CDU Washington Writer

WASHINGTON – The annual Transcatheter Cardiovascular Therapeutics (TCT) conference, held at the Washington Convention Center last month, once again was jam-packed with a huge menu of choices guaranteed to satiate the appetite of any interventional cardiologist, medical device executive or Wall Street analyst. The choice of available programs was by far the largest since TCT debuted 17 years ago. With 12,000 attendees estimated to have jammed the meeting rooms of the convention center during the six-day symposium, the messages presented in these sessions reached a wide audience.

Essentially kicking off the 2005 edition of the conference, two of the gathering’s leading lights provided a look at present and future treatment modalities in this burgeoning space. Atop the discussion as usual were drug-eluting stents, whose popularity has surged in a relatively short timeframe, with continued growth projected.

Gregg Stone, MD, of the conference-sponsoring Cardiovascular Research Foundation (New York), seized on that theme in describing the products as representative of a revolutionary change in treatment. He said that by the end of 2005, 90% of U.S. stent implants would be of the drug-eluting variety. So far, it’s a market that includes only two FDA-approved products – the sirolimus-eluting Cypher stent from the Cordis (Miami Lakes, Florida) unit of Johnson & Johnson (New Brunswick, New Jersey) and the paclitaxel-eluting Taxus stent from Boston Scientific (Natick, Massachusetts).

Stone called for a large, independent, head-to-head trial between the products to better differentiate them. “We would truly need a mega trial,” he said, “to sort out whether there are differences between these two.” A number of comparison trials have taken or are taking place, but none have been of the scope envisioned by Stone.

Going forward, he stressed continued efforts to reduce high restenosis rates found in complex lesions, as well as efforts to reduce in-stent thrombosis. Still looking down the road, he pointed to the myriad additional drug-eluting stents in development. “Competition is fierce,” Stone said. “It is our hope that this will further reduce their price.”

Later, he made a number of forecasts. Among his projections, Stone said that access to primary angioplasty would extensively grow in the U.S. for treating acute myocardial infarction. He also predicted that structural heart disease would “become the hottest area in transvascular therapeutics.”

Stone’s colleague at the Cardiovascular Research Foundation, Martin Leon, MD, addressed several other related issues.

In discussing end-stage heart disease, he said that gene-based angiogenesis approaches to treatment would “continue to disappoint,” but said that cell-based therapies hold more promise. “Our interventional future is being redefined,” Leon said.

He also pointed to accelerated growth in the cardiovascular imaging arena, with several different imaging modalities gaining favor. Such an imaging revolution “will finally transform the cath lab,” he said, later adding that the continued integration of non-invasive with invasive imaging would help “improve efficacy and hopefully safety.”

Leon also predicted sustained growth in endovascular therapies, given improved physician awareness and training through simulation systems, though he lamented that most newly proposed endovascular therapies are poorly validated.

Nevertheless, he counted physician training as among challenges facing the industry going forward, as well as regulatory issues and socio-economic thresholds that limit the adoption of these new therapies.

Medtronic still upbeat after endpoint missed

Although its Endeavor drug-eluting stent missed its primary endpoint in the ENDEAVOR III study, Medtronic (Minneapolis) remains bullish on the product’s prospects. “The efficacy profile of this product is very well characterized,” said Scott Ward, president of Medtronic Vascular (Santa Rosa, California). “And actually, we’re really pleased with these results.”

Both Ward and the study’s primary investigator, David Kandzari, MD, of Duke Medical Center (Durham, North Carolina), stressed Endeavor’s positive impact on clinical outcomes to date as predictive of its benefit to patients. And in doing so, they didn’t hide behind the missed primary endpoint.

The study compared Endeavor, which is coated with zotarolimus, to the sirolimus-eluting Cypher stent from Cordis.

Data reported by Kandzari during the initial late-breaking clinical trials session of the TCT conference showed that Endeavor failed to exhibit non-inferiority to Cypher in a comparison of late-lumen loss. Specifically, 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 was just 0.01 mm more than the trial’s predetermined non-inferiority margin of difference.

Ward and Kandzari pointed specifically to Endeavor’s target lesion revascularization rate of 6.3% in the study as the best indicator of its efficacy; Cypher’s target lesion revascularization rate was 3.5%. “In real-world practice,” Kandzari said, “the most important outcome is a clinical event.” He said that patients return for additional procedures following outcomes such as target lesion revascularization, not because of measures such as late lumen loss, and Endeavor’s comparable target lesion revascularization rate to Cypher is indicative of the device’s success.

That sentiment was echoed by Ward, who said that “despite narrowly missing” the trial’s primary endpoint, “physicians, patients and the FDA are most interested in clinical outcomes.” There were no significant differences among clinical outcomes at nine months between Endeavor and Cypher.

In addition to target lesion revascularization, those secondary measures included major adverse cardiac events (7.6% for Endeavor vs. 7.1% for Cypher) such as death (0.6% for Endeavor vs. 0% for Cypher), Q-wave myocardial infarction (0% for both), non Q-wave myocardial infarction (0.6% for Endeavor vs. 3.5% for Cypher) and coronary artery bypass grafting (0% for both).

The products also had similar target vessel revascularization and failure rates (6 % and 12% for Endeavor, respectively, vs. 5.3% and 11.5% for Cypher, respectively).

“The clinical outcomes appear quite favorable,” Kandzari said.

Ward added that Medtronic’s continued clinical development and regulatory plans remain on schedule. Notably, the ENDEAVOR IV study continues to enroll patients as planned and eventually will provide necessary safety data for the company’s filing plans. He said ENDEAVOR IV, which is comparing Endeavor to the paclitaxel-eluting Taxus stent from Boston Scientific, would complete enrollment next spring and allow Medtronic to file its pre-market application by the end of next summer.

That sets up a potential approval date sometime in 2007, “so our program remains very much on track,” Ward said.

However, that optimism was tempered somewhat by Patrick Serruys, MD, PhD, of the Thoraxcenter (Rotterdam, the Netherlands). In reviewing the data, he noted that among high-risk patients, in-segment late loss is commonly associated with increased risk of target lesion revascularization. Therefore, he postulated that ENDEAVOR III’s failure to meet such an endpoint could “become even more evident in a high-risk patient cohort.”

Nonetheless, the product is approved in Europe, where it received a CE mark in July. Importantly, Ward noted, the latest data are consistent with prior clinical findings on the Endeavor stent. In 1,300 patients who have received the stent in clinical trials to date, 95.1 percent did not need target lesion revascularization at nine months, and there have been no cases of in-stent thrombosis among those 1,300 patients 10 days past the procedure.

Data backs Taxus use in higher-risk patients

A study presented at TCT backed the performance of Boston Scientific’s (Taxus Express(2) paclitaxel-eluting coronary stent system for the treatment of coronary artery disease in diabetic patients, particularly higher-risk insulin-requiring diabetics.

Boston Sci said the TAXUS V clinical trial expands on the TAXUS IV pivotal trial by studying what the company termed “the most challenging lesions and highest-risk patients ever studied in a randomized, controlled clinical trial in the U.S.” Nine-month sub-population data from TAXUS V was presented by Naim Farhat, MD, of North Ohio Heart Center (Elyria, Ohio).

“The TAXUS V diabetic sub-population data provides impressive results on the outcome of the TAXUS stent system in treating complex patients, especially insulin-requiring diabetics,” said Farhat. “Most significantly, the data ... shows an observed increasing benefit of the Taxus system in the higher-risk insulin sub-group as compared to control and other diabetic patients.”

TAXUS V is a randomized, double-blinded trial that enrolled 1,172 patients at 66 sites in the U.S., assessing the safety and efficacy of a slow-release formulation paclitaxel-eluting coronary stent system in reducing restenosis in de novo lesions 10 mm to 46 mm in length and 2.25 mm to 4 mm in diameter.

Boston Scientific reported in March that the trial met its primary endpoint of nine-month target vessel revascularization, as well as all secondary endpoints.

Farhat said the diabetic sub-population analysis demonstrated “significant improvements” among diabetic patients receiving the TAXUS paclitaxel-eluting system vs. those in the bare-metal control group and further improvements among insulin-requiring diabetic patients. The nine-month target lesion revascularization rate (TLR) for the medically treated diabetic sub-population of the Taxus stent group was 9.6% compared with 17.5% in the control group, a reduction comparable to the non-diabetic sub-population (45% in both cases). Among insulin-requiring diabetic patients, the TLR rate was 8.3% compared to 17.3% in the control group, a reduction of 52%.

The diabetic sub-population also reported an in-segment binary restenosis rate of 18.2% in the Taxus group compared with 38.4% in the control group, a reduction of 53%. Among insulin-requiring diabetic patients, the restenosis rate was 20.9% in the Taxus group compared with 46.7% in the control group, a reduction of 55%.

Cypher shows benefits in CTOs

The PRISON II (for Primary Stenting of Occluded Native Coronary Arteries) study demonstrated the benefit of using the sirolimus-eluting Cypher stent from Cordis (Miami in treating chronic total occlusions compared to the bare-metal Bx Velocity stent. In terms of the 200-patient trial’s primary endpoint, in-stent restenosis rates were 7% in Cypher patients and 36% in the bare-metal stent arm.

“It’s evident that you should use drug-eluting stents in these kinds of patients,” said Maarten Suttorp, MD, PhD, of St. Antonius Hospital (Nieuwegein, the Netherlands).

Secondary measures in the study further elucidated Cypher’s profile: its rate of target lesion revascularization was 4% compared to 19% for the bare metal stent, the target vessel failure rate was 8% vs. 24%, major adverse cardiac events were 4% compared to 20%, and in-stent late loss was 0.05 mm vs. 1.09 mm.

In J&J’s third-quarter earnings report, released on Tuesday, the company noted that Cypher has been used in treating more than 1.5 million coronary artery disease patients.

“In chronic total occlusions, you have two challenges,” explained Brian Firth, MD, PhD, J&J’s vice president of medical affairs and health economics worldwide. “The first is getting the artery open, which you can do 70% to 80% of the time. And when you do get a wire or balloon through, you’re still faced with a high restenosis rate and a high reintervention rate. So the question posed here is whether you are better off putting in a Cypher stent or a bare-metal stent. And the answer is hands down” a Cypher stent.

Meta-analysis gives edge to Cypher

A head-to-head comparison showed that the Cypher stent from Cordis outperforms Taxus in target lesion revascularization and restenosis rates. Specifically, the Cypher stent reduced the need for re-treatment by about 30% compared to Boston Scientific’s Taxus stent.

Those conclusions were drawn by a meta-analysis of the two drug-eluting stents in seven studies that include a total of 4,214 patients. The work was done by Stephan Winndecker, MD, and Peter Juni, MD, both of University Hospital Bern (Bern, Switzerland).

“This rigorously conducted meta-analysis establishes the highest level of scientific evidence of the relative performance of these two drug-eluting stents,” said Dennis Donohoe, MD, vice president of worldwide clinical research and regulatory affairs for Cordis. “The Cypher stent’s strong clinical performance across these trials is clearly demonstrated and will be of great value to physicians and patients.”

A range of other studies reported at TCT further boosted Cypher’s profile. A post-market surveillance study from China, which included a large percentage of complex lesions, generated data similar to that seen in other Cypher registries to date. A separate multi-study analysis showed that high-risk patients with long coronary blockages had better clinical outcomes with multiple, overlapping or non-overlapping Cypher stents than those who received bare-metal stents.

In another study, an analysis of data pooled across four drug-eluting stent clinical trials found that high-risk patients with long coronary blockages had better clinical outcomes with multiple, overlapping or non-overlapping Cypher stents than for those patients who received bare-metal stents.

Campbell Rogers, MD, of Brigham & Women’s Hospital (Boston), presented the data featuring analysis from the SIRIUS, E-SIRIUS, C-SIRIUS and DIRECT trials, which included 271 patients who received multiple, long stents – at least two stents 18 mm or longer – in a single vessel.

The trial results sowed there was no evidence of increased total or non Q-wave myocardial infarction (MI) rates for Cypher stent patients who received multiple long stents, overlapping or non-overlapping, compared to a well-matched bare-metal stent control group at 30 days post-procedure. And the 30-day non Q-wave MI rate was significantly lower for the Cypher stent cohort (0%) than for the bare-metal stent cohort (3.6%).

Rogers said the detailed angiographic analysis is consistent with the clinical findings in that it shows that the lesions treated with multiple long Cypher stents had “significantly fewer” side branch occlusions than those treated with multiple long bare-metal stents.

The data he reported said the use of multiple long Cypher stents resulted in a lower overall major adverse cardiac event (MACE) rate at 30 days post-procedure: 1.3% vs. 3.6% for the bare-metal control group.

The nine-month safety summary, which includes death and heart attack, also showed positive results in favor of the Cypher stent, 7.6% vs. 37.8%. Thrombosis rates at nine months were comparable, at 0.6% for the Cypher patients and 0.9% for the bare-metal cohort.

The Cypher arm had a nine-month target lesion revascularization rate of 5.7% vs. 35.1% for bare metal, while target vessel revascularization rates were 13.3% for Cypher and 36% for the bare-metal group.

Dennis Donohoe, MD, vice president of clinical research and regulatory affairs for Cordis, said the analysis conducted on “this highly complex patient group is another example of the strong performance of the Cypher stent across a broad range of challenging cases.”

EVENT registry shows growth of DES use

A still-developing registry, called EVENT, involves a multi-center gathering of outcomes from percutaneous coronary intervention (PCI) during the drug-eluting stent era. David Cohen, MD, of the Harvard Clinical Research Institute (Boston), noted that their use has grown to more than 92% of procedures, based on data from the first 2,500 patients included in the registry.

“Drug-eluting stents are being used widely,” Cohen said, “and we’re using about 1.6 per procedure.”

Among this initial cohort of patients, 52.5% received Cypher stents and the balance were stented with Taxus. Six-month outcomes are generally favorable, with an overall rate of documented stent thrombosis of about 1% and a target lesion revascularization rate of about 2.5%. In addition, Cohen noted that pre-procedure troponin elevation is “quote common and it is independently associated with ischemic complications,” about doubling the risk. Also, death rates were 1.6% and myocardial infarction rates averaged 9.4%.

In reviewing the registry findings to date, James Margolis, MD, of the Miami Heart Institute (Miami Beach, Florida), noted his concern with those latter figures. He said that although the procedure has grown to be easy and accepted, he noted that “we have not solved all the problems associated with PCI [percutaneous coronary intervention]. We can still do better, and we have a long, long way to go.”

Stenting compared to other treatments

data from the LE MANS (Left Main Stenting) study, presented during a late-breaking clinical trials session, showed that left ventricular ejection fraction was significantly improved in patients treated with PCI compared to those who underwent bypass surgery, meeting the trial’s primary endpoint.

“Left main stenting is a valuable method of treatment in patients with left main disease,” said Pawel Buszman, MD, of the Upper Silesian Heart Center (Katowice, Poland). That conclusion was echoed by Antonio Colombo, MD, of San Raffaele Hospital (Milan, Italy), who said the results “bring out some important points,” although he added that many surgeons might question such an approach. But he added that a larger randomized trial could further elucidate these findings.

Secondary endpoints demonstrated better safety outcomes among stented patients a month after the procedure, as well as equivalent safety rates a year later. The study’s randomized cohort included 52 stented patients and 53 who had surgery. “This is the first trial showing similar long-term MACE in PCI and CABG,” Buszman said.

The study was sponsored by a grant from the Polish Ministry of Science and Informatics.

Data from another late-breaking trial, Senior PAMI (formally known as A Prospective Randomized Trial of Primary Angioplasty Versus Thrombolytic Therapy for Acute Myocardial Infarction in the Elderly), showed primary angioplasty to be superior to thrombolytic therapy in patients between 70 and 80 years old at reducing combined death, disabling stroke and reinfarction.

The findings, reported by Cindy Grines, MD, of William Beaumont Hospital (Royal Oak, Michigan), also pointed to other advantages of angioplasty in reducing intracranial bleeding and lowering reinfarction and recurrent ischemia. In fact, she noted that “the biggest benefit of angioplasty appeared in the ischemic endpoints.”

However, the study did not meet its primary endpoint in reducing 30-day death or disabling strokes, a result perhaps brought on by the inclusion of patients older than 80, whom Grines said fare poorly regardless of reperfusion strategy.

The randomized trial included 352 patients between 70 and 80, and 131 older than 80.

The study was funded by grants from Guidant (Indianapolis), Eli Lilly and Co. (also Indianapolis), Boston Scientific (Natick, Massachusetts) and Cordis (Miami Lakes, Florida).

Clinical data presented in another session showed that percutaneous coronary intervention isn’t necessarily the best treatment paradigm for many diabetics. “There’s no doubt that bypass surgery is superior” to stenting in diabetics, said Bernard Gersh, MD, of the Mayo Clinic (Rochester, Minnesota). He noted that especially in the short term, coronary artery bypasses prove more effective as the surgical procedure is more comprehensive. In particular, he said that replacing a vessel not only removes a target lesion but also nearby areas that would be of worry down the road. Stenting, on the other hand, addresses only a target lesion and ignores other areas of future concern.

“The vascular biology of diabetes is such that it would favor surgery,” Gersh said. Specifically, he later added that “diabetics with diffuse and severe disease should be sent to surgery.”

Other stenting studies

• Axxess Plus, a study that looked at a bifurcation stent of the same name from Devax (Irvine, California), showed that incorporating the drug biolumis into the device reduces late loss by 75%. More specifically, late loss with the drug-eluting product was 0.11 mm compared to 0.46 mm with the bare-metal stent. Also, in-stent restenosis in the parent vessel was 5.6%, and it represented the first multicenter trial to find a restenosis rate of less than 10% in stented side branches, said Eberhard Grube, MD, of Heart Center Siegburg (Siegburg, Germany). At 30 days, there was a 0% rate of target vessel revascularization, which grew to 7.5% after 210 days of follow-up. Also, the 30-day rate of major adverse cardiac events was 5%, which nearly doubled to 9% at 210 days.

• The JUPITER II study failed to demonstrate the benefit of using a tacrolimus-eluting stent, the Janus Carbostent from Sorin Group (Milan, Italy), compared to the company’s bare-metal, carbon-coated Tecnic stent in treating patients with coronary artery disease. The Janus Carbostent uses a non-polymeric drug elution technology designed to precisely elute the drug tacrolimus only toward the targeted vessel wall where it is needed.

Specifically, use of the Janus stent resulted in a 0.40 mm in segment late lumen loss at six months, hardly better than the 0.45 mm generated by the Tecnic stent. Still, principal investigator Marie-Claude Morice, MD, head of cardiology at the Institut Cardiovasculaire Paris Sud (Massey, France), said the program should not be abandoned given tacrolimus’ selectivity to smooth muscle cells. “There is still work to do,” she said, adding that perhaps a better outcome would be seen in higher-risk patients.

At the EuroPCR meeting in Paris last May, Morice, principal investigator for the trial, reported interim results that she said provided a “strong indication” of an excellent clinical efficacy and a good safety profile for the Janus stent.

• A randomized study showed that a polymer-free rapamycin stent’s anti-restenotic effect is not inferior to Boston Sci’s Taxus Express2, a polymer-based product. The trial, called ISAR-TEST, stemmed from concerns associated with the use of polymers such as chronic inflammatory reactions, delayed and incomplete re-endothelialization, late stent thrombosis and restenosis.

Adnan Kastrati, MD, of the University of Munich (Munich, Germany), reported that there were no major differences of late lumen loss between the experimental polymer-free stent and Taxus. Such data were consistent for in stent and in segment late lumen loss. “The findings of this study represent the first successful non-polymer approach to drug-eluting stent technology in interventional cardiology,” he said.

The ISAR-TEST trial included 450 patients, split evenly into two arms.

• The SISR trial showed the Cordis Cypher stent to be “vastly superior” to intravascular brachytherapy in treating in-stent restenosis, said David Holmes, PhD, of the Mayo Clinic (Rochester, Minnesota).

The randomized study met its primary endpoint that measured target vessel failure at nine months. Among the 259 patients in the Cypher arm, that rate was 12.4% compared to 21.6% in 125 brachytherapy patients. Also, there was less late loss in the Cypher group, and Holmes concluded that since drug-eluting stents continue to prove that they lead to better clinical outcomes in this setting, brachytherapy would become “past tense.”