Endeavor DES, Medtronic.

While the buzz surrounding bioabsorbable stents continues to build, there are new evolutions within drug-eluting stent (DES) technology that vendors say will soon (and already may) be available for the shelves of your cath lab

Boston Scientific
Following the Guidant acquisition, Boston Scientific had access to two pharmacological platforms—paclitaxel or everolimus. While Taxus Liberté uses paclitaxel, Promus has the same drug platform as Abbott’s Xience stent with everolimus; the new Taxus/Promus Element stents deliver paclitaxel and everolimus, respectively.

Besides the improved drug performance, the newer-generation stents also capitalize on improved platform design, according to Keith Dawkins, MD, associate chief medical officer at Boston Scientific. Geometrically, stent platforms have changed “to deliver the drug in a more uniform manner” and architecturally, “strut thickness has been reduced to cause fewer complications during the procedure,” Dawkins says.

In the fourth quarter, the company will release Taxus Element with paclitaxel and Promus Element with everolimus in Europe. These stents utilize a platinum chromium alloy, which helps them maintain “high radial strength and allow for good visualization,” Dawkins says. The PERSEUS trial, investigating Taxus Element, has completed enrollment and results will be presented at the 2010 ACC conference. The PLATINUM trial, assessing Promus Element, is currently enrolling patients.

Through its acquisition of Labcoat Limited in January, Boston Scientific can utilize a technology that coats DES with metered droplets of a bioerodable polymer. “A small dose of bioerodable drug is placed on the outside of the stent using inkjet technology, so we end up with a bare-metal stent [BMS],” Dawkins explains. The nine-month data of Labcoat’s JacTax stent (Taxus Liberté BMS coated with an abluminal biodegradable polymer containing paclitaxel), presented at the 2008 TCT conference, showed promise for restenosis and strut coverage.

“If we can return to a BMS state, we can reduce the chance of late stent thrombosis, while also reducing the requirement of long-term dual-antiplatelet therapy,” Dawkins says.
Boston Scientific is pursuing bioabsorbable stents through two avenues. The company acquired the BVS technology, along with Abbott, through the Guidant acquisition. Since then, however, both companies have pursued different paths, resulting in independent platforms. Through its 2004 acquisition of REVA Medical, Boston Scientific is developing balloon-expandable, bioresorbable DES that combine geometric and bioabsorbable polymer properties. However, Dawkins acknowledges that the pursuit of bioabsorbable stents will clinically follow Taxus Element and Labcoat technologies.

Medtronic
Cy Wilcox, PhD, vice president of science and technology for Medtronic’s cardiovascular division, says that the Endeavor zotarolimus-eluting stent uses phosphorylcholine (PC) as a binder to hold the drug onto the stent, not as a drug delivery polymer. The drug layer of the Endeavor stent is 90 percent zotarolimus and 10 percent PC; with full drug elution, this layer disappears, leaving behind only a 1-micron PC base coat. Also, zotarolimus was developed for use on a DES.

“The BioLinx polymer system used in our Resolute zotarolimus-eluting stent is a blend of three polymers: the drug is mixed with two hydrophilic polymers and one hydrophobic polymer, and sprayed as a uniform layer onto the stent,” Wilcox says. “With the BioLinx polymer system, we are able to present a hydrophilic outer surface to the body, which provides biocompatibility, but retain a hydrophobic core, to enable us to control drug delivery over longer periods of time,” he says. Some studies have shown the BioLinx polymer results in low inflammatory scores.

The Resolute DES system, which is available in about 100 countries outside the U.S., utilizes BioLinx and the Driver BMS platform. “The only difference between Endeavor and Resolute is the polymer on top of the stent—with Endeavor, there is a 1-micron PC basecoat with a 4.3-micron polymer-drug layer; with Resolute, there is a 1.4-micron parylene basecoat with a 4.2-micron coat of the drug mixed with the BioLinx polymer,” Wilcox says. At the 2008 TCT meeting, the first clinical study of the stent, the original RESOLUTE trial, showed a 1.5 percent rate of target lesion revascularization and no instances of stent thrombosis in 130 patients at two years. The broader RESOLUTE clinical program will enroll more than 6,000 patients.

Cordis
Cordis’ Nevo investigational stent features a cobalt chromium stent, designed for deliverability, and sirolimus, which is also on the Cypher stent, according to Campbell Rogers, MD, chief scientific officer and global head of R&D at Cordis. Nevo also uses a bioerodable polymer, which is designed to completely erode after three to four months, leaving a BMS. Through Cordis’ 2007 acquisition of Conor Medsystems’ reservoir technology, the delivery of the drug sirolimus with Nevo does not emanate from the surface, but rather through reservoirs from within the stent.

Rogers says that the Nevo reservoir design enables a focused drug delivery, and limits the polymer’s exposure to the vessel wall. “Also, any potential damage to the polymer for surface-coated devices is now alleviated,” he says. The Nevo surface is 75 percent bare upon insertion. The six-month data of NEVO RES I, a device-oriented, randomized study, comparing Nevo to Taxus Liberté with a surrogate endpoint of in-stent loss, was presented at the 2009 EuroPCR. The trial results: in-stent loss of 0.13 mm for Nevo, compared to 0.36 mm for Taxus Liberté; 99.5 percent device success; 97.5 percent procedural success; and a strong trend for a lower stent thrombosis rate with Nevo. The study involved 394 patients.

Cordis’ Cypher Select Plus, which is available for sale outside the U.S., has a similar coating and drug dose as the original Cypher stent, but the platform and delivery system have been altered to enhance deliverability, especially for complex lesions, according to Rogers. 

The e-SELECT Registry, evaluating 13,514 Cypher Select Plus patients in 320 centers, presented strong safety data at six months at the 2009 EuroPCR conference. There were 75 cases of definite stent thrombosis and 12 cases of probable stent thrombosis. Of all the stent thrombosis cases, 70 percent occurred in the first four weeks after implantation. However, any deviation from dual-antiplatelet therapy was associated with a marked increase in the risk of stent thrombosis at 30 and 180 days.    

Abbott Vascular
Xience V’s design is based on the Vision cobalt chromium alloy BMS, which has thinner struts and the Multi-link geometric design. “By thinning the struts and employing a thinner polymer layer, along with having a lower drug dose, we allow the vessel to heal around the stent, which could potentially result in lower adverse events, such as stent thrombosis and MI,” says Charles Simonton, MD, chief medical officer at Abbott Vascular.

Also in the pipeline for Abbott is the Xience Prime everolimus DES, which utilizes the same drug and polymer as Xience V, and is based upon the design of the Multi-link family. However, Xience Prime is “modified, with the balloon system being crimped, and the design is slightly altered to allow for improved deliverability,” Simonton explains. The company plans to launch Xience Prime in Europe later this year after receiving CE Mark in June.

The newer bioabsorbable everolimus stent design mirrors the Multi-link design, but is made of polylactic acid. The polymer has two layers—the drug-eluting, amorphous layer on the stent’s surface, which dissolves over three months. It leaves behind a crystalline layer of polymer that forms the skeleton of the stent, which then dissolves over the course of 18 to 24 months.

The two-year ABSORB data of Abbott’s bioabsorbable stent, presented at the 2008 TCT conference, revealed that the vessel lumen had enlarged in the 30 patients with single coronary artery lesions. There were no cardiac deaths, retreatment of diseased lesions or stent thrombosis reported. Abbott hopes to release its 30-day data from the second phase of ABSORB, involving 80 patients, by year’s end. Simonton speculates that if the trials continue to produce positive results, the European regulatory process could begin as early as 2012.

Expanding Indications for DES

In February, Cordis’ Cypher Select Plus stent received EU approval for patients with diabetes, chronic total occlusion, multivessel disease and bifurcations. While Cypher Select Plus was previously indicated for de novo lesions, in-stent restenosis and small vessels, it received CE marking for acute MI (AMI) in August 2008. Medtronic’s Endeavor DES recently received CE Mark for treating patients with acute coronary syndrome, including unstable angina and AMI, as a result of the E-Five study. Its new indications also include patients with diabetes. Separately, the company is investigating a shorter dual-antiplatelet therapy duration for Endeavor patients, based on the results of the DATE Registry presented at EuroPCR. A second investigator-sponsored trial in Brazil, OPTIMIZE, is underway which will randomize 3,200 patients to three or 12 months of aspirin and clopidogrel following Endeavor implantation. Abbott is studying Xience Nano (2.25 mm diameter) for small vessels in the SPIRIT Small Vessel trial. The company also will be examining data from the SPIRIT IV trial to determine the effectiveness of Xience V in more complex populations, including those with multi-vessel disease and diabetes. Plans are in the works to develop Xience Prime SV for small vessels, and Xience Prime LL for long lesions with lengths up to 38 mm. The Xience Prime received CE Mark in June. Boston Scientific is pursuing labeling specific for AMI for its Taxus DES and is exploring DES usage in patients with left main and multi-vessel disease. The company recently gained FDA approval for the Taxus Liberté Atom for vessels as small as 2.25 mm in diameter, and its Taxus Liberté long stent (38 mm) is currently under FDA review.