to two years of follow up, no new major adverse cardiac events (MACE), bioabsorption of the stent at two years after implantation, restoration of vasomotion (ability of the blood vessel to contract and expand) at two years and reduction in plaque area in treated arteries.

Key endpoints of the ABSORB trial include assessments of safety with additional annual clinical follow-up for up to five years and assessment of the acute performance of the stent, including successful deployment of the system.

Other resorbable stents in development include:

• Biotronik's (Berlin, Germany) Absorbable Metal Stent is being evaluated in the PROGRESS-1 trial. Results with the initial version of the device, which is fabricated from magnesium, were disappointing, with a 27.9% target lesion revascularization rate at one year and late loss of 1.0 mm. However, no long-term adverse events have occurred, and it is completely bioabsorbed at 28 months post-implant.

Biotronik is now developing a second-generation version of the device, the AMS2, which has a modified alloy for added strength, since the primary cause of the high restenosis rate is elastic recoil. A third version, the AMS3, will provide drug elution for further reduction of restenosis (Cardiovascular Devices & Drugs, October 2007).

• Endovasc (Montgomery, Texas) formed a joint venture with TissueGen (Arlington, Texas), named Endovasc-TissueGen Research Sponsors, to develop a biodegradable DES. Endovasc co-licensed its time-released prostaglandin E-1 drug and TissueGen is contributing technology relating to bidegradable, drug-releasing polymer fiber scaffolds (Medical Device Daily, Aug. 22, 2003).

In the spring of 2007, Endovasc reported the creation of BioFlow as a new, wholly owned subsidiary, to manage the continued development of biodegradable stents. Endovasc and Nathan Blumberg, MD, jointly transferred the intellectual property from both of the previous joint ventures involving TissueGen into BioFlow (CD&D, June 2007). Diane Dottavio, PhD, president/CEO of Endovasc, told CD&D that the first project of BioFlow would be to develop a biodegradable urinary stent for ureteral application.

• Terumo Medical (Somerset, New Jersey), a unit of Terumo (Japan), is developing Nobori Core DES. The Terumo stent was compared to the Cypher from Cordis (Miami Lakes, Florida) in a non-randomized study that included 54 patients treated with the Nobori Core and 53 treated with Cypher with data reported in 2007.

At nine-month follow-up, the restenosis rate for the Nobori stent was only 1.7% compared to 4.2% for Cypher, and late loss was 0.1 mm compared to 0.12 mm for Cypher. And evaluation of endothelial function revealed no abnormalities for patients receiving the Terumo stent while there was some evidence of dysfunction for the Cypher. (CD&D, October 2007).