By HOLLAND JOHNSON
CDU Associate Managing Editor
And MARK McCARTY
CDU Washington Editor

WASHINGTON — The 2006 edition of the Transcatheter Cardiovascular Therapeutics conference unfolded in fairly typical fashion, focusing largely on the increasing debates concerning the value of drug-eluting stents and featuring also a variety of new reports on stem cell therapies — and providing a sort of warm-up to the similar debates and presentations to come at the American Heart Association (AHA; Dallas) meeting shortly after.

Boston Scientific (Natick, Massachusetts) and Cordis (Miami Lakes, Florida) were active in presenting their usual studies which, again offering no surprises, served to say "our stent is better than theirs." Attendees have seen so many of these studies, however, that Medtronic — which is poised to enter the DES market in the U.S. this coming year — served to upstage Boston Scientific and Cordis with its report, issued before the start of the TCT meeting, that it was initiating a large-scale clinical trial focusing on DES safety. Medtronic said that its Patient Related OuTcomes with Endeavor versus Cypher stenting Trial (PROTECT) will be the largest randomized trial ever conducted to assess key safety measures of two DES devices, comparing its Endeavor zotarolimus-eluting DES — the DES it has positioned for FDA approval — against Cordis' Cypher.

Primary endpoint for the PROTECT study will be stent thrombosis, with secondary endpoints that include death and non-fatal myocardial infarction and other customary clinical efficacy endpoints, Medtronic said. The study will enroll 8,000 "real- world" patients at 200 clinical centers in Europe and other international markets and follow patients for an additional two years. "Real-world" patients, the company said, refers to patients seen by physicians in everyday clinical practice, including those with complex medical conditions — a designation clearly meant to differentiate vs. more carefully selected trial patients.

"That's all comers," Medtronic spokesperson Scott Papillon told Cardiovascular Device Update, "the patients who would typically come into a physician's clinic on an everyday basis."

While the timing of the trial may appear calculated as piggy-backing on the current DES debate, Papillon insisted that it was only coincidental. "More than a year ago, we started talking to physicians about it," he said. "It's in response to the call for more [long-term] safety [data] but not necessarily tied to the recent activity that everyone is hearing about."

Results of the trial will be watched closely, of course, but no matter what those results are, the study still will be likely to beg a very large question. PROTECT's key terms are "long-term," "safety," and patients who are "real-world," all targeting the current concerns being raised about DES safety.

But the study circles far afield from the major key concerns being raised about DES stents — the need to evaluate DES vs. bare-metal stents (BMS) in long-term trials by an organization other than a DES manufacturer. No matter what degree of rigor is demonstrated in a company-sponsored trial, such a trial will always be shadowed by a certain amount of skepticism.

Asked if Medtronic had concerns that the DES market has peaked and is now in correction mode due to real-life concerns, Papillon acknowledged these as valid issues, but stressed that the problems are with the first-generation stents. "We think that Endeavor as the next-generation stent offers some answers to that," he said. Among the improvements that he cited for Endeavor over its older brethren include a polymer/drug combo with excellent safety data thus far.

The Endeavor did fail to meets its primary endpoint in a study against Cypher last year. In ENDEAVOR III, the Endeavor stent failed to exhibit non-inferiority in comparison of late-lumen loss. The 282 patients treated with Endeavor had an average in-segment late loss of 0.34 mm at eight months compared to 0.13 mm among the 94 Cypher-treated patients. That 0.21 mm difference, however, was just 0.01 mm more than the trial's predetermined non-inferiority margin of difference.

In response, Papillon said that the late-loss data was determined as not applicable and that late loss has not been shown to lead to adverse clinical outcomes. He noted that Endeavor was "at least as good as the Cypher" in the secondary endpoints and that safety was not studied in ENDEAVOR III.

A stiffer headwind coming?

Whatever the high hopes Medtronic has for ENDEAVOR, the company — and any others attempting to come on line with DES or DES-type combinations of drugs and devices — may face a somewhat stiffer headwind at the FDA and perhaps a longer review process. Its panel and reviewers are going to be asking many more and much tougher questions than Cordis and Boston Scientific had to deal with — or face some heavy outside criticism from those already ready and poised to bash the FDA as having not enough conceren for safety. The data required will probably be somewhat longer-term, and there will certainly be a demand for very much more post-marketing data and surveillance.

Stem cells — 'too much controversy'

Besides the emphasis on the DES vs. BMS debate, the 2006 TCT also featured the growing drumbeat of stem cell therapy studies found in the cardiovascular venue, a research emphasis that continues aggressive percolation in the research arenas but with little evidence of breaking into the commercial and profit-producing venues very soon.

Tim Henry, MD, an interventional cardiologist at the Minneapolis Heart Institute (Minnesota), gave an overview of what he considered to be the current state of stem cell research targeting congestive heart failure and other diseases. "Right now, there's too much controversy and, on the other hand, too much hype" surrounding this research, Henry said. He said that the current spate of controversies is focused on a particular kind of stem cell, which he termed "the wrong question," adding that there are a number of stem cell types in the adult human body, all having at least some therapeutic potential. The first question researchers should ask, he said, is "what condition am I trying to treat?"

Henry said that the ability of stem cells to release needed biochemicals to nearby cells, commonly referred to as a paracrine mechanism, is probably as vital a part of their ability to repair organs as anything else. However, he predicted that in the future, "stem cells could be used as couriers to deliver gene therapy." As for diseased hearts, there are "really not a lot of hard data" for this, he said.

One of the studies referred to by Henry appeared in the September 2004 edition of Circulation, by Emerson Perin, MD, director of new cardiovascular interventional technology at the Texas Heart Institute (Houston). It described the injection of a patient's own bone marrow mononuclear cells in an effort to treat ischemic cardiomyopathy. The authors acknowledge, however, that they do not know which of the mononuclear stem cells found in the bone marrow are responsible for some of the observed ameliorative effect on ischemic myocardium. What may be considered the "usual suspects" of this category include mesenchymal stem cells, stem cells that are progenitors of hematopoietic and endothelial cells, and those stem cells responsible for generating various lymphocytes. They say that the study demonstrated safety by virtue of having triggered no immune response and the results indicate statistically significant improvement in exercise capacity and reduced symptoms of angina. On the other hand, the trial enrolled only 23 patients, nine of whom were controls.

Henry briefly discussed the recently completed Phase I trial for Provacel, made by Osiris Pharmaceuticals (Baltimore), intended to treat myocardial infarction by means of mesenchymal stem cells. In the animal models, the mesenchymals migrated to the heart by homing in on the source of markers of inflammation. But the cells in the Provacel trial will follow inflammation markers to other parts of the body. Lacking any biological trail, the mesenchymal cells head for the bone marrow, essentially going home if there is no work to be done. Henry said that this early work "absolutely does not" prove efficacy, but he noted that the trial made use of allogeneic cells, raising the possibility of "one healthy donor" donating stem cells to many others — "a huge step forward."

Genes and the 'gamut' of cells

Nicolas Chronos, chief scientific officer at the American Cardiovascular Research Institute (At-lanta), outlined the current state of gene research into heart disease, noting up front that "a whole gamut of cells are involved" in the inflammation leading to atherosclerosis," thus offering a range of potential tools, but also requiring a wide range of expensive and time-consuming research. At present, reduction of low-density lipoprotein (LDL) is really the mainstay of clinical practice for cardiologists, and that as things stand, "we're treating the end stage" of atherosclerosis, Chronos said. Gene therapy holds out hope of intervening before a heart becomes heavily diseased, but some research seems geared to bypassing genes altogether.

"We can think of gene therapy as just another way of delivering proteins," said Chronos, hinting that proteomics may move past genomics as the most promising area of research. One of the confounders of any such research, he said, is that patients who have been treated for various heart diseases "have a very, very high incidence of the placebo effect."

One approach to fending off atherosclerosis, Chronos said, might be to target a gene such as hypoxia-inducible factor (HIF 1), which he said embodies "the cell's ability to measure the latent oxygen in the environment" and correlates with the onset of atherosclerosis. HIF 1, he said, can induce angiogenesis and could play an important role in treating heart disease.

At present, Genzyme (Cambridge, Massachusetts) has an HIF 1 product in Phase II clinical trials to deal with vascular disease in the lower extremities, and the National Cancer Institute is recruiting for a Phase I trial to see if topotecan hydrochloride can suppress HIF 1 and hence cut off the blood supply in an unspecified group of cancerous tumors. These efforts, however, will not likely result in very near-term clinical application, he said.

As something more promising, Chronos discussed research at the University of Pennsylvania School of Medicine (Philadelphia) involving intravenous delivery of an adenoviral source of human apolipoprotein E (apoE) in apoE-deficient mice to see if this xenogeneic source might prevent atherosclerosis. The research team, headed by Ken Kitajima, MD, found that "extensive atherosclerosis was present in the thoracic aortas and aortic roots" of the controls after one year of treatment but "completely prevented" in the experimental group.

Topol to head new institute

Among one of the more intriguing reports out of the TCT meeting was that Eric Topol, MD, former chairman of the department of cardiovascular medicine at the Cleveland Clinic (Cleveland), was named to head a new Translational Science Institute and Genomic Medicine Program for Scripps Health (San Diego) healthcare system. Topol left the Cleveland Clinic last year in what was considered the fall-out of his failed effort to be named CEO of the clinic. This departure was also widely seen as the result of conflicts with Toby Cosgrove, MD, who did win the clinic CEO position. Thus, the appointment of Topol to the new institute provides him a new platform for his work in genetic-related disorders.

Chris Van Gorder, president/CEO of Scripps, said that Topol is "the first of many physician/scientists we hope to bring to Scripps in other clinical specialties. Just as Dr. Topol took the Cleveland Clinic to the No. 1 heart program in the nation, we know his contributions will help Scripps realize its vision of becoming the destination heart program for the West Coast."

Scripps in October reported a major expansion of its clinical research program, led by academic oncologist and clinical researcher Brian Issell, MD. Topol and Issell will work together to expand Scripp's clinical research.

"Scripps has everything it needs to be a world leader in cardiovascular medicine, genomics and translational science," Topol said. "The excellent clinical reputation of Scripps Health coupled with its longstanding relationship with The Scripps Research Institute, the genetic diversity of the San Diego population and its high concentration of exceptional biotechnology creates the ideal environment to develop a leading genomics and translational science program."

Topol is also program director for the Specialized Center of Clinically Oriented Research on the molecular determinants of coronary artery disease, supported by an $18 million grant from the National Institutes of Health, and a professor of genetics at the School of Medicine of Case Western Reserve University (Cleveland).

His work in the genomics of coronary disease led to the discovery of the first autosomal dominant mutation-inducing coronary disease and heart attack, bringing him a variety of awards.