The past three to four years have been marked by stent frenzy. The frenzy has passed. Now comes stent "mania." That is clearly the future prospect for drug-eluting stent (DES) technology and the resultant proliferation of research in this arena, according to Martin Leon, MD, speaking to a nearly full auditorium of attendees during the American Heart Association (Dallas) scientific sessions in November. Leon, chairman of the Cardiovascular Research Foundation (New York) and perhaps the leading voice backing development of DES technology in the U.S., described this new wave of drug/device combinations as essentially "disruptive" in nature and, as a result, set to lead "an emerging biotech revolution."

With commercialization and broad use of two drug-eluting stent products in the U.S., any "fear factor" concerning their use has now faded, with the result, he said, that the market will be seeing their "more liberal use" and their use in "higher-risk scenarios." This will come with a growing tsunami of new clinical trials and registries and a "telescoped effort in multi-disciplinary research" focused on DES, he said. That statement was borne out at the AHA meeting, with several dozen studies either totally focused on comparing DES devices with one another, or with one another against bare-metal stents, or the use of DES devices in conjunction with other therapies.

Leon gave a sprint-style overview of the range of current studies, all demonstrating the superiority of DES to bare-metal stents in reducing restenosis, but he referred also to the reports of occasional acute thrombosis in these trials. Although indicating no significantly greater level of thrombosis for DES devices than bare metal stents, the frequency of occurrence beyond the current short-term studies has yet to be determined, and Leon said clinicians "must be cautious" in application of the technology. Thrombosis, he said, "has raised itself as an issue that needs to be sorted out," and he encouraged the view that, for the DES sector in general, "safety is more important than anti-restenosis efficacy."

Leon said that the wealth of future studies will be extremely diverse, focusing on a variety of patient populations and conditions, including increased DES applications in diabetes, in treating what he termed "diffuse disease" and long coronary lesions, in addressing "the problem of in-stent restenosis" and in treating "left main disease." Additionally, he pointed to the variety of studies that will involve analysis of the three main components of DES technology: the stent, the drug and the delivery system and the varieties of each likely to emerge. On the horizon also are a variety of new biologics and cell technologies that will be combined with stents. All of these variables, he said, will produce "a dizzying amount of data."

Leon's introductory comments were followed by presentations of six reports on DES devices, with five providing conclusions, all favorable to their use:

ENDEAVOR I studied 100 patients with symptomatic ischemic heart disease due to lesions of native coronary arteries, treated with the Medtronic (Minneapolis) Endeavor stent system at eight centers. Conclusion: At one year, binary restenosis was 3.3% compared with 2.1% at four months, indicating "sustained clinical effectiveness and minimal change in vessel dimensions" as well as safety.

Rapamycin and paclitaxel-eluting stents were compared in treating 596 lesions in 453 patients, those lesions indicating a high risk for restenosis. Conclusion: Both kinds of devices provide "similar safety profiles for complex coronary lesions ... [and both] seem to be similarly efficient for longer-term outcome."

A study compared the Cordis (Miami Lakes, Florida) Cypher sirolimus-eluting stent with the Boston Scientific (Natick, Massachusets) Taxus paclitaxel-eluting stent. Conclusion: Both demonstrated safety and effectiveness and no differences were found "with respect to procedural outcome and clinical events up to 30 days." The study will be followed up with "extended angiographic" data.

Sirolimus-eluting stent use was compared to intracoronary brachytherapy, with random assignment to 106 patients. Conclusion: sirolimus-eluting implantation "may be more effective in achieving greater lumen gain and reducing neointimal hyperplasia than brachytherapy for treatment of diffuse IRS [in-stent restenosis]."

A study compared the effects of percutaneous coronary intervention with drug-eluting stents vs. MIDCAB [minimally invasive direct coronary artery bypass] in patients with isolated left anterior descending coronary artery stenosis. Conclusions: "DES implantation and MIDCAB surgery showed similar rates of myocardial infarction, the need for repeated revascularization, and death during six months of follow-up. Lower average number of stays with similar postoperative complications in DES implantation seems more attractive to patients who need to undergo proximal LAD [left anterior descendant] revascularization procedures."

The SPIRIT FIRST trial assessed the feasibility and performance of the Guidant (Indianapolis) Multi-Link Vision everolimus-eluting coronary stent system in treating patients with de novo coronary artery lesions in 60 patients randomized to the Multi-Link ES vs. an uncoated Multi-Link

Some pure research reported at AHA points, as indicated by Leon, to some of the future directions for new drug/stent biologic/stent intersections:

A stent-based gene transfer approach explored the theory that successful gene transfer to the arterial wall can be achieved by covalent attachment of adenoviruses (Ad) to bare-metal stents via a cleavable synthetic linker, allowing for sustained release of functional Ad. Feasibility of the approach was concluded.

Korean researchers reported development of a curcumin-coated stent with applications. They concluded that curcumin, a natural compound in human diet, "can be one of the safest and best drugs for prevention of restenosis."

Eptifibatide, a glycoprotein thought to inhibit smooth muscle cell development, was studied with the results suggesting potential for stent-based delivery for this application.

A study evaluating the presence of nitric oxide (NO) produced by the endothelium suggests that NO levels may serve as an index of inflammation in evaluating the levels of restenosis produced by brachytherapy, bare-metal stents and sirolimus-eluting stents.

US-aided therapy improves effect of tPA

According to a study released by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH; Bethesda, Maryland), using ultrasound (US) in combination with the drug tissue plasminogen activator (tPA) can improve response to an ischemic stroke. The study, which involved 126 patients, is the first-of-its-kind human trial comparing the safety and efficacy of US/tPA vs. tPA alone, NIH said.

According to the NIH, previous studies have shown that tPA, when administered within three hours of onset of ischemic stroke, can greatly improve a patient's chance for a full recovery. Researchers wanted to test the effectiveness of using transcranial Doppler (TCD) US in combination with tPA, and to ensure that US did not cause bleeding into the brain. US measures blood flow velocity in large arteries.

Ultrasound also causes vibrations among the molecules on and within clot structures, which in turn creates more binding sites for tPA interaction and subsequent clot breakdown. The researchers believe that the vibration improves drug transport to and around the clot and helps to open more blocked vessels faster than can be expected with tPA therapy alone.

All study patients suffered an ischemic stroke and received intravenous tPA within three hours of stroke onset. The 63 patients in the control group received tPA alone, while the other 63 patients received tPA in combination with continuous TCD monitoring that started shortly before the patients received the drug. A small device attached to a head frame was used to deliver the US. Results showed that 49% of patients who received continuous US and tPA showed "dramatic" clinical improvement and little or no blockage within two hours after therapy began, compared to 30% who received tPA alone. Thirty-eight percent of the patients who received continuous US and tPA showed no blockage within two hours, compared to 13% who received tPA alone. In all, according to NIH, 73% of patients who received the combined therapy showed complete or partial clearance of the clot, compared to 50% in the control group.

Bleeding into the brain was experienced by 4.8% of patients in both groups. Researchers said the early improvement of blood flow to the brain resulted in a trend that 13.5% more patients who received continuous US/tPA had recovered completely by three months after their stroke. Study results also showed that patients who experienced complete clearance of their clot within two hours following treatment had the greatest likelihood of regaining body strength, speech, and other functions affected by stroke.

"In the past 30 years, scientists around the world have shown that ultrasound is fast, gentle, and effective in helping tPA to break up clots," Andrei Alexandrov, MD, associate professor of neurology at the University of Texas School of Medicine (Houston) and study director. "For the first time, we have demonstrated this benefit in patients. This approach enhances flow to the brain and augments clinical recovery within minutes of treatment initiation." The findings were published in the Nov. 18 issue of the New England Journal of Medicine.

NIH puts early stop to stroke study

The National Heart, Lung, and Blood Institute (NHLBI) of the NIH last month put an early stop to a clinical trial studying whether children with sickle cell anemia at high risk for stroke could at some point after a minimum of 30 months (range 30-91 months) safely stop receiving the periodic blood transfusions that prevent strokes. The study found a return to high risk of stroke in children who stopped receiving the transfusions. The NHLBI issued a clinical alert on the study, advising physicians that stopping transfusions cannot be recommended. The document urged them to carefully discuss with patients and their families the stroke prevention benefits of continuing periodic transfusions as well as the risks of these transfusions, which can include such long-term side effects as iron overload.

The results of the Stroke Prevention Trial II (STOP II) were presented as a "late-breaking" announcement at last month's annual meeting of the American Society of Hematology (ASH) in San Diego and posted the alert on the National Library of Medicine's Clinical Alert and Advisories web page. STOP II investigators were notifying patients enrolled in the study and their families.

STOP II, which began in 2000, expected to recruit 100 patients age 2 to 18 over 6 years. When the study was stopped two years early in November, 79 patients had been enrolled. At the time the study was halted, 14 of the 41 patients who had been randomly assigned to stop transfusions reverted to high risk of stroke as measured by a special ultrasound technique and two patients had suffered a stroke. There were no strokes or reversions to high stroke risk in the group that continued with transfusions.

"This important study shows the value of continuing periodic blood transfusions in preventing the serious and debilitating consequences of stroke," said NHLBI Acting Director Barbara Alving, MD. "At the same time, there are risks of chronic transfusions and the decision to continue with this treatment must be made on a case-by-case basis," she said.

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