CD&D Contributing Editor

CHICAGO — Growth in the cardiovascular device market has slowed recently as safety issues with first-generation drug-eluting stents (DES) have combined with controversy re-garding the benefits of interventional therapy, compared to medical treatment, to drive decreased utilization. The greatest decrease in utilization was in the U.S., where uptake was initially most rapid, suggesting a rebound effect from the early enthusiasm for the technology.

More recently the market has shown some signs of recovery, fueled by reports contradicting the early studies that had raised safety issues, new guidelines emphasizing more care in selection of patients and a greater emphasis on compliance with follow-on anti-platelet therapy.

But the projections for long-term growth remain conservative. With the approval earlier this year of one second-generation DES product — the Endeavor from Medtronic (Minneapolis) — and other second-generation DES devices poised for roll-out, safety concerns are expected to be reduced even further. But the entrance of new competitors has the potential for raising the prospect of pricing pressures that will constrain market expansion even if utilization increases.

Discussion of these issues and reports concerning the current, new and on-the-horizon DES technologies was a large focus of this year's 57th Scientific Session of the American College of Cardiology (Washington), in company statements, clinical presentations and hallway conversations. Additionally, because of the problems that possibly may be embedded in the stenting strategy itself, conference presentations also featured a range of tantalizing alternative methods for opening clogged arteries with a potential concomitant reduction in adverse events.

DES declines largest in U.S.

Gregory Miskkel, MD, of Prairie Medical Center (Springfield, Illinois), related the experience at his institution over the past two years, where DES use dropped from 98% of coronary stent procedures to 62% between January 2006 and January 2008. In Europe, the decline in DES use has been less dramatic, dipping from 55% to 46.2% of stent procedures from Q106 to Q407, according to Stephan Windecker, MD, of University Hospital (Bern, Switzerland), but safety concerns continue to limit DES use.

Overall, reports from the conference clearly contrasted with the early studies of DES which had emphasized the reductions in the need for follow-on redo procedures as the result of reclogging or restenosis. The more recent studies — at least in what is emphasized by presenters — tend to focus on the reduction of adverse events, primarily late stent thrombosis. Reports concerning these second-generation devices show promise for reducing thrombosis, with similar efficacy in prevention of restenosis.

Robbert De Winter, MD, of the Academic Medical Center (Amsterdam, the Netherlands), discussed the most recent results of clinical trials of the Genous stent under development by Orbus Neich (Wanchai, Hong Kong). The Genous employs a bioactive coating that binds circulating endothelial progenitor cells, creating a highly biocompatible surface that is designed to reduce stent thrombosis while minimizing neointimal proliferation.

A number of trials are on-going with the device, and in Europe a significant number of patients who have received Genous stent implants are now included in the e-HEALING registry. Results at one year from the e-HEALING registry show a stent thrombosis rate of 1%, comparable to the Cypher stent from Cordis/J&J (Miami Lakes, Florida/New Brunswick, New Jersey), and better than that for the Taxus stent from Boston Scientific (Natick, Massachusetts), according to De Winter. However, only one month of dual anti-platelet therapy is required with the Genous stent vs. a minimum of six months for Cypher.

That is potentially a significant advantage, since issues regarding long-term patient adherence to anti-platelet therapy comprise the No. 1 reason for use of a bare metal stent (BMS) rather than a DES. The Genous data do, however, indicate a somewhat higher restenosis rate compared to Cypher and Taxus, which Orbus Neich plans to address with the addition of sirolimus or a similar anti-proliferative drug to the stent.

Another promising stent was described at the ACC conference by Eberhard Grube, MD, of the Helios Heart Center (Seigburg, Germany).

The Excella DES, under development by Elixir Medical (Sunnyvale, California), employs a polymer coating which has a prior history of use in implantable devices and elution of Novolimus, an mTOR inhibitor macrocyclic lactone. The Excella features small-diameter struts to provide less inflammatory reaction and elutes a smaller amount of drug compared to the DES devices now on the market. It is also more flexible than the existing DES devices, in principle facilitating implantation in tortuous vessels.

A first-in-man trial of the device in 15 patients found a 0.3 mm late loss at nine months, slightly higher than the best rates observed with first-generation DES. Binary restenosis was 0%, and no stent thrombosis was observed. The company is proceeding with a larger randomized trial.

Thinner — offering more control?

Medlogics Device (Santa Rosa, California) is developing a new DES, based on its Synergy drug coating, an ultra-thin (<2 µm) coating technology designed to provide a more controllable, biodegradable layer on a stent for drug elution. This coating strategy is designed to provide more precise rate of drug elution, and to be resistant to peeling and cracking following implantation.

The stent will be based on Medlogics' Cobra BMS platform, which features struts with a thickness of 71 µm, thinner than the struts of the MultiLink Vision stent from Abbott Vascular (Santa Clara, California) or the Driver stent from Medtronic. The Cobra BMS received CE-marking this past February and was released to the market in Europe.

Results of initial studies with another promising new DES, the VESTAsync stent from MIV Therapeutics (MIVT; Vancouver, British Columbia), were presented at the ACC sessions by Jose Costa, MD, of the Institute Danta Pazzanesse (Sao Paulo, Brazil).

The VESTAsync employs a polymer-free hydroxyapatite nanoporous surface coating combined with sirolimus encapsulated in lipid micelles for drug delivery. The VESTAsync also uses the MIV GenX Thin Strut stent platform, resulting in significantly thinner struts (66 microns) compared to the newest DES devices, such as the Xience V from Abbott Vascular and the Endeavor from Medtronic (89 microns and 96 microns respectively).

At nine month follow-up, late loss in a cohort of 11 patients implanted with the VESTAsync was 0.37 mm, and no late thrombosis or major adverse coronary events were reported.

The next DES likely to enter the market in the U.S., joining the Cypher, Taxus and Endeavor stents, is the Xience V from Abbott Vascular. Xience V already has been launched outside the U.S.

The most recent clinical trial results for the XIENCE V were reported at the sessions by Patrick Serruys, MD of Thoraxcenter (Rotterdam, The Netherlands), who described two year data from the SPIRIT II trial.

Key results from that trial include a 0.9% rate of stent thrombosis, vs. a 1.4% rate for Taxus. Late stent thrombosis was 0.9% for Xience V, vs. 0% for Taxus in the trial. Target lesion revascularization was reduced by 44% for Xience V vs. Taxus, at 3.8% for Xience vs. 6.8% for Taxus. In-stent and in-segment restenosis were not significantly different at two years (2.1% vs. 2.9% in-stent, and 5.2% vs. 8.6% in-segment for Xience V vs. Taxus respectively); however, a late catch-up phenomenon is evident since the restenosis rates were more strongly in favor of Xience V at one year.

In a commentary on the Serruys presentation, David Cohen, MD, of Saint Luke's Mid America Heart Institute (Kansas City, Missouri), noted that restenosis rates do not show a major increase between the first and second year of follow-up for Cypher and Taxus, and that BMS devices generally exhibit a late gain (regression of stenosis) over that interval.

Cohen also said, however, that there was no excessive number of late adverse events associated with the catch-up phenomenon for Xience V, a trend that remains unexplained.

Alternative strategy: drug-eluting balloon

A number of additional technologies for reducing restenosis while avoiding thrombosis and the other adverse effects such as hypersensitivity reactions associated with first-generation DES devices were described at the ACC sessions.

One approach eliminates the use of a stent for drug delivery by loading the drug onto the exterior surface of an angioplasty balloon. The Paccocath is a drug-eluting balloon catheter that has been used in peripheral angioplasty and for treatment of in-stent restenosis.

The theory this relies on is that the delivery of an anti-restenosis drug from a balloon provides a more homogeneous distribution of drug compared to stent-based delivery.

A next-generation version of the Paccocath is being developed that employs the Sequent balloon catheter from B Braun Medical (Melsungen, Germany), coated with paclitaxel. The device has been evaluated with good results in the PEPCAD1 SVD trial, with a target lesion revascularization rate of 4.9%.

Results of the PEPCAD II ISR trial were presented at the conference by Martin Unverdorben, MD, PhD, of the University of Frankfurt (Frankfurt/Main, Germany). The trial assessed treatment of in-stent restenosis in BMS devices and compared treatment with the SeQuent Please paclitaxel-eluting balloon catheter versus treatment with the Taxus.

A highly significant difference in late lumen loss and in target lesion revascularization was observed at six-month follow-up. Late loss was 0.2 mm vs. 0.45 mm for the drug-eluting balloon compared to Taxus in the intention-to-treat analysis, and the respective target lesion revascularization rates were 3.1% vs. 16.7% based on treatment received.

As discussed by Bruno Scheller, MD, of the Universitätsklinikum des Saarlandes (Homborg/Saar, Germany) at the sessions, the PEPCAD III trial will follow with an evaluation of a B Braun Coroflex Blue stent mounted on the drug-eluting balloon, which will protect against vessel recoil after balloon angioplasty and will also avoid issues with geographic miss if a bare metal stent is placed in a separate procedure.

The drug-eluting balloon has the advantage of avoiding a permanent implant with the associated risk of long-term adverse tissue responses as can occur with present-generation DES devices.

Concerns regarding drug-eluting balloons have centered on the lack of controlled long-term delivery of the drug to the tissue, as is achieved using drug-eluting stents.

However, based on the results of the PEPCAD trial, the drug-eluting balloon is effective in preventing restenosis with its drug delivery profile, at least in the treatment of in-stent restenosis.

The benefit compared to DES devices such as TAXUS, however, may be less than indicated by the trial results, since the target lesion revascularization rate for TAXUS in PEPCAD II ISR was considerably higher than would be expected based on other TAXUS trial data.

Alternative strategy: a 'protective' stent

Other technologies for improving outcomes in cardiovascular interventional procedures include the MGuard protective stent from InSpire MD (Tel Aviv, Israel) and thrombus aspiration using the Export catheter from Medtronic, as shown in the Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction (TAPAS) trial.

In the TAPAS study, as described at the sessions by Felix Zijlstra, MD, of the University Medical Center (Groningen, The Netherlands), thrombus aspiration in patients with ST-segment elevation myocardial infarction (STEMI) in a 1,071-patient randomized trial resulted in a significant reduction in blush grade, as well as a halving of the 1-year mortality rate, from 7.9% to 4.2%, for patients in the aspiration group.

Trial data showed that 49% of the patients in the aspiration group had thrombus present as detected by angiography, indicating benefit for aspiration in STEMI patients even when thrombus was not visible.

The trial, however, was not powered to prove a difference in mortality, but rather to demonstrate improvement in blush grade, prompting Zijlstra to comment that some physicians may want to see results from a much larger trial before changing practice patterns.

Conventional practice prior to the results of the TAPAS trial has been to only use thrombus aspiration or thrombectomy if a large clot is visible, and in fact results of some studies such as the AIMI trial which used the AngioJet rheolytic thrombectomy system from Possis Medical (Minneapolis) for thrombus removal in STEMI patients have shown an increase in infarct size for patients treated with thrombectomy.

One possible explanation for the difference in outcome in the TAPAS trial may be that direct stenting was used in the aspiration group, but not in the control group.

Nevertheless, Zijlstra believes that the TAPAS results provide sufficient evidence to justify routine use of thrombus aspiration in STEMI patients prior to stenting, particularly since the aspiration procedure is relatively easy to perform and inexpensive. The Export catheter has been used in over 150,000 patients worldwide since its introduction, and has a list price of $695 in the U.S.

Inspire MD's MGuard stent, which is available under a CE mark in Europe, is designed to address another issue in stenting of high-risk patients, that of embolization when treating vessels such as saphenous vein grafts.

The MGuard is a stainless steel stent with a polymeric (poly ethylene terephthalate) mesh covering designed to block release of plaque from the vessel wall during and after an interventional procedure, while still allowing migration of endothelial cells through the mesh to enable formation of a biocompatible luminal surface.

Initial results with the device have been encouraging, with a 0.3 mm late loss reported and no major adverse coronary events at 30-day follow-up of patients receiving implants in degenerated vein grafts and native coronary arteries.

The MGuard is a balloon-expandable stent designed to expand first at the ends of the stent to ensure that debris is trapped. The mesh is formed using a knitting process. Inspire MD believes the mesh can also be used as a platform for drug delivery, providing more uniform coverage of the vessel wall and more efficient drug delivery compared to existing drug-eluting stents, perhaps enabling lower doses of drug to be employed.

The company is also developing a carotid stent that will employ nitinol for the metal framework along with the protective mesh. That device is now in animal studies.