April 10, 2008

April 10, 2008 (Chicago, IL) - The good news from the GENESIS trial is that a closely watched but currently not marketed drug-eluting stent (DES) capable of delivering more than one drug at a time apparently works as intended [1]. The bad news is that the in-stent lesion recurrence rate with one of the drugs, which had been promising against restenosis in preclinical studies, was sky-high.

The trial compared three DES approaches for de novo coronary lesions using the Conor Medsystems cobalt-chromium stent, which is lined with hundreds of tiny reservoirs designed for the sustained release of one or more drug-polymer combinations. The Conor stent containing a full dose of pimecrolimus induced well over twice the restenosis response, as measured by angiography and other ways, compared with a Conor stent containing paclitaxel. A third one containing a half dose of pimecrolimus and a full dose of paclitaxel consistently elicited responses measuring somewhere between the other two.

Designed as a noninferiority trial, GENESIS was terminated before reaching its planned enrollment as the poor outcomes in the pimecrolimus-only group--including an unexpected, nearly 40% six-month rate of major adverse cardiac events (MACE)--became evident, according to Dr Stefan Verheye (Antwerp Cardiovascular Institute, Belgium). With the reduced population size, none of the imaging or clinical differences reached statistical significance, observed Verheye, who presented the study's six-month outcomes here last week at the American College of Cardiology 57th Annual Scientific Session/i2 Summit-SCAI Annual Meeting.

One of the tested stents, the company's model containing paclitaxel, called the CoStar, had been available in Europe and was aiming for an FDA-approval decision when news of a poor performance against the Taxus (Boston Scientific) in the US COSTAR-2 trial came out last year. As reported at the time by heartwire , the CoStar was then pulled from cath-lab shelves everywhere by Johnson & Johnson (J&J), whose purchase of Conor had been completed the previous January. The company said it was making plans to refurbish, refit, and reintroduce the stent with other drugs and with drug combinations.

Later in 2007, as heartwire also reported, the CoStar was seen to improve angiographic and clinical outcomes compared with a bare Conor stent in the EUROSTAR-2 trial. Those results, along with a common perception that the stent's unique drug-delivery features and the potential for multiple-drug release made a lot of sense, left some in the interventional community lamenting its departure.

"I've used this device. I think it’s a good device. I think it's very odd that it disappeared from the industry landscape for commercial reasons," said Dr Anthony H Gershlick (University Hospitals of Leicester, UK), the featured discussant for Verheye's presentation of GENESIS. "The stent is and was a good concept," he said, adding that despite the trial's negative outcome, stent delivery of multiple drugs in PCI should move forward.

Verheye characterized GENESIS as a demonstration that the idea works. "The GENESIS trial is the first to use Conor reservoir technology to enable dual drug delivery for the treatment of de novo coronary lesions," he said. "Clearly, the trial demonstrates the ability to deliver two drugs independently, with each drug having an effect on the tissue response to coronary interventions." Pimecrolimus apparently isn't a good choice for restenosis prevention in humans, he observed, but "the reservoir platform shows safety and feasibility in delivering two different drugs with different release kinetics."

The Conor stent's purported advantages, in addition to the reservoirs designed for more controlled and sustained drug delivery than occurs with conventional coated DES, include less polymer contact with the vessel wall, Verheye said. Polymer-wall interactions may promote complications with DES and are a recently appreciated Achilles' heel of the technology.

Pimecrolimus, which Conor licensed from Novartis prior to the J&J acquisition, had been combined with paclitaxel in GENESIS based on theoretically complementary pharmacokinetics and cellular actions as well as a promising performance in animal studies, Verheye observed. It works in vessels primarily as an anti-inflammatory, not as an antiproliferative, and so was thought not to disrupt stent endothelialization.

However, lesion recurrence rates with pimecrolimus alone were so high that the drug seemed almost to cause restenosis rather than prevent it. Late loss at six months was almost 2.5 times as extensive as what was seen with the paclitaxel-only stent. The mean severity of restenosis with pimecrolimus, as gauged by percentage of luminal diameter, was nearly 50%.

Quantitative angiography outcomes at six months in GENESIS

In-stent parameter Paclitaxel, n=42 Paclitaxel+pimecrolimus, n=95 Pimecrolimus, n=93
Late loss* (mm) 0.58 0.96 1.40
Minimum lumen diameter (mm) 2.27 1.89 1.41
Percent-stenosis (%) 18.9 33.7 49.7

*Primary end point

GENESIS enrolled patients with single de novo coronary lesions <25 mm in length, with a reference-vessel diameter of 2.5 mm to 3.5 mm, at sites in the UK, Belgium, France, Germany, and Israel, with a planned target of 375 patients.

Patients were randomized in a 1:2:2 manner to be stented with the CoStar, which contained 10-µg paclitaxel; the Conor SymBio, which carried 162.5-µg pimecrolimus and 10 µg paclitaxel; or the Conor Corio, with 325-µg pimecrolimus. Patients received dual antiplatelet therapy for six months, Verheye reported.

Pre- and postprocedure quantitative angiographic findings were similar in the three groups, but after six months, from group to group as pimecrolimus involvement increased, there was a pattern of progressively less favorable in-lesion and in-stent restenosis as measured by late loss, minimum lumen diameter, percent-stenosis, binary restenosis rate, and intravascular ultrasound (IVUS) lesion measurements.

The 30-day MACE rate also seemed elevated in the pimecrolimus-only group: 6%, as compared with 1% in the dual-drug group and zero for the paclitaxel-only stent. And clinical outcomes at six months followed a similar pattern, the pimecrolimus-only stent's skyscraping MACE rate driven by a surplus of target-vessel revascularizations.

J&J recently announced the launch of an international trial called RES-ELUTION, which is randomizing a projected 380 patients to receive the Conor stent loaded with sirolimus vs the Taxus for de novo coronary lesions. The trial is sponsored by the megacompany's PCI-oriented subsidiaries, Conor and Cordis, the latter of which markets the Cypher sirolimus-based DES.

Intravascular ultrasound outcomes at six months in GENESIS

In-stent parameter Paclitaxel, n=16 (%) Paclitaxel+pimecrolimus, n=26 (%) Pimecrolimus, n=16 (%)
IVUS neointimal volume 16.6 27.1 41.2

Six-month clinical outcomes in GENESIS

Six-month outcomes Paclitaxel, n=49 (%) Paclitaxel+pimecrolimus, n=97 (%) Pimecrolimus, n=100 (%)
MACE 2.0* 14.4 39.0
TVR 2.0 14.4 35.0

*p<0.0001 for paclitaxel-only stent vs either pimecrolimus-containing stents
MACE=major adverse cardiac events; TVR=target-vessel revascularization

Neither Verheye nor Gershlick had industry relationships to disclose

  1. Verheye S. Safety and efficacy outcomes of dual pimecrolimus/paclitaxel drug delivery versus single drug delivery using Conor reservoir technology: GENESIS trial six-month results. American College of Cardiology 2008 Scientific Sessions/i2 Summit-SCAI Annual Meeting; March 31, 2008; Chicago, IL. Late-breaking clinical trials 3.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.



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