By KEVIN NEW, CDU Washington Editor
and LARRY HAIMOVITCH, CDU Contributing Editor

WASHINGTON – Much like the real estate mantra about location, drug-eluting stents grabbed the lion's share of attention during the late-September Transcatheter Cardiovascular Therapeutics 2002 conference at the Washington Convention Center. While it isn't unusual for medical meetings to have a "buzz" about them for some new technology or technique, to have one dominate thought and talk to the extent that drug-coated stents did at this year's TCT gathering was at least a bit out of the ordinary.

The meeting featured reports of clinical trials featuring coated stents from sector leader Cordis/ J&J (Miami Lakes, Florida), as well as from pursuers Boston Scientific (Natick, Massachusetts) and Guidant (Indianapolis, Indiana). Also featured were interesting sessions on the regulatory environment for these attention-getting devices, as well as a spirited debate as to whether they represent a revolutionary step in medicine or a case of misguided hysteria. Almost every program entry that had the words "drug coated" and "stent" attached guaranteed an overflow audience, many numbering in the thousands.

And, lest one think that TCT was totally stent-centric, the five-day program featured numerous worthwhile presentations on other technologies, including stroke prevention, which is attracting growing attention among clinicians. New imaging technologies for cardiology were another point of interest.

In the first overflow session at this year's gathering, TCT impresario Martin Leon, MD, co-principal investigator of the SIRIUS trial conducted by Cordis, a business of Johnson & Johnson (New Brunswick, New Jersey), said that drug-eluting stents that are longer – even as little as 10 mm in additional length – offer higher success in battling restenosis in patients with de novo, or previously untreated, coronary lesions. "The longer the stent, the better the restenosis rates are. We found that for every 10 mm of added stent, we gained an additional 13% [in reduction] of restenosis," Leon said.

The therapeutic importance of that longer length in conjunction with a drug was the main message he delivered. Perhaps one of the most anticipated clinical trials of the year, the SIRIUS results elevated the hubbub surrounding drug-coated stents, which are set to come on-line commercially next year, with Cordis clearly poised to lead the field out of the sales gate.

The SIRIUS trial showed minimal in-stent lumen loss. The 3.2% rate of angiographic in-stent restenosis represents a 91% reduction vs. the metal stent, Leon said.

Those results will "lead to considerable changes in the treatment of cardiovascular disease," said Eric Topol, MD, of the Cleveland Clinic Foundation (Cleveland, Ohio), and also the moderator of the opening "Late-Breaking Clinical Trials" session.

The SIRIUS trial was purposely created with high-risk patients in mind to tout the superior advantages of drug-coated stents vs. bare metal stents, said Leon, director and CEO of the Cardiovascular Research Foundation (New York), which also is the organizer of the annual TCT conference. A majority of patients were at risk of restenosis. About 26% of the patients also had diabetes. Additional risk factors of patients included longer lesions – with an average of 14.4 mm, hyperlipidemia and hypertension. Some patients also had undergone percutaneous coronary procedures or coronary artery bypass.

About 27% of the study patients had lesions requiring placing two overlapping stents, which led the researchers to their findings. "We used an average of 1.4 stents per patient," Leon said. Furthermore, the device shows promising safety results as well. A nine-month follow-up demonstrated an event-free survival rate of 92.7% vs. 80.7% of patients with metal stents. Also at nine months, patients had a 75% reduction in target lesion revascularization rates.

In another report, Jeffrey Moses, MD, co-principal investigator and a faculty member with the Cardiovascular Research Foundation at Lenox Hill Heart and Vascular Institute (New York), presented results from a randomized, double-blind controlled clinical trial involving 53 treatment centers in the U.S. A total of 1,058 patients were involved: one group received the drug-eluting stent while the others received a bare metal coronary stent.

"The findings are very positive and consistent with results of earlier studies," Moses said. "There are no significant differences between our earlier data and our final data. There were no issues associated with safety," he reported via satellite hookup from his facility in New York. Sirolimus, or cytostatic drugs, work differently than their cell-killing counterparts. Sirolimus inhibits cell proliferation by preventing their multiplication. This trial – the Randomized Study with the Sirolimus-eluting Velocity Balloon-Expandable Stent – ended this past spring.

Boston Scientific (BSC) was the second "big-gun" stent manufacturer to release highly anticipated data, reporting on its TAXUS II clinical trial during another late-breaking clinical trials session. Boston Sci's data showed impressive results at treating cardiac patients facing the more invasive bypass surgery currently used to treat them. The company's Express stent uses a polymer carrier and releases the anti-coagulant paclitaxel, which is marketed under the brand name Taxol.

"There was a net volume obstruction reduction of 70% in the first cohort of patients, which is truly impressive," Antonio Columbo, MD, principal investigator of the trial, told the attendees. Columbo is a cardiologist at Centro Cuore Columbus (Milan, Italy).

"This is one of the most anticipated moments at TCT this year," Leon, moderator for the session, told the thousands in attendance.

The TAXUS-II trial, divided into two groups receiving different dosage patterns, involved 536 patients at a total of 34 centers from 14 countries. "The only difference between the slow-release group and moderate-release group was the dosage patterns in the first two days following the procedure," Columbo noted. The amount of the drug remained the same in both groups, he said.

In the slow-release group, the restenosis rate inside the stent was 2.3%. Major adverse cardiac events at 30 days following the procedure was 8.5% compared to 19.5% in those receiving a bare stent. Overall, restenosis was reduced by 70% with the drug-coated stent vs. 6% in the bare stent. In the moderate-release group, the patients fared a little better with major adverse cardiac events: 2% vs. the 4% of those with a bare metal stent. The restenosis rate inside the stent was 4.7%. Overall, restenosis for the drug-coated patients was 62% compared to 7.8% in the bare-stent group, Columbo said.

The results are extremely encouraging for patients with blocked arteries in the U.S., Gregg Stone, MD, a member of the Clinical Research Foundation and faculty member at Lenox Hill Heart and Vascular Institute, told reporters at a press conference. Stone is the principal investigator of the U.S.-based TAXUS-IV trial.

Stone estimated that more than 800,000 stent procedures are performed annually in the U.S. The rate of in-stent restenosis is as high as 20% to 30%, he predicted. "That translates into about 160,000 patients having to undergo a repeat angioplasty or even bypass surgery," he noted.

"The Taxol [drug-eluting] stent – once approved by the FDA – will drastically reduce the number of necessary bypass surgeries and reduce the recurrence of scarring following an angioplasty with stents to around 5%," Stone said.

The most important surprise in the study was using a longer balloon angioplasty followed by a longer stent in the moderate-release patient group, Columbo said. "I would have never predicted these results, based on a 20 mm balloon followed by a 16 mm stent," he added.

Boston Scientific also reported 30-day safety data from its TAXUS IV trial involving 1,326 patients at 72 sites in the U.S. The randomized, double-blind, pivotal trial is designed to assess the safety and efficacy of a paclitaxel-eluting coronary stent in reducing restenosis in de novo lesions 10 mm to 28 mm in length and 2.5 mm to 3.75 mm in diameter. The study is using Boston Scientific's Express stent, internally developed and approved by the FDA in late summer after receiving the CE mark last year.

The company said the results supported safety, demonstrated by low MACE (major adverse cardiac events) rates, which Boston Scientific said were consistent with results from the TAXUS I and TAXUS II results. The MACE rates for the paclitaxel-eluting stent were similar to those for the control bare stent, as stated by BSC.

Boston Scientific also reported additional analysis of the TAXUS II data. The additional analysis found what BSC called "a significant improvement" in late loss for the diabetic population in the drug-eluting stent group compared to the bare stent control group, late loss being an angiographic measure of the long-term benefits of stenting. The analysis also found a trend toward improvement in binary restenosis rates in diabetic patients in the drug-eluting stent group compared to those in the control group.

Boston Scientific also said the elective arm of its VICTORY trial showed a 9% unadjusted intent to treat rate of major adverse cardiac events during a six-month period with the stent, as opposed to 12% rates with the control arm. The six-month restenosis rate was 19% with the stent compared with 24% for the control arm. The Express stent is a laser-cut, balloon-expandable stent that has a "tandem architecture" design that has elements to enhance flexibility and radiopacity. The Express stent was launched internationally last September.

Boston Scientific received FDA approval in mid-September for its Express2 stent, which has the same Express stent design with a laser-bonded flexible tip for easier tracking. The company said it believes the Express2 stents will provide it with a basis for creating a drug-coated stent system.

BSC has worldwide co-exclusive rights from Angiotech Pharmaceuticals (Vancouver, British Columbia) to use paclitaxel to coat its coronary stent products and other vascular and non-vascular products.

Following the results reported for trials involving products by its competitors, Guidant (Indianapolis, Indiana) reported preliminary results from the first cohort of patients enrolled in the DELIVER II trial. The DELIVER II study is designed to evaluate the benefit of the paclitaxel-coated Achieve drug-eluting coronary stent system in patients with lesions at high risk of restenosis. The trial enrolled 1,533 patients, including patients with chronic total occlusions, bifurcations, long lesions, small vessels, diabetes, multi-vessel disease and in-stent restenosis.

Eberhard Grube, MD, of Herzzentrum Siegburg (Siegburg, Germany), principal investigator for the study, presented preliminary results reporting a 30-day MACE rate of 3% for the first 500 patients enrolled in the trial. "In such a high-risk population, 30-day MACE rates between 10% and 20% are the norm," Grube said. He said the preliminary data "supports the benefit of paclitaxel eluting stents in high-risk patients." The MACE rates include any deaths, myocardial infarctions and target lesion revascularization within the 30-day period.

John Capek, PhD, president of Guidant's Vascular Intervention business, said the DELIVER II trial is the "first and largest trial evaluating a drug-eluting stent in a high-risk patient population." He said the trial "presents an opportunity to advance knowledge about the benefit of paclitaxel-eluting stents for the treatment of coronary artery disease in the most challenging clinical settings," and added that Guidant is "pleased with the low MACE results for the first cohort of patients enrolled in the ... trial."

DELIVER II is an unblinded, non-randomized trial that will follow patients implanted with the Achieve stent system for a period of up to three years. The primary endpoint of the study is the target lesion revascularization rate, measuring long-term clinical success. The study also will report on a number of secondary endpoints including safety, device success and cost-effectiveness. The trial completed enrollment in 76 centers outside the U.S. in early September.

Regulatory hurdles in post-market era

With clinical data apparently proving that drug-eluting stents are the golden child device of the new millennium, the next hurdle will be to establish a balance between pre- and post-market data. Jumping from the premarket approval (PMA) process to the post-market surveillance phase will be a challenging race for any device manufacturer to win, however. That's because neither the FDA nor the device industry has a benchmark on how to ensure the drug-coated devices are safe and effective well beyond their intended use.

Despite the efforts of the FDA in establishing an office for combination products, the challenge for device manufacturers lies in the fact that no manufacturer has yet garnered the coveted prize of approval for U.S. marketing. As one conference attendee put it during a surprisingly sparsely attended session, "The industry is in need of a carrot, and the absence of a stick is no carrot."

"Based on the results of the SIRIUS trial ... the drug-eluting stent arena will go haywire. The competition will be intense," Roxana Mehran, MD, director of clinical research and data analysis and management research at the Lenox Hill Heart and Vascular Institute, told the attendees. Mehran has clinical credibility behind her statement. She is one of the co-investigators behind the Cordis-sponsored SIRIUS trial and benefits from the company's existing approved status in Europe, which gives U.S. investigators access to a database gold mine.

Gathering more comprehensive post-market data will only benefit the manufacturer and the FDA, Mehran said. "There will be huge changes taking place. Doctors will put stents in places you'd never think of, and the FDA should allow for such changes [in the indicated] use of the device if it is favorable," she said. The study at Lenox Hill is benefiting from the deep pockets of Cordis, and it can therefore collect more high-quality data during the post-market phase, one attendee countered during a question-and-answer period. Lenox Hill benefits from the e-Cypher registry, which is a patient database of all European recipients and the corresponding clinical trial data. Mehran admitted her facility was indeed lucky in terms of trials it can administer. "The patients who enroll meet the three requirements we established for an e-registry: protection of patient privacy; ensuring the informed consent document had been signed; and ensuring the unit is HIPAA-compliant," she said.

The post-market surveillance database Cordis chose can help regulators in the U.S. make a decision to approve the device faster, Mehran said. "If the FDA can have a 'wish' during this presentation, then my wish is that the emphasis can be shifted to the post-market phase to get faster approval for these devices that patients need, but we need the commitment from the FDA," she added.

But the key in establishing the pre- and post-market challenge, Mehran said, lies in validating what data are entered into an online database. "What's not being done, either from the manufacturers or the providers, is making sure that the data entered are valid and accurate. Right now, there's no one to verify the accuracy of an entry," she said.

In a closing remark, however, an FDA official stated that the agency is in need of some changes to meet the desired response times for the drug-eluting stent challenge. "We are supportive of the statements you've presented, but within the FDA itself there needs to be a shift in some resources from the PMA side to the post-market side in order for your changes to take effect," Susan Gardner warned.

"We can't make any shifts in the pre- and post-market balance without a commitment from the industry," she said.

The contrasting views presented during a mid-conference plenary point-counterpoint presentation that drew an audience of thousands said the stent-frenzy era likely to ensue in catheterization labs across the U.S. is either a revolutionary step in medicine or a case of misguided hysteria.

For his part, Leon said, "The stent frenzy we're in the midst of is the greatest advance in cardiology since the introduction of the balloon." In fact, he said he was so confident in his prediction that he jokingly forecast that cardiac surgeons would have to get a new day job with the advent of the drug-eluting stent.

But more long-term data are needed to prove the effectiveness of the devices, Renu Virmani, MD, a member of the Armed Forces Institute of Pathology (Washington), cautioned the TCT audience. "You cardiologists don't have the necessary tools to prove the benefits of these products. Nine months of data is not a sufficient period to make determinations. We need five years' and 10 years' worth of data," she said.

Leon, during his pro-stent presentation, equated the refined drug-eluting stents to the sleek sports cars of stents vs. earlier versions that he described as akin to Model Ts. "Just because we started with the Model Ts doesn't mean we should give up and push the Porsche off the cliff," he said. Animal studies are needed to ensure patient safety, Leon noted, but the data shouldn't be used in comparison to humans, he said. "We can't base our results in patients, based on barnyard animals, because we are humans."

The evolution of the stent is moving toward a kinder, gentler device, Leon said. "Studies are under way to develop stents with more effective elution techniques by dripping the drugs on the carrier agent. The EASTER trials are now under way to determine if estrogen-coated stents are superior," he added.

But Virmani countered with the argument that too many histological questions remain surrounding the effectiveness of the drug-eluting stents. "The oral, systemic or intravenous modes of delivering the drugs at the time of stent placement might be a better choice. Polymers are not biodegradable," she warned. The misguided problem with cardiologists, said Virmani, lies in the tools used to determine the effectiveness of the drug-eluting stents. "You have your angiograms and IVUS [intravascular ultrasound] readings, but these tools aren't good enough," she warned. "You need better tools to determine the toxic effects of the drugs."

Virmani referred to current animal studies at the National Institutes of Health (Bethesda, Maryland) whereby the subject is implanted with a bare stent and then receives a particular dosage of a drug intravenously. "What they are finding is that a small amount of the drug administered intravenously is just as effective 28 days later," she said.

"Drugs don't last forever, and once they are gone from the stent, inflammation will no doubt return," Virmani said.

A 'new ballgame'

The impressive SIRIUS clinical trial data reported by Cordis will no doubt spur a bevy of device manufacturers to mimic the home run, but designing a winning clinical trial could leave many still on the bench. "If you're designing a new stent with a new drug, it becomes a whole new ballgame," Jonette Foy of the FDA's Center for Devices and Radiological Health told attendees at another TCT session.

Stents with an already approved drug from [the FDA] will get approval faster than those that use a new medical entity, or drug, Foy told the standing-room-only crowd. "The worst-case scenario is if both the device and the drug are unapproved," she warned.

The important bench elements in a trial are the in vitro pharmacokinetics and the chemical, manufacturing, and control principles of good clinical practice, Foy said. "That seems to be a big hurdle for manufacturers that have been contacting us," she added. Other items FDA staff will look at include the coating integrity, the durability, fatigue and corrosion, and particulate analysis of the carrier. "For the drug chemistry data, we would collaborate with CDER on that, if the drug has been approved," Foy said.

Another important component to the clinical trial is to establish a correlation between animal and human study data. "The in vivo data should demonstrate a correlation to the in vitro data," she noted.

But Bram Zuckerman, MD, deputy director of the Cardiovascular and Respiratory Devices division of the CDRH, gave stent manufacturers credit for paving the road in the industry. "We should be able to handle the glut of stent PMAs, thanks to the groundwork that the manufacturers helped establish. But the clinical trial issue is still an unanswered question," he said.

Additionally, according to Foy, FDA staff will want to see an evaluation of the following: the uncoated stent; the uncoated stent vs. the stent and carrier; the uncoated stent vs. the stent, carrier, and drug; and the clinical dose vs. overdose amounts. "It's also important to include data for the intended clinical uses. If you intend for the stent to be longer, then data to support the length should be included," she advised.

Clinical trials also should contain an executive summary, a comparison of local and systemic pharmacokinetics and an animal study report with local, regional and systemic information.

Establishing clinical considerations in the early stages is important as well, CDRH's John Hyde, MD, told the attendees. "You should demonstrate the contribution of the drug to the stent as well as its superiority over a bare metal stent," he advised.

The data should be clinically meaningful, Hyde said. "We'd like to see an assessment of the stent at nine months, even though some of the earlier stents have only shown assessment at six months." Postmarket follow-up also should be extended, he noted. "When developing a PMA, you should expect to offer surveillance up to five years as well as have a reliable data safety monitoring board. I'd recommend one that is online, one that can make decisions quickly to alert you to any problems."

Stroke prevention draws large audiences

Another topic that has begun to attract significant attention in the interventional cardiology community gained some of the TCT limelight as well. As discussed in detail in the September issue of Cardiovascular Device Update, catheter-based devices have begun to have a meaningful impact in the prevention of recurrent stroke. These percutaneous devices, which debuted about 25 years ago, have undergone significant refinements and have been specifically designed to prevent a recurrent "cryptogenic" stroke. The latter term has become accepted as a means to describe an ischemic stroke that has no identifiable cause. It has been estimated that about 25% to 30% of all ischemic strokes – or about 200,000 strokes annually in the U.S. – are cryptogenic.

Epidemiological evidence gathered in recent years strongly suggests that cardiac structural abnormalities may be a significant cause of stroke. The most common abnormality is a congenital heart defect known as a patent foramen ovale (PFO), which is a flap-like opening between the atrial septum. Closure usually occurs in most adults after birth, but incomplete closure or a patent foramen ovale has been shown to persist in 5% to 35% of the adult population.

The traditional means of managing these stroke patients has either been medical management (anti-coagulation therapy) or open-heart surgical repair. The former is plagued with a lack of compliance and efficacy, while the latter is highly invasive and very expensive. This has created a major market opportunity for minimally invasive catheter technology. It has been estimated that the worldwide market potential for PFO closure is about 500,000 procedures annually.

The two market leaders in this embryonic field are NMT Medical (Boston, Massachusetts) and AGA Medical (Golden Valley, Minnesota). The former sponsored a TCT symposium called "Catheter-Based Closure of PFO, ASD and VSD," which was extremely well-attended, while the former sponsored an industry breakfast titled "Percutaneous Shunt Closure with the Amplatzer Occluder." In addition, there were several sessions during TCT devoted to presenting the most recent clinical results with both companies' devices.

Despite the setback and negative publicity arising from the FDA Circulatory System Devices Panel's mid-September meeting, the clinical results for NMT's PFO closure devices (the second-generation CardioSeal and third-generation StarFlex) have been very solid. At a TCT session, Dr. Bob Sommers of Lenox Hill Hospital presented the results of 265 CardioSeal PFO implants performed between November 1999 and January 2001 at seven highly regarded U.S. hospitals. The follow-up period ranged from seven months to 25 months. The results were impressive, with 260 of these patients having no residual shunt or a complete closure of their PFO at the time of their last follow-up exam. Complete PFO closure suggests that a recurrent cardiac source of stroke is highly unlikely. Safety of the device and the procedure also was impressive, with minimal notable problems.

Sommers said that catheter-based PFO closure is an "extremely safe and effective procedure that can be performed with excellent results after a brief training period by an interventional cardiologist." He also stated that percutaneous PFO closure appears to significantly reduce the stroke recurrence rate vs. medical management. He closed his prepared presentation by saying that the question "Does PFO closure prevent recurrent neurological events?" could only be answered definitively with a multi-center randomized, prospective clinical trial.

In the Q & A that followed, Sommers noted tremendous enthusiasm in the interventional cardiology community for PFO closure but that neurology physicians, whom he described as "much more conservative and data-driven," were a negative factor in the market adoption rate. "We are looking to the neurologist to lead the charge and address the huge untapped population of PFO patients who need therapy," he said.

These comments were supported by the next speaker at the symposium, Dr. John Rhodes, a neurologist from the Cleveland Clinic Foundation. He noted that there had been excellent safety and efficacy PFO closure data generated at his institution using the CardioSeal device and that it represented a "viable and attractive alternative" to lifelong pharmacological therapy to prevent secondary strokes. He exhorted his neurological physician colleagues to work together with interventional cardiologists for better patient care. "This is a very strong and definitive objective for both communities to strive for," he said.

Speaking to a standing-room-only crowd, Dr. Steven Cramer, a neurologist from the University of Washington School of Medicine (Seattle, Washington), made a strong case that there is significant percentage of the population that has a PFO and that there is a clear association between PFOs and cryptogenic stroke. In addition, he supported the notion that medical management to prevent a secondary stroke results in a high recurrence rate, although he admitted that the exact rate was unknown.

Responding to his own rhetorical question, "Can PFO closure improve outcomes?" Cramer said, "we need further studies and we have a long way to go to prove this." The need for a randomized, prospective muticenter trial was emphasized by the panel at the recent Circulatory System Devices Panel meeting.

At the AGA Medical-sponsored meeting, it was disclosed that the company has recently been given the FDA's go-ahead to initiate such a study, which will be called the Randomized Evaluation of Recurrent Stroke TIA or Peripheral Embolism Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial. It will involve enrolling 500 patients at 25 centers who will be randomized to either the Amplatzer PFO Occluder or best medical management, with a follow-up period of two years. The primary endpoint will be the recurrent neurological event rate (i.e., stroke or transient ischemic attack), with the goal of achieving equivalent results from both approaches.

Bigger magnetic fields, faster images

Cardiologists and interventional radiologists will have access to bigger magnetic fields and faster images with the next generation of magnetic resonance imaging (MRI) machines. "Device manufacturers are already working on bigger machines. It's just a matter of when they are introduced," Robert Balaban, a researcher at the National Heart, Lung and Blood Institute of the National Institutes of Health (Bethesda, Maryland), told TCT attendees.

Balaban outlined four elements that are moving the technological advances forward. First, MRIs will be equipped with higher magnetic fields. Second, the higher fields will come with more speed and faster images, he predicted. Third, improvements in coils will give physicians improved diagnostic abilities. Improvements in chemistry will yield better contrast agents as well, Balaban said.

Higher magnetic fields already are being tested, he said. "There are experimental machines offering 7 and 8 Tesla, but the question is how high will we go? There are biophysical limitations to the higher fields." Balaban noted that a study conducted in Berlin concluded that 3 Tesla is a good compromise for the patient and physician. "Three Tesla offers the speed but prevents the physical side effects of the higher speeds, such as twitches and pain."

The higher magnetic fields present an additional problem, Balaban noted. "The higher speeds present much more data. The amount of data is overwhelming the instrument's capability, and that is probably the biggest embarrassment to the industry right now, but I think this will be fixed quickly," he said.

"One of the biggest barriers to interventional MRI has been the lack of tools to see the soft tissue and inflammation," Balaban said. "But over the next five years there will be advances in the coils." The biggest advance in coils will be the advent of intra-vascular coils, he added. "There will be specialized coils for peripheral MRI and vessel wall imaging."

The development of contrast agents with better capabilities is still in its infancy, Balaban noted. "The biggest goal in terms of science is to develop a true vascular contrast agent. But I think we'll see that within the next two years," he said.

Physicians will have agents that go inside the cells without leaving the toxic elements behind, he explained. "This will probably be done through the use of water proton-agent proton exchanges," Balaban said. "Within five years there will be specialized contrast agents for infarction, blood clots, inflammation and atheroma macrophages," he noted.

In another approach, Guidant reported on a study using optical coherence tomography (OCT), a new coronary imaging technology that provides resolution 10 times greater than intravascular ultrasound, to examine highly detailed images of complex coronary lesions in patients with coronary artery disease. Results of the Guidant-supported study, conducted at Massachusetts General Hospital (Boston, Massachusetts) and presented by Ik-Kyung Jang, MD, PhD, found OCT able to successfully detect morphological characteristics of coronary lesions that have been associated with heart attack. The study measured these characteristics in 63 patients, including lipid pools and their thin fibrous caps that are susceptible to rupture, threatening the vessel and potentially leading to heart attack and death. Jang said, "This information far surpasses what traditional angiography and IVUS can do, and it develops OCT to a point of readiness for natural history studies to link these features with clinical events." The OCT system used in the study was developed at Wellman Laboratories of Photomedicine, based at Massachusetts General Hospital within the Department of Dermatology at Harvard Medical School (Boston, Massachusetts).

Therapeutic ultrasound developer PharmaSonics (Sunnyvale, California) said at TCT that it would initiate a clinical investigation of its anti-restenotic Intravascular Sonotherapy for the treatment of diabetic patients implanted with drug-eluting stents. The European Diabetics-Sonotherapy Prevention of Arterial Restenosis and Krappy Lesions (DiSPARKLE) trial also will examine the use of Sonotherapy in the treatment of total target vessels for the reduction of coronary atherosclerosis disease progression.

The DiSPARKLE trial will examine the safety and efficacy of Sonotherapy treatment in diabetic patients to enhance the efficiency of drug-eluting stents. The study will also investigate the application of Sonotherapy treatment to the total coronary target vessel for the reduction of atherosclerotic disease progression, and for stabilizing vulnerable plaques that might develop within the non-stented segments of the target coronary artery.

The company indicated that the trial represents a "significant broadening" of the investigation of Sonotherapy treatment beyond the reduction of coronary restenosis into new and emerging applications as an adjunct to drug-eluting stents and for the stabilization of vulnerable plaques. "The remaining high rate of restenosis, recently observed in diabetic patients receiving drug eluting stents, requires the development of new approaches for this difficult patient population," said principal investigator Antonio Colombo of Centro Cuore Columbus, after successfully performing the first DiSPARKLE live case at the TCT. "As recent research suggests, Sonotherapy may play a role in increasing the effectiveness of drug-eluting stents and in inhibiting atherosclerotic disease progression overall."

DiSPARKLE, a randomized, double-blind study of 180 diabetic patients, will compare the use of Sonotherapy treatment vs. a sham control in de novo coronary lesions. In the treatment group, Sonotherapy will be applied after implantation of drug-eluting stents to the stented segment, as well as the proximal and distal segments.

"There will be a need for using Sonotherapy in conjunction with drug-eluting stents to treat diabetic patients," said Menahem Nassi, PhD, president and CEO of PharmaSonics. He said that it is his impression, based on what Colombo told him, "that diabetics are still a tough group to handle, even with a drug-eluting stent." He added that the trial would probably use one of Cordis' Cypher stents, which are approved for use in Europe. The study will be limited to coronary arteries with diameters of 3.5 mm or less. It will include multi-vessel stenting and Sonotherapy treatment lengths ranging from a minimum of 40 mm to a maximum of 80 mm.

The primary endpoint of the DiSPARKLE trial will be binary restenosis within the drug eluting stent as measured by quantitative coronary angiography (QCA); other endpoints include one- and nine-month MACE. The endpoints for atherosclerotic disease progression will include angiographic assessment and MACE rates within the Sonotherapy-treated vessel segments outside the stent.

Nassi noted that the initiation of the DiSPARKLE trial under Colombo's leadership "strengthens PharmaSonics' Sonotherapy potential to participate in new and emerging interventional cardiology markets, as an adjunct to drug-eluting stents and as a treatment for vulnerable plaque." He noted that this is especially important in light of the anticipated release of the Sound Wave Inhibition of Neointimal Growth (SWING) trial results later this year, "which we expect will establish the anti-restenotic efficacy of Sonotherapy when used in conjunction with bare stents." The SWING results will be released at this month's annual scientific sessions of the American Heart Association (Dallas, Texas) in Chicago, Illinois.

Another presentation summarizing preclinical work in drug delivery conducted at the University of Sheffield (Sheffield, UK) also was released by PharmaSonics. The study showed a four-fold increase in drug (DNA) uptake from drug-eluting stents by vascular smooth muscle cells with Sonotherapy treatment enhancing drug-delivery, compared to sham controls, which consisted of drug-eluting stents alone.

In addition to the anti-restenotic applications, PharmaSonics is developing its therapeutic ultrasound technology to treat atherosclerotic disease progression (vulnerable plaque), optimize the drug delivery characteristics of drug-eluting stents and enhance the non-viral delivery of genes for myocardial or peripheral angiogenesis.

The company said recently that it had been issued four additional U.S. patents and has received a notice of allowance for four other patent applications for its Sonotherapy technology that support some of the aforementioned new uses of the system. The issued and allowed patents provide coverage into new and emerging markets such as hemodialysis and drug-gene delivery. Allowed under U.S. patent No. 6,372,498 is the use of Sonotherapy to enhance the transfection of vascular smooth muscle cells by combining gene delivery with Sonotherapy. Ultrasound has been shown to increase membrane permeability and facilitate diffusion of therapeutic agents such as drugs, nucleic acid, and genetic matter into tissue. Combining Sonotherapy with gene delivery may enhance the efficacy of gene expression, reduce dosing needs and allow for a broader use of gene therapeutic agents with non-viral vectors the company said.

PharmaSonics has obtained the CE mark for the commercialization of the Sonotherapy procedure in de novo stents. Boston Scientific holds the exclusive distribution rights throughout Europe and all other regions outside the U.S., Canada and Japan. European sales are scheduled to begin in January.