Medical Device Daily Washington Editor

The benefits of drug-eluting stents (DESs) over their plain-jane antecedents have been brought into question in a pair of journal articles and at the recently-completed World Congress of Cardiology meeting in Barcelona, Spain. Thanks to all the stimulus, at least one major insurer has promised to review its data to examine whether the difference in cost mirrors a difference in benefit.

However, some studies suggest that there is a real benefit to be had from coatings such as paclitaxel and sirolimus, and the companies that manufacture those stents will surely make their best cases for their products even as the FDA plans an advisory panel meeting to look into safety issues. At stake is a $5 billion global market that has fed middle-class stock portfolios and executive salaries, and the clash of studies and opinions offers little in the way of a forecast of the outcome.

A pair of presentations at the Sept. 2-6 World Congress of Cardiology offered a microcosm of the conflict over DES devices, with one presenter insisting that rates of cardiac death and non-fatal infarction were up for patients with drug-eluting stents compared to plain-metal stents and the other arguing a very different case.

Eduardo Camenzind of University Hospital Geneva (Switzerland), said that a review of Basel Stent Cost-effectiveness Trial – Late Thrombotic Events (BASKET-LATE) data suggests that the rates of cardiac death and non-fatal myocardial infarction were higher in patients with DES than those with their bare-metal cousins. Camenzind insisted that “the problem is likely to be significantly underreported since if people die on the street, they don't fulfill the angiographic criteria to be classified as in-stent thrombosis.”

Camenzind's meta-analysis was also said to have suggested that there was an overall 2.4% increase in the incidence of death or infarction in patients who got the Cypher over those who elected to go with bare-metal stents.

On the opposite end of the stent debate at Barcelona, Antonio Colombo, MD, of San Raffaele Hospital (Milan), said that data from the four-year TAXUS II trial indicated “low target lesion revascularization rates [and] low cardiac death rates.” The reported cardiac death rates for both dose levels was 1.6%, not a meaningful difference from the 1.5% in the bare-metal stent control group.

Still, TAXUS II showed that both dose levels cut restenosis sharply. The controls, who received bare-metal stents, experienced a restenosis rate of 15.7% compared to the 7.2% level in low-dose stent and 3.7% in the medium-dose stent.

Colombo argued that “[t]his technology has truly changed the way physicians treat coronary artery disease.”

The New England Journal of Medicine has published articles covering two other studies as well as an editorial on those studies that jointly do little to clear matters up. A study of the Cypher, made by Cordis (Miami Lakes, Florida), did not find any significant difference between the controls and the study groups for death or reinfarction, nor did thrombosis become more problematic with the test article than with the control. However, the study showed “a significantly reduced . . . rate of target-vessel revascularization at one year.”

As for the paclitaxel-eluting Taxus made by Boston Scientific (Natick, Massachusetts), Laarman, et al, report that “there was a trend toward a lower rate of serious adverse events…than in the uncoated-stent group, but that the P score, which was 0.09, was not robust enough to be deemed significant despite a 4% drop in adverse events. The study also demonstrated no difference in stent thrombosis after one year.

On the point of serious adverse cardiac events, Charles Rudnick, a media relations representative with Boston, said that the inferential power of the NEJM study could have been improved with a larger enrollment, which was less than 700.

He also told Medical Device Daily that “[t]he body of evidence available demonstrates that Taxus provides a significant benefit as compared to bare-metal stents and is as safe as bare-metal stents. Both these studies have to be placed in the perspective of a broader body of clinical data available.”

In his NEJM editorial, Frans Van de Werf, MD, wrote that DES technology does indeed “significantly reduce the risk of both restenosis and target-vessel revascularization after elective PCI (percutaneous coronary intervention) as compared with uncoated stents.” However, he cautioned against comparisons of the two studies on several accounts. Still, while design and inclusion criteria were different, “the results seem to be in line with those of studies” comparing the two, namely “lower rates of restenosis and repeated intervention, with the sirolimus-eluting stent [failing to demonstrate] significant differences in myocardial infarction or death.”

Van de Werf pointed out that the Taxus study used “two specific uncoated stents . . . whereas with the TYPHOON (Cypher) trial, any uncoated stent was allowed.” He concluded that while the data from both studies shows that DESs can be used safely and “are likely to reduce the need for repeated revascularization…the results do not demonstrate that criteria for selecting a drug-eluting stent for this indication should differ from those for elective procedures.” Van de Werf added that “larger trials…with longer follow-up are needed before routine implantation of drug-eluting stents can be recommended for all patients undergoing primary PCI.”

The net effect of all this for Kaiser Permanente (Oakland, California) is to spur the healthcare giant to conduct a retrospective study of the safety and efficacy of DESs in its patient population, which totals 8.5 million.

Kaiser doctors are said to have implanted an average of 1.5 DESs in each of the 3,500 angioplasties performed in 2003. Calvin Weisberger, chief cardiologist for Kaiser, estimates that the rate of implantation currently is about three times the 2003 rate.

“There are relatively few people to start with who are even a candidate” for a DES, Weisberger said, noting that seemingly “everyone got one.” He alluded to a me-too syndrome in healthcare by noting that many patients are of the mindset that “if he gets it, I want it.”

Mariela Melendez, the director of communications at Cordis Cardiology , told MDD that “[I] n four controlled randomized trials of Cypher vs. bare metal stents involving approximately 1,800 patients followed over four years, we have seen five cases of very late stent thrombosis with the Cypher Sirolimus-eluting stent, compared to no such cases observed with bare metal stents.”

However, she said that while these cases did not constitute a “statistically significant difference, it is an important clinical challenge that we continue to investigate.”