At this writing, three patients remained alive and supported on the AbioCor totally implanted heart, made by Abiomed (Danvers, Massachusetts), as part of the company's FDA-approved five-patient clinical trial of the device. Shortly before this issue of Cardiovascular Device Update went to press, the trial recorded its second death on Dec. 13 – the fourth person overall to be implanted – at UCLA Medical Center (Los Angeles, California). Though not identified by name, that patient was described as a 74-year-old male, and the UCLA implant team of Dr. Hillel Laks, Dr. Daniel Marelli and Dr. Jaime Moriguchi, said that he succumbed, not because of any problem with the AbioCor, but because of "multiple organ failure."

Implanted with the AbioCor on Oct. 17, this fourth implanted patient lived 56 days on the AbioCor, and succumbed just days after the death of Robert Tools, the first person in the trial implanted at Jewish Hospital (Louisville, Kentucky) on July 2 and supported by the heart for 150 days. Those 56 days of life for the unnamed patient at UCLA came close to the clinical trial endpoint of two months that Abiomed unofficially has said indicates success of the AbioCor, and the 150 days of life on the heart for Tools was considered a clear positive by analysts covering this device sector.

Greg Simpson, analyst for A.G. Edwards (St. Louis, Missouri), emphasized the human side of the Abiomed trial offered by Tools, who had become somewhat of a media personality, oft-interviewed on TV. Tools, Simpson told CDU, "put a face and a personality" to the clinical trial, a fact that made his death difficult to accept as a positive. But Simpson added that "in strict clinical terms," those additional months of life for Tools added up to "clearly, absolutely, a great success." Echoing that assessment, Kurt Kruger of Banc of America Securities (San Francisco, California) put Tools' death "more in the 'expected event' category," noting that the AbioCor had worked well.

Besides the two deaths in the first clinical trial, the first patient in a second five-patient trial died during heart implantation Nov. 28 at St. Luke's Episcopal Hospital (Houston, Texas), with the surgical team from the Texas Heart Institute (also Houston), saying that the patient most likely succumbed to the effects of anticoagulation medication, not the failure of the artificial heart. In all three cases, the deaths were attributed to the debilitated condition of the patients going into the trials rather than any malfunction on the part of the AbioCor. Thus, the very poor condition of those patients offers a case of the proverbial double-edged sword: While it undoubtedly will serve to reduce the amount of additional time each patient may have on the AbioCor device, it is a basic requirement for receiving the heart. In reacting to the death at the UCLA Medical Center, Dr. David Lederman, chief executive officer of Abiomed, issued a statement underlining a key criteria for patient inclusion: "That patients have biventricular heart failure with no viable treatment alternative and a high probability of death within 30 days."

Lederman added, "All of us have known from the start that our initial clinical trial patients would of necessity be near death and extraordinarily fragile, and that we would face a broad range of clinical challenges." But each patient in the trial, he said, "provides us with new information that will potentially contribute to the saving of thousands of lives in the not-too-distant future." Additionally, he expressed continued confidence in the AbioCor, saying that it "will prove to be a replacement heart that can provide both significant life extension and good quality of life for heart failure patients who would otherwise have no hope."

While restating the company's position of issuing limited information about the trial, Abiomed reported that the other three patients in the trial "remain alive and [are] recovering well with no meaningful clinical problems." At the time of that statement, they had been supported on the heart for 91, 77, and 37 days respectively.

Two face coated-stent setbacks

While prospects for the drug-coated stent sector appear fairly rosy, some questions have been raised in that arena for Boston Scientific (Natick, Massachusetts) and Johnson & Johnson (J&J; New Brunswick, New Jersey), according to an investor report released last month. Kevin Kotler, an analyst for investment bank ABN Amro (New York), said in early December that some clinician sources have indicated several cases of a "candy wrapper effect," also called an edge effect, in that company's drug-eluting Cypher stent used for treating in-stent restenosis. As the name implies, this is a condition in which restenosis occurs on the edges of a stent, not within it. Kotler said the problems surfaced in a 40-patient uncontrolled clinical trial investigating the treatment of in-stent restenosis with the Cypher and that this same effect was observed during radiation trials.

The possibility of an edge effect had been discussed by Nicholas Chronos, MD, director of the Atlanta Cardiovascular Research Institute (Atlanta, Georgia) at the American Heart Association's (AHA; Dallas, Texas) scientific sessions in Anaheim, California, in November. During a presentation at AHA on the pharmacology of the various stent contenders, Chronos also noted the disturbing similarities between radiated stents and their coated cousins. There is, he observed, an associated thrombotic response. And in regards to the preclinical evaluation presented thus far with drug-eluting stents, he said, "there is still a lot of work to do." He also cautioned that at this time, there is still a strong potential for a negative shift in the data.

Cordis (Miami Lakes, Florida), the J&J affiliate that makes the Cypher stent, has thus far reported positive results on the device. In the RAVEL – for RAndomized Study with the Sirolimus-eluting VELocity Balloon Expandable Stent – trial, the company reported zero restenosis after placement of the device in patients with coronary artery disease. Sirolimus, the active drug released from the stent, is a naturally occurring antibiotic marketed under the name Rapimune. The drug is used to prevent renal transplant rejection and prevents cell replication rather than killing cells (cytostatic rather than cytotoxic).

Cordis spokesperson John McKeegan said that his company has not observed the problems cited by Kotler. He said that researchers at the company had heard the rumors, "but they've looked at all the Inman data and there's nothing that supports any candy wrapper effect."

Edge effect findings could have implications for the entire drug-coated stent sector. While acknowledging that additional data needs to be collected studying the edges of these Cypher patients, ABN Amro's Kotler said that these reports raise the possibility that using Cypher or any other drug-coated stent "may require more research in the areas of dosing, placement, etc. than previously thought." He added in his report that if this problem persists, it might provide a broader opportunity for brachytherapy technologies treating in-stent restenosis, currently offered by Novoste (Norcross, Georgia) and Radiance Medical Systems (Irvine, California).

On a related front, Boston Scientific reported that it had been asked to answer some questions surrounding its October investigational device exemption filing for its TAXUS IV U.S. drug-coated stent trial. This setback will probably delay initiation of the trial from its planned start in December until this month or next. Boston Scientific said it expected to answer all of the FDA's questions fairly quickly, and the company has targeted the end of 2003 as the launch date for the device in the U.S.

Three other TAXUS clinical trials are under way overseas, mostly in Europe, that are designed to collect clinical information on the company's paclitaxel-eluting stent technology for reducing coronary restenosis. In the TAXUS II trial, the slow-release cohort enrollment was completed in October, and the moderate release cohort is slated for enrollment completion in January. The company said that six-month follow-up data is expected for both cohorts by mid-2002. TAXUS III completed enrollment in July, and six-month data will be presented the March annual meeting of the American College of Cardiology (Bethesda, Maryland) in Atlanta, Georgia. Boston Scientific made headlines in September when it reported zero restenosis and zero thrombosis rates in early results of the 61-patient TAXUS I trial.

While saying that the delay was not a major one for Boston Scientific, Kotler said that it puts the company in fourth place in the U.S. drug-coated stent race. He placed J&J in front, followed by the joint venture team of Guidant (Indianapolis, Indiana) and Cook (Bloomington, Indiana), with Cook's own program alone in third place. Lehman Brothers (New York) med-tech analyst David Gruber, MD, also said the delay would not make much of a difference. However, he cited regulatory uncertainty within the FDA approval process as a concern. And that applies "not only to Boston Scientific, but [also to] Guidant and Cook as well."