CDU Executive Editor

Some notes on the continuing clinical battles, with Cardica making a recommendation; WSJ creates a DES rumor; NEJM weighs in but with no definitive conclusions; overall impact, 2007 and beyond, still unknown.

The clinical trial stent wars continue — drug-eluting stents (DES) vs. their bare-metal (BMS) predecessors; Cypher vs. Taxus, Cordis vs. Boston Scientific — with considerable marketing sound and fury. And it’s not yet known what it will all signify, long-term.

But Bernard Hausen, president/CEO of cardiovascular device developer Cardica (Redwood City, California), says that one of the things the DES hubbub has done is to create a rather large clinical red herring. He says that it has diverted the focus from an important clinical issue in the heart disease sector that is of special importance to patients: the choice between stenting and bypass surgery and which, for some categories of patients, is the better option.

What he currenlty finds in the increasing questions concerning DES, and DES vs. BMS, is the opportunity to refocus attention on coronary artery bypass surgery (CABG) as a gold standard treatment. And Hausen, not suprisingly, tends to come down on the side of the surgical approach since Cardica is the developer of the C-Port xA Distal Anastomosis System, designed to enable more effective connection of blood vessels during CABG.

But in a recent interview with Cardiovascular Device Update, Hausen didn’t push CABG as a one-approach-cures-all solution. Rather, he offered a recommendation and a proposed plan for helping patients make a choice between the interventional and open procedures.

Disadvantages, yes, but big benefits also

Importantly, he didn’t downplay the off-putting details of CABG, usually described to patients as needing always to “crack” the chest.

CABG “has big cuts, it’s painful, much more of an intervention than stenting,” Hausen acknowledged. “It’s very easy to admit that it’s a much bigger procedure.”

However, he said that, despite these disadvantages, there has been a general “underestimating” and “under-reporting of the real world of CABG surgery.” As an example, he cited a half-dozen large databases showing a “survival benefit of CABG over PCI” (percutatneous coronary intervention).

Careful to be specific, he cites the advantages of CABG in three-vessel repair as opposed to use of multiple stenting via PCI. In this case, he cites a “consistent survival benefit of 5% in three to five years” for surgery compared to the interventional procedure. And he hypothesizes that this advantage is the result of entirely avoiding the damaged arteries rather than using a “scarring effect” to treat a lesion via stent.

“When you do bypass surgery,” he says, “you go beyond the lesions. You’re in the clean area of the coronary and that can explain some of the excellent results. And when you use an arterial graft, the arteries express certain factors into the blood that help the vessel stay open.”

He charged that patients aren’t presented the relevant statistics or explanations about the two procedures, the absence partly the product of a turf battle between specialties.

“There is no real education of alternative procedures,” he said. “If they would do that, cardiologists would have to make some data presentation that shows what the outcome really is.” If done, he added, “Patients would actually think more seriously about risking a higher mortality [as the result of stenting] against the invasiveness of the [CABG] procedure.”

In addition to the benefits in an initial procedure, he cited “increasing crossovers of patients from PCI to CABG.” In this case, he said that the survival benefit for surgery “increases 120%.”

Needed: a panel approach

But as noted, Hausen doesn’t lean on such statistics as closing the debate. Rather, he said that what is needed is something other than the battle over procedural turf, in which a specialist pushes his/her procedure as preferable.

What he recommended is what he described as common in cases of lung cancer, in which the procedural decision is made by a group of specialists

“There should be a review board,” he said. “A cardiologist, a cardiac surgeon, an interventionalist get together and look objectively at what this patient has in terms of lesions. I am advocating some objective board that evaluates these patients so that there is no conflict of interest but an objective assessment of the patient’s needs.”

He continued: “If you take this to the next level, if you are a patient and you’re given, objectively, all the data,” there will be more scientfic clarity in the decision-making.

Hausen said he believes that such a strategy also would eventually combine with new developments in CABG to reduce the use of PCI. And, not surprisingly, he believes some of these new developments will come from Cardica’s approach to improving the surgical strategy.

The future

“Looking into the future, what we’re doing right now is selling our product to surgeons to use in an open-chest setting — what they’re used to and how they get used to this new technology.”

Hausen said that Cardica is on a path very much paralleling developments in orthopedics, in the use of surgery through tiny incisions and thorascopic instruments to perform CABG, with robotics also coming into this picture. “We’ve already done the animal work with this,” he said, asserting: “I wouldn’t be surprised if we are the first in Europe to do [CABG] in a closed-chest setting.

He reported that the company currently is collaborating with surgical robotics company Intuitive Surgical (Sunnyvale, California) to develop a CABG approach that completely avoids the cracked chest.

“They have the robot, we have the instruments,” Hausen said.

But he added that “with or without a robot, patients will be discharged from the hospital very soon with a lot less pain and discomfort.” And he added that he is seeing “within the cardiac surgical community an exuberance about this alternative. I know that cardiac surgeons are becoming more and more vocal, [because] seeing patients after multiple stents and infarcts and now they get to operate on a heart that has been permanently injured.”

WSJ gets it wrong

Apart from such clinical concerns, the awareness of the DES technology has translated to a focus by the general media. And that focus clearly is a sharp sword with two edges, providing disadvantage as well as advantage.

As an example, the sector was spooked a bit in early February by a Wall Street Journal article indicating that the Centers for Medicare and Medicaid Services was considering restricting coverage of the devices as an outgrowth of increasing concerns about their safety.

That story was immediately refuted by CMS, though its statements left open the possibility that future action could come if there is a growing amount of negative evidence about the devices.

A CMS spokesperson told CDU: “We know the FDA has raised concerns [about DES efficacy], so we’re studying the issue. But we haven’t opened any coverage decision, and we don’t know if we will.”

And in a press statement issued by the agency, Barry Straube, CMS chief medical officer, said, “Staff are always keeping up with developments and evolving evidence throughout the healthcare technology sector, assessing whether new evidence warrants CMS attention. There is no plan for any change in current policy towards drug-eluting stents at the present time” — the phrase “at the present time” being a mild qualifier.

The WSJ story reported that Medicare paid about $14.7 billion for DES operations in 2005. That figure represented about half of all implants of the devices that year. And a reduction of coverage by CMS would seriously pare back these revenues.

However, the WSJ reporter apparently had read more into a conversation about the agency’s national coverage decisions (NCDs) than was actually there, inferring from a discussion that an NCD is likely, when in fact, no such determination has been made.

The story caused reverberations in the Street. Stock in the three U.S. companies involved in the DES sector — Boston Scientific, J&J, Medtronic (Minneapolis) and Abbott Laboratories (Abbott Park, Illinois) — saw their share prices drop following the story. Analysts immediately sought to quell fears raised by the WSJ report, with their own reports that any CMS action on DES was not likely to be imminent.

. . . and NEJM coverage inconclusive

Shortly after the WSJ story, the New England Journal of Medicine printed a clutch of articles on DES, reporting and commenting on a variety of studies that had been presented at the FDA’s two-day meeting in December on the use of DES. The result of the reports and commentaries appeared to point to one conclusion: that the clinical jury is still out on a variety of issues concerning DES devices — their safety, their efficacy as compared to BMS and whether or not the FDA’s regulatory pathways in approving DES were properly conducted.

Some of the reports showed increased risk when the stents are used as directed. But Gregory Curfman, MD, a cardiologist and editor of the NEJM, in an editorial, said that DES, when used in FDA-approved ways, are “free and clear.” But he offered the increasingly frequent caveat, that patients are safest when complying with a follow-on regimen of blood thinners for a year or more. And Curfman and his colleagues in an editorial said that off-label use — about 60% of all use — further muddies the DES data waters.

DES “were approved for use in stable patients with relatively noncomplex coronary stenoses,” they wrote, “but they have been used in many patients whose clinical features and coronary anatomy fall outside the original specifications.” Such off-label use “has made assessments of stent safety beyond the setting of clinical trials more challenging.”

Curfman also noted that while the FDA panel in December agreed that the use of antiplatelet therapy in the form of Plavix after placement of a DES, “the optimal duration of therapy has not been established yet.”

Perhaps the most negative study data came from the NEJM’s reprise of a 20,000-patient analysis from Sweden showing an increased risk of death in patients implanted with a DES compared to a BMS up to three years after implantation.

Responding in a statement, Boston Scientific criticized that study, saying that the data did not come from patients randomized to DES or BMS devices. It said that, instead, the study tracked patients from a national database and that the DES-implanted patients were sicker.

Too much pullback?

Gregg Stone, a professor of medicine at Columbia University (New York) and the author of an analysis of Boston Scientific’s stent data published in the NEJM, expressed concern that doctors had pulled back too much from using DES, even in off-label uses. “I do believe it’s going down too much,” said Stone. “I believe these articles will stabilize it and lead to an uptick.”

In an accompanying perspective piece, William Maisel, MD, of Beth Israel Deaconess Hospital (Boston) and the chair of the December FDA advisory panel meeting on DES, wrote that in the Swedish registry stent selection “was not randomized among registry patients, so the observed differences may be due to confounding factors such as physician bias in stent preference. Thus, current data are inadequate for assessment of the relative benefit of off-label use of drug-eluting stents as compared with either bare-metal stents or coronary-artery bypass surgery.”

In a podcast that accompanied the journal articles, Steven Nissen, MD, a cardiologist at the Cleveland Clinic Foundation (Cleveland) and current president of the American College of Cardiology (Washington), presented an opposing view, saying that the Swedish study suggests that bigger clinical trials comparing the two types of stents are greatly needed.

“If the Swedes are right, we will regret putting [DES] into individuals,” Nissen said.

So . . . . where does the market go?

The ultimate question here is clear: What are the prospects for the DES market in 2007 and beyond?

In an audioconference on the day following release of the NEJM’s reports, sponsored by CDU’s sister publication Medical Device Daily, titled “Unblocking the Truth About Coronary Stents,” Deepak Bhatt, MD, associate director of the Cleveland Clinic Cardiovascular Coordinating Center (Cleveland), said he did not believe the NEJM articles and commentary would greatly impact physician practice.

“They’re all well-done studies,” Bhatt said, “but they all, in a sense, are reaching different conclusions, depending on how you’re interpreting them.”

Bhatt said that recent disclosure of negative data has somewhat impacted the utilization of DES, but only by about 5%-10% over the peak of DES use that he characterized as being “in the 90-plus-percent range.”

He suggested, however, that the underlining of DES issues by a journal with the prestige of NEJM would serve to continue a focus on the sector. “I don’t think the issue is going to go away either,” he said.

Providing the financial view of the issue during the audioconference was Thom Gunderson, a managing director and senior research analyst at Piper Jaffray in Minneapolis, who noted that one potential fall-out from the debate would be to put increased focus on some of the new stent technologies being developed, primarily stents that are absorbed by the body (bioabsorbable), therefore leaving no device, drug or polymer artifact in the vessel.

Bhatt suggested that off these three parts of DES architecture, the polymer may be a primary culprit in the increased appearance of thrombosis in DES use, though he noted that this was an impression, and not yet demonstrated by the research.

While most observers of the sector do not see abandonment of DES by the medical community, they also are not predicting a large market upturn for the current generation of the devices in the U.S.

One of these, Millennium Research Group (Waltham, Massachusetts), in a recent report on the interventional cardiology device sector, said that it sees a “rebound” for DES, but driven primarily by the “the emergence of new competitors, Medtronic and Abbott Vascular (Santa Clara, California), with their next-generation devices. Millennium noted that Medtronic’s Endeavor DES and Abbott Vascular’s Xience already have been released in the European market and are poised for FDA approval.

“While 2006 was a tough year for DES, we see this as a relatively short-term decline,” said Bina Mistry, analyst at Millenium. “With new competitors entering the market and the continual release of positive clinical data, physician preference will revert back to DES, significantly expanding the market. We forecast the U.S. market will follow the same path as Europe, with the DES market set to record notable market share shifts.”